Advanced Management Options for Endometriosis

Current Women’s Health Reviews Volume 6, Number 2, May 2010

Current Concepts in Female Infertility Management (Part I)

Guest Editors: Sajal Gupta and Ashok Agarwal

Contents

Biography of Contributors

68

Preface

71

Management of Infertility:

Low-Cost Infertility Management

Ahmed Abdel-Aziz Ismail and Sharif Hassan Sakr

73

Female Infertility and Antioxidants

Lucky H. Sekhon, Sajal Gupta, Yesul Kim and Ashok Agarwal

84

Role of Oxidative Stress in Polycystic Ovary Syndrome

Joo Yeon Lee, Chin-Kun Baw, Sajal Gupta, Nabil Aziz and Ashok Agarwal

96

Polycystic Ovary Syndrome in Adolescents

Mohamed Yahya Abdelrahman, Mohamed A. Bedaiwy, Elizabeth A. Kiracofe

and Marjorie Greenfield

108

Advanced Management Options for Endometriosis

Jashoman Banerjee, Mona H. Mallikarjunaiah and John M. Murphy

123

Prevention and Management of Ovarian Hyperstimulation Syndrome

Botros Rizk and Christopher B. Rizk

130

Non-Surgical Treatment Options for Symptomatic Uterine Leiomyomas

Julierut Tantibhedhyangkul and Millie A. Behera

146

Contd…..

Surgery:

Surgical Management Options for Patients with Infertility and

Endometriosis

Michelle Catenacci and Tommaso Falcone

161

Surgical Strategies for Fertility Preservation in Women with Cancer

Mohamed A. Bedaiwy, Kristine Zanotti, Ahmed Y. Shahin,

Mohamed Yahya Abdel Rahman and William W. Hurd

167

Innovative Roles for Surgical Robotics in Reproductive Surgery

Ehab Barakat, Mohamed Bedaiwy and Tommaso Falcone

177

Surgical Management of Müllerian Duct Anomalies

Ali M. El Saman, Jennifer A. Velotta and Mohamed A. Bedaiwy

183

68 Current Women’s Health Reviews, 2010, 6, 68-70

1573-4048/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.

BIOGRAPHY OF CONTRIBUTORS

Jashoman Banerjee, MD

Jashoman Banerjee is a trained Ob-Gyn specialist from India. He is currently graduating as a chief

resident in Ob-Gyn from the University of Toledo Medical Center in Toledo, Ohio. Dr. Banerjee will

start his fellowship in reproductive endocrinology and infertility at Wayne State University. He has

actively participated in extensive research involving endometriosis and infertility at the Cleveland

Clinic Foundation. His other research interests are to explore effects of oxidative stress on oocyte qual-

ity and ovarian cryopreservation as means of fertility preservation. He has published his research work

in peer reviewed journals.

Tommaso Falcone, MD, FRCS(C), FACOG

Tommaso Falcone is the Professor and Chairman of the Department of Obstetrics-Gynecology at

the Cleveland Clinic. Dr. Falcone is certified by the American Board of Obstetrics and Gynecology

in general obstetrics and gynecology, as well as reproductive endocrinology. He is also certified by

the Royal College of Physicians and Surgeons of Canada. Dr. Falcone has published more than 200

scientific papers, abstracts, and book chapters. He is co-author of a laparoscopic surgery atlas and is

an ad hoc reviewer of many journals. He serves on the editorial board of the Journal of Gynecologic

Surgery.

Majorie Greenfield, MD

Marjorie Greenfield is a board-certified obstetrician-gynecologist and fellow of the American College

of Obstetrics and Gynecology. Dr. Greenfield has practiced and taught obstetrics and gynecology since

1987, currently as Professor and Division Director of General Obstetrics and Gynecology

at MacDonald Women’s Hospital, University Hospitals Case Medical Center. In addition to clinical

practice and teaching, she writes extensively for the Web and had several publications and authored

books.

William W. Hurd, MD

William W. Hurd is a Professor of Reproductive Biology and holds the Lilian Hanna Baldwin en-

dowed Chair in Gynecology and Obstetrics at Case Western Reserve University School of Medicine in

Cleveland, Ohio. He is Chief of Reproductive Endocrinology Infertility at University Hospitals Case

Medical Center. For two decades, he has been an active researcher in the area of laparoscopic safety,

and is the past President of the Society of Reproductive Surgeons. Currently, Dr. Hurd is a member of

the American College of Surgeons Liaison Committee for Obstetrics and Gynecology and is a member

of the Board of Directors of the Society of Gynecologic Surgeons.

Lucky H. Sekhon, MD

Lucky H. Sekhon is a graduate of Royal College of Surgeons in Ireland (RCSI). She obtained

her Bachelors of Science in Biology from McGill University in Montreal, Canada. Her major research

interests lie in the field of reproductive endocrinology and infertility.

Biography Current Women’s Health Reviews, 2010, Vol. 6, No. 2 69

Botros Peter Rizk, MD

Botros Rizk is Professor and Chief of the Division of Reproductive Endocrinology and Infertility of the

Department of Ob-Gyn at the University of South Alabama. His main research interests include the

modern management, prediction and the genetics of ovarian hyperstimulation syndrome (OHSS), as

well as the role of vascular endothelial growth factor and interleukins in the pathogenesis of severe

OHSS. He has authored more than 300 peer-reviewed published papers, book chapters and has edited

and authored ten medical textbooks on various topics in reproductive medicine.

Ali M. El Saman, MD

Ali M. El Saman received his medical degree from Assiut University School of Medicine in Egypt. He

is an Associate Professor of Obstetrics and Gynecology. He has special interests in innovative medical

technologies especially those related to endoscopy and has got five patents related to medical

innovations and is registering for another 5 patents. His clinical and research activities are concentrated

mainly on innovative treatment modalities of mullerian duct anomalies and was successfully generated

16 peer-reviewed publications, being the first author in the majority.

Julierut Tantibhedhyangkul, MD

Julierut Tantibhedhyangkul is a reproductive endocrinologist at the Cleveland Clinic in Cleveland,

Ohio. Dr. Tantibhedhyangkul earned her medical degree from Siriraj Hospital, Mahidol University

in Bangkok, Thailand. She completed her obstetrics and gynecology residency at the University

Hospitals of Cleveland, Case Western Reserve University in Cleveland, Ohio, followed by fellowship

training in reproductive endocrinology and infertility at Duke University Medical Center in Durham,

North Carolina. She has joined the Obstetrics, Gynecology and Women’s Health Institute at the Cleve-

land Clinic since 2008. Her special interests include infertility, polycystic ovary syndrome and uterine

fibroids.

Michelle Catenacci, MD

Michelle Catenacci is a graduate from Wayne State University School of Medicine. After medical

school, she completed a four year residency training program in Obstetrics and Gynecology at

Case Western Reserve University MetroHealth/Cleveland Clinic Foundation Program. Currently, Dr.

Catenacci is a fellow in Reproductive Endocrinology and Infertility at the Cleveland Clinic Founda-

tion. Her research interests include fertility preservation for cancer patients and endometriosis related

infertility.

Sajal Gupta, MD

Sajal Gupta is an Ob-Gyn specialist with a special interest in the field of reproductive endocrinology

and infertility. She is a member of Cleveland Clinic Professional Staff and serves as the Assistant Co-

ordinator of Research at the Center for Reproductive Medicine. She has published over 40 original

articles, invited reviews and chapters. Dr. Gupta serves as a reviewer for Human Reproduction, Fertil-

ity & Sterility, and European Journal of Obstetrics and Gynecology. She is a co-investigator or princi-

pal investigator on 8 research grants. Her current research interests include the role of oxidative stress

in female infertility, endometriosis, assisted reproductive techniques and gamete cryobiology.

70 Current Women’s Health Reviews, 2010, Vol. 6, No. 2 Biography

Ahmed Abdel Aziz Ismail, MD

Ahmed Abdel Aziz Ismail graduated with a Baccalaureate of Medicine and Surgery from Alexandria

University. He completed his masters in obstetrics and gynecology with a 1st on order from Alxandria

University, Egypt. He has been a Professor of Obstetrics and Gynecology at University of Alexandria

from 1993 till date. He is a member of British Medical Ultrasound Society, Middle East Fertility Society

and Egyptian Fertility Society. He has received several awards such as award in family planning from the

Academy of Scientific Research and Technology, Egypt and award for scientific research promotion.

Ashok Agarwal, Ph.D, HCLD

Ashok Agarwal is a Professor in the Lerner College of Medicine at Case Western Reserve University and

the Director of Center for Reproductive Medicine, and the Clinical Andrology Laboratory at The Cleve-

land Clinic, Cleveland Ohio, United States. He has published over 500 scientific articles and reviews and

is currently editing 8 text books in different areas of andrology/embryology, male and female infertility

and fertility preservation. His research program is known internationally for its focus on disease oriented

cutting edge research in the fileld of human reproduction. His team has presented over 700 papers at

national and international meetings. More than 200 scientists, clinicians and biologists have received

their training in Ashok’s Lab. His long term research interests include unraveling the role of oxidants-

antioxidants, genomic integrity, and apoptosis in the pathophysiology of male and female reproduction.

Preface Current Women’s Health Reviews, 2010, Vol. 6, No. 2 71

PREFACE

This Special Issue on "Recent Advances in Reproductive Endocrinology and Women’s Health" published by Current

Women’s Health Reviews is a two–volume series on both cutting edge and contemporary topics of importance to general

gynecologists and specialists alike.

The first volume “Current Concepts in Female Infertility Management” is dedicated to important topics such as

endometriosis, PCOS and fibroids, which affect millions of women worldwide. Professor Abdel-Aziz Ismail discusses low-cost

infertility management options. His comments—that we should not fail to specify the best cost-effective regimen for our

patients and that evidence-based choices can be made without compromising success rates--are very pertinent. Dr. Sekhon has

written an excellent and comprehensive chapter analyzing the role that antioxidant supplementation plays in improving female

fertility and pregnancy outcomes. This article reviews the current literature on the effects of antioxidant therapy and elucidates

whether antioxidant supplementation is useful in preventing and/or treating infertility and poor pregnancy outcomes related to

various obstetric and gynaecologic conditions.

There are two articles on PCOS in this special issue by researchers from CASE Medical Center, Cleveland Clinic and Liverpool

Women’s Hospital. The article on adolescent PCOS characterizes polycystic ovary syndrome as a heterogeneous

endocrinopathy that affects girls and women during their reproductive years. The exact etiology of PCOS is still a topic of

debate. This chapter explains why PCOS is a multifactorial syndrome, involving genetic, endocrinologic, metabolic and

environmental factors and illustrates that further research on the basic pathophysiology of PCOS and the roles of the different

etiologic components will aid in the understanding of this condition and help clinicians in their management of adolescents with

PCOS. The second article on PCOS, written by Lee et al, substantiates the etiological relationship between PCOS and

metabolic syndrome. The authors report a lack of clarity on the role oxidative stress plays in the pathogenesis of PCOS and

suggest that there is an association amongst the oxidative microenvironment of the ovarian tissue and ovarian steroidogenesis

and follicular development.

The article on Advanced Management Options for Endometriosis focuses on new treatment options for endometriosis while it

also briefly describes the pathogenesis, diagnosis and controversies of existing treatment modalities. According to the authors,

assisted reproduction holds promise in patients with advanced endometriosis. They highlight that most of the newer therapies

are still experimental, but results in animal models show promise, which have served as an impetus for conducting human trials.

Professor Botros Rizk has written an excellent and authoritative chapter on OHSS that explains how this syndrome remains the

most serious complication of ovulation induction. According to the authors, OHSS could be successfully prevented in the future

if a high index of suspicion is exercised and methodical steps are taken. Newer technologies such as in vitro maturation might

completely eliminate its occurrence.

Dr. Tan and colleagues discuss the limitations of current treatment options for women with symptomatic uterine fibroids such

as mechanical methods of excision, ablation, and devascularization. According to the authors, increased use of conservative,

non-surgical procedures will expand patient eligibility and allow safe and effective long-term resolution of fibroid-related

symptoms.

In addition, four articles by leading experts in the field of reproductive health cover various women’s health issues:

• The article on robotics in reproductive surgery, written by Drs. Barakat and Falcone, evaluates the current application of

robotics in reproductive surgery. The article highlights the advantages of robotic surgery over conventional laparoscopic

surgery.

• Drs. Catenacci and Falcone highlight the pathogenesis of endometriosis and review the current clinical evidence for treatment

in regards to improving fertility outcomes. The authors comment that as treatment evolves in this direction, the role diagnostic

laparoscopy plays in infertile patients is becoming uncertain. Specifically, the value of diagnostic laparoscopy for patients who

do not suffer from pain and have normal imaging studies is in question. Due to the controversial effects that Stage I/II

endometriosis has on infertility, recommendations are moving away from performing diagnostic laparoscopies in infertile

patients. Ultimately, this will lead to fewer surgeries and increased medical management for patients with infertility-related

endometriosis.

• Drs. Bedaiwy and Hurd discuss that the future of fertility preservation for women of reproductive age with cancer is likely to

involve removal of ovarian tissue, followed by in vitro follicle culture of the tissue and removal of oocytes. The article

highlights that more effective techniques are being developed for cryopreservation of both oocytes and embryos. The authors

explain that the surgical approaches for fertility preservation can also be used for reproductive-age women diagnosed with

cancer who require pelvic irradiation or systemic chemotherapy.

• Dr. Saman and colleagues highlight the available treatment options for müllerian duct anomalies with a special emphasis on

simple and advanced surgical approaches. Surgical options are presented based on a novel treatment plan classification system

adapted from the American Fertility Society classification of müllerian duct anomalies. The authors have taken care to include

all previously termed unclassified anomalies as well as the important category of longitudinal fusion defects. Important

72 Current Women’s Health Reviews, 2010, Vol. 6, No. 2 Preface

diagnostic approaches are discussed with special emphasis on detection of associated anomalies of the urinary system and other

relevant systems

We hope that the readers will enjoy reading the latest, informative and authoritative articles by some of the most recognized

and prolific leaders in reproductive endocrinology from across the globe. We would like to extend our appreciation to all the

authors for their hard work and valuable contributions. We are indebted to our colleagues and associates in Cleveland Clinic for

their valuable contributions. We gratefully acknowledge the fabulous support of Ms. Amy Slugg Moore (Manager, Medical

Editing Services) for her help. We are grateful to Prof. Jose Belizan, Editor in Chief of Current Women’s Health Review, for his

constant encouragement and support. We are most thankful to the editorial team of CWHR for their support and hard work.

Finally, we extend our sincere thanks for the opportunity to serve as a Guest Editor on the special issue of CWHR. We are

confident that readers will benefit from the latest knowledge incorporated in these valuable articles.

Sajal Gupta, MD, TS (ABB)

(Co-Guest Editor)

Assistant Coordinator & Project Staff

Center for Reproductive Medicine

Glickman Urological and Kidney Institute &

OB/ GYN and Women’s Health Institute

Cleveland Clinic

Cleveland, OH 44195

USA

Tel: 216-444-9485

Fax: 216-445-6049

E-mail: [email protected]

Ashok Agarwal, PhD, HCLD

(Guest Editor)

Professor, Lerner College of Medicine

and Case Western Reserve University

Director, Andrology Laboratory and

Reproductive Tissue Bank

Director, Center for Reproductive

Medicine Staff, Glickman Urological

& Kidney Institute and Ob-Gyn

and Women's Health Institute

Cleveland Clinic

Cleveland, OH 44195

USA

Tel: 216-444-9485

Fax: 216-445-6049


Current Women’s Health Reviews, 2010, 6, 73-83 73


Low-Cost Infertility Management

Ahmed Abdel-Aziz Ismail* and Sharif Hassan Sakr

Department of Obstetrics and Gynecology, University of Alexandria, Egypt

Abstract: Objectives: To review the evidence regarding the magnitude of infertility as well as the various proposed

approaches highlighting the use of the most cost-effective investigatory and treatment regimens.

Data Sources and Methods: Medline and Pubmed were searched for all relevant papers published between 1975 and 2009

using a combination of the following keywords: ‘affordable, cost-effective, infertility, IVF, investigations, treatment’.

Results: In an era of evidence-based medicine, we often fail to specify the most cost-effective regimen for an infertile

couple. Setting a predetermined algorithm can help simplify the management approach. Prevention and education are

important as well.

Conclusions: A cost-effective approach that does not compromise success rates should be offered to all couples seeking

help for infertility. This includes making evidence-based choices when choosing investigatory tools and treatment options.

The “patient- friendly” regimen should not necessarily be equated with “minimal stimulation IVF” because to provide the

best medical care for patients, it should be evidence-based and without bias. The ESHRE Task Force is working to tackle

the challenge of providing a cost-effective simplified assisted reproduction program in developing countries.

Keywords: Infertility, low cost, cost-effective, cheap, investigations, treatment, IVF.

LOW-COST INFERTILITY MANAGEMENT

Magnitude of the Problem

Infertility is defined as the inability to conceive after at

least 1 full year of unprotected sexual intercourse [1-3]. It is

estimated that worldwide, between 70 and 80 million

couples suffer from infertility, and most of these are

residents of developing countries, including the Middle East

[4, 5].

The prevalence of subfertility and infertility differs

tremendously between developing countries. The figures

are as low as 9% in some African countries such as Gambia

[6] and as high as 35% in Nigeria [7, 8]. The reported

international prevalence of infertility ranges from 4% to 14%

with a consensus estimate of 10% among married and

cohabiting couples [9-11].

What accounts for the variation in infertility levels? It is

important to understand that there is a core of about five

percent of all couples who suffer from anatomical, genetic,

endocrinological, and immunological problems that cause

infertility [10]. The remaining couples are infertile largely

because of preventable conditions such as sexually

transmitted infections (STIs), parasitic diseases, health care

practices and policies, and exposure to potentially toxic

substances in the diet or the environment.

Worldwide, STIs are the leading preventable cause

of infertility. A World Health Organization (WHO) multi-

*Address correspondence to this author at the Department of Obstetrics and

Gynecology, University of Alexandria, Egypt; Tel: 002 034962020;

Fax: +203-4299986; E-mail: [email protected]

national study found that 64% of infertile women in sub-

Saharan Africa had some sort of infection (vaginal and/or

cervical), which is about double the rate of other regions.

Tubal problems and other infection-related diagnoses also

are associated with postpartum and post-abortion complica-

tions. The results of the WHO study suggest that repeated

pregnancies play a greater role in the etiology of infertility in

Africa and Latin America, while repeated abortions are more

important in Asia and developed countries. Health care

practices and policies also contribute to infertility, most

notably unhygienic obstetric practices, which can lead to

postpartum infections. Septic abortions and their complica-

tions are another important factor [12].

Inappropriate gynecological practices also may also lead

to infertility. In Egypt, for example, physicians routinely

misdiagnose cervical erosion and then treat it inappropriately

with cervical electrocautery, potentially causing infertility in

the process [13].

In the Middle East, the prevalence of infertility varies

between 10% and 15% in married couples because of a high

prevalence of post-partum infection, post-abortive infection,

iatrogenic infertility, schistosomiasis and tuberculosis (TB)

[14, 15]. Bilateral tubal occlusion is the most common

underlying cause of infertility following such infections [12,

16].

Tubal and pelvic infertility are the leading causes of

female infertility in many countries in the Middle East. Other

infectious and parasitic diseases—and the medications used

to treat them—contribute to infertility. For example, in India,

where 40% of the population is exposed to TB, genital TB

contributes to female infertility [17]. In Africa, schistoso-

miasis, malaria, and sickle-cell disease all contribute to

74 Current Women’s Health Reviews, 2010, Vol. 6, No. 2 Ismail and Sakr

infertility [18]. It has been proposed that the success of

malaria-control programs may help explain a reduction in

infertility rates seen in Tanzania over the past 20 years [19].

In Nigeria, where hernia repairs are routinely performed

by inexperienced surgeons, there is a pattern of male

infertility due to vascular injuries sustained during these

procedures [20]. Increasingly, men and women in develop-

ing countries face exposure to environmental and workplace

pollution, which can play a role in infertility.

Infertility is a major problem in these countries and

causes extensive social and psychological suffering. Provid-

ing infertility treatment in resource-poor countries should be

part of an integrated reproductive care program that includes

family planning and motherhood care [21].

It is important to note that the problem of infertility is not

limited to developing countries. Nearly all European

countries are currently experiencing long-term downtrends in

fertility and, consequently, a reduction in the proportion of

working-age individuals [22]. As a result, many govern-

ments around the world are currently providing incentives to

their citizens to promote parenthood [23]. However, to date,

there has been little recognition of the role of infertility

services in these programs. Therefore, there is mounting

pressure on governments to enhance their “baby-friendly”

policies as a measure to reverse future reductions in fertility

[24].

The limited availability of resources mandates their

judicious use. The definition of “better care” should not be

equated with “aggressive care.” More aggressive care may

result in a quicker establishment of pregnancy and higher

pregnancy rates per treatment attempt. However, they may

also result in a higher incidence of multiple implantations.

Better care should be defined as a balance between attempts

to achieve pregnancy quickly and efficiently with as low of a

multiple implantation rate as possible [25].

Cost-effective care must also satisfy patient demands.

High-quality patient care may not necessarily lead to patient

satisfaction if the patients’ expectations are not met. Once

these expectations are defined, then they can be met by the

provider or if not, addressed with the patient in the hopes

that the expectations can be redirected. Failure to do so will

result in high drop-out rates from treatment- a wasteful use

of resources [26].

The ultimate goal is to create an approach that provides

the greatest chance for pregnancy and birth while using

limited resources in the most cost-effective fashion. To

fulfill that goal, simplified treatment algorithms that attempt

to minimize costs at every step of the management process

have been proposed. Norbert Gleicher has proposed an

algorithm that would help 80% of the couples who proceed

through all the treatment steps to conceive, provided there

are no drop-outs during any of the treatment steps (see Fig. 1) [27].

Interestingly, a prospective randomized trial that

compared this algorithm to the use of in vitro fertiliza-

tion (IVF) as an initial infertility treatment showed that

it was more cost effective and efficient, largely due to a

larger number of “treatment independent” pregnancies that

occurred during use of the algorithm than in between IVF

cycles [28]. Although not universally acceptable, this

algorithm has proven acceptable to many providers in the

United States and has been accepted by the insurance

industry in states with mandated insurance coverage as the

basis for contractual agreements [29].

Preliminary results from a prospective study analyzing a

cohort of patients who used this algorithm support the

outcome data in Fig. (1), although there are considerable

drop-out rates at each treatment step. Obviously, this

decreases the chances of conception [26].

To design a cost-effective, medically appropriate

evaluation and treatment plan, we must consider the patient's

age. While there is little necessity to initiate aggressive

therapy for the 20 year old with unexplained infertility, those

older than 35 years deserve a more aggressive approach.

LEVEL 1 OF CARE

1. Prevention

It is often argued that in the Middle East, where there are

many low income and middle income countries, the solution

to the problem of infertility is in the prevention of post-

partum infection, unsafe abortion, iatrogenic infertility, TB,

schistosomiasis and STIs, which are preventable causes of

infertility [14]. Reducing the incidence of postpartum

infections can be achieved through safer birth practices,

including the training of traditional birth attendants on how

to used hygienic practices during deliveries, and by

developing mechanisms to help women with potentially

complicated deliveries to deliver in clinics.

The most effective ways to reduce postabortion infec-

tions are:

(1) Promoting family planning, because effective contracep-

tion eliminates the need for abortion;

(2) Providing treatment for postabortion complications at a

variety of health facilities.

Where other diseases are a common cause of infertility,

aggressive campaigns to control their spread may have an

impact. For example, reducing the incidence of TB or

treating affected women before TB spreads to the genital

tract would prevent many cases of female infertility in India

[17].

Likewise, testicular biopsies of Nigerian and Ghanaian

men, which found a high incidence of inflammatory lesions,

suggest that efforts to control and treat schistosomiasis

would reduce levels of both male and female infertility

in these countries [18]. While preventing reproductive

tract infections may be the most effective way to reduce

infertility problems in developing countries, this long-term

strategy does not address the need for immediate infertility

treatment.

2. Judicious/Cost-Effective use of Diagnostic Work Up/

Monitoring

Any one of a long list of tests can be used to determine

the cause of infertility during the diagnostic evaluation of

Low-Cost Infertility Management Current Women’s Health Reviews, 2010, Vol. 6, No. 2 75

infertile couple. Lack of agreement exists, however, among

trained infertility specialists in regards to which tests have

good prognostic utility and the criteria of normality of many

of these tests i.e. a universally accepted range of normality,

whether it is for a hormonal level or an imaging technique.

Only those tests that are cost effective and correlate directly

with the likelihood of conception should be used. These tests

include conventional semen analysis, documentation of

ovulation by measuring midluteal progesterone levels and

assessing uterine factor and tubal patency with hystero-

salpingography (HSG) or sono-hysterography.

A comprehensive semen analysis following WHO

guidelines is fundamental at the primary care level if one is

to make a rational initial diagnosis and select the appropriate

clinical management [30]. Despite its limitations, conven-

tional semen analysis is the cornerstone for assessment of

male factor infertility; computer assisted semen analysis

(CASA) is not superior. A study conducted by Krause W. in

1995 concluded that the determination of elaborate motility

characteristics via CASA is of limited value when opti-

mizing the evaluation of male fertility [31].

Previously, the postcoital test (PCT), which assesses

sperm motility in a sample of postcoital cervical mucus, was

considered an integral part of the basic infertility evaluation.

However, past investigations revealed a poor correlation

between postcoital sperm motility and pregnancy outcome

[32]. In addition, a 1995 blinded, prospective study found

that there was poor test reproducibility amongst trained

observers, further questioning the validity of the PCT as a

diagnostic tool [33].

In 2000, Oehninger, et al., conducted a meta-analysis to

determine the diagnostic accuracy and predictive value of

various sperm function assays in couples undergoing IVF.

They assessed the following tests: CASA, acrosome reaction

testing, the zona-free hamster egg penetration test or sperm-

penetration assay (SPA) and sperm-zona pellucida binding

assays. The results showed that the sperm-zona pellucida

binding test and the induced-acrosome reaction assays for

Fig. (1). Treatment algorithm for infertility and expected pregnancy rates [27].


fertilization outcome had the highest predictive power. On

the other hand, the findings indicated that the SPA had a

poor clinical value when used as a predictor of fertilization.

Furthermore, the authors stated that there was a real need for

standardization and further investigation of the potential

clinical utility of CASA systems. The authors concluded

that basic semen analysis remains the cornerstone in

the evaluation of the male partner and validated sperm

functional tests should expand the initial work up as

indicated [34].

Female factor infertility is usually assessed by tracking

ovulation, examining the uterus for malformations/polyps/

fibroids, etc. and determining tubal patency and ovarian

reserve. When assessing ovarian reserve, patient’s age is one

of the main determinants; with advancing age, fertility

declines. This is due to progressive follicular depletion and

increased abnormalities in the aging oocytes (oocyte

aneuploidy) [35]. Testing includes obtaining a cycle day 3

serum follicle-stimulating hormone (FSH) and estradiol

level and performing a clomiphene citrate (CC) challenge

test and/or an ultrasonographic ovarian antral follicle count

[36].

A patient with menstrual abnormalities should be

investigated for underlying causes such as polycystic ovarian

syndrome, thyroid disease, hyperprolactinemia, and

hypothalamic causes secondary to weight changes. It is

worth mentioning that a group of researchers from Australia

conducted a cost-savings analysis of a weight loss program

for obese infertile women (in Australian dollars). Their

results showed that weight loss improved the reproductive

outcome for all forms of fertility treatments and cost

considerably less. Prior to the programme, 67 women had

treatment costing a total of A$550 000 for two live births, a

cost of A$275 000 per baby. After the programme, the same

women had treatment costing a total of A$210 000 for 45

babies, a cost of A$4600 per baby [37].

Eumenorrhea—normal menstrual cycles by history—is a

highly accurate marker of ovulation, and anovulatory levels

of serum progesterone (< 3 ng/mL) are found in only a very

small minority of eumenorrheic patients [38]. Obviously, if a

pregnancy occurs or if an oocyte can be isolated from the

reproductive tract, it means that a patient is ovulating. But

neither can be used clinically as reference methods for

predicting or confirming ovulation in infertile women [39].

Although it is now well accepted that the basal body

temperature (BBT) graph is an unreliable marker for the

prediction of ovulation [40], it still could be used as a simple

method for retrospective identification of the presumptive

day of ovulation [41]. Among the numerous parameters used

to detect the day of ovulation, the identification of the

luteinizing hormone (LH) surge appears to be the most

reliable indicator of impending ovulation [42].

In a 2001 study assessing reliability of ovulation tests in

infertile women, Guermandi E., et al. concluded that urinary

LH was accurate in predicting ovulation with ultrasono-

graphy as the standard for detection, but time varied widely

(LH surge was detected in urine from 72 hours before

ovulation to the same day of ultrasonographic disappearance

of the follicle). The nadir of BBT predicted ovulation poorly.

The BBT chart was less accurate at confirming ovulation

than urinary LH testing and serum progesterone assessment.

A single serum progesterone assessment in the midluteal

phase seemed as effective as repeated serum progesterone

measures [43].

In a comparison of low-tech and high-tech methods of

monitoring CC ovulation induction, it was shown that

urinary detection of the LH surge and vaginal ultrasound

offered no advantage over BBT charts alone in achieving

pregnancy [44].

Although endometrial biopsy results were previously

used to diagnose luteal phase defects, they do not correlate

with fertility status and hence are no longer recommended

[45]. From the above data, it can be concluded that midluteal

serum progesterone and ultrasound may be the two most

cost-effective means of documenting ovulation.

In a study assessing the feasibility and acceptability of an

out-patient-based investigation of infertile couples

(ultrasound, diagnostic hysteroscopy and culdoscopy), the

average time needed to perform these three procedures was

41.2 minutes. Most patients appreciated the fact that only 1

hospital visit was needed and that the results were

immediately available. However, this “One Stop” approach

to the investigation of infertility is not suitable for or desired

by all infertile couples [46].

3. Judicious/Cost-Effective use of Medical Treatment/

Surgery (Endoscopy)

Proper utilization of surgical procedures, usually

endoscopic procedures, represents the single most significant

factor in providing cost-effective infertility care [47].

Assessment of the uterine contour and tubal patency is an

integral part of the basic infertility evaluation [36]. Hyster-

osalpingography is the gold standard for the assessment of

tubal and uterine factors. Along with laparoscopic dye

pertubation, it can best assess tubal patency: the concordance

of HSG with laparoscopic dye pertubation is estimated to be

near 90% [48].

Severi F.M. et al. showed that hydrosonography can

accurately evaluate the uterine cavity and any malfor-

mations, particularly in young women, reaching a diagnostic

accuracy similar to that of hysteroscopy. They also found

that the accuracy of hydrosonography is similar to that of

HSG, when the two techniques are compared with laparo-

scopic chromopertubation [49].

Moreover, Goldberg found that in the evaluation of

patients with infertility or recurrent pregnancy loss and

uterine abnormalities, hydrosonography was more accurate

than HSG and provided additional information about uterine

abnormalities, particularly on the relative proportion of the

intracavitary and intramyometrial components of submucus

myomas [50].

In a study to determine the feasibility and acceptability of

an out-patient based infertility investigation that used a

screening test for tubal occlusion called hysterosalpingo-

contrast sonography (HyCoSy), the results showed that the

former was a valuable and cost effective alternative to

laparoscopy and the dye test [51].

https://www.researchgate.net/publication/19555415_Enhancement_of_Human_Monocyte_and_Peritoneal_Macrophage_Chemiluminescence_Activities_in_Women_With_Endometriosis?el=1_x_8&enrichId=rgreq-cc3cacd9-8bef-4bfd-8a1d-3385fe894fb2&enrichSource=Y292ZXJQYWdlOzIzMzcwNjU5NjtBUzoxMDE1NDU3NTY1OTQxODdAMTQwMTIyMTgwNDU3NQ==


The Practice Committee of the American Society for

Reproductive Medicine (ASRM 2006) has published

guidelines for standard infertility evaluation. It includes a

semen analysis, assessment of ovulation, a hysterosalpingo-

gram, and, if indicated, tests for ovarian reserve and laparo-

scopy.

The role of laparoscopy in the investigation of infertility

has changed over the past decade. Whereas laparoscopy used

to be part of the basic infertility workup, it is now reserved

for selected cases. According to the guidelines of the ASRM,

laparoscopy should be performed in women with

unexplained infertility or signs and symptoms of endo-

metriosis or when reversible adhesive tubal disease is

suspected [36].

The idea of a `one-stop shop' for subfertility investigation

is certainly an attractive one for both patients and clinicians

alike. It is simply aimed at checking the “Seed, Soil and

Passage” involved in conception and can be performed

within an hour. There is evidence to suggest that the use of

an ultrasound-based system is not only more acceptable to

couples, but it is also more cost-effective and provides

diagnostic information of a caliber comparable with that of

more traditional investigative methods. It is diagnostically

accurate, expeditious and reliable. The HycoSy test can also

be performed at the same time if necessary [52]--it is

minimally invasive and provides both the patient and

clinician

with useful prognostic information. The male

partner can have a detailed sperm test at the same time.

In agreement with the ‘one stop approach’, Ekerhovd E,

et al. also proposed the use of the ultrasound for the

assessment of infertility, including the evaluation of tubal

patency [53].

In the end, it would be fair enough to say that the

feasibility of transvaginal ultrasound use, in the infertility

clinic, for the assessment of female factor infertility makes it

the most cost-effective tool; i.e. transvaginal ultrasound

replaces the need for assessing ovarian reserve by measuring

the ovarian volume and the antral follicular count, replaces

the need for tubal and uterine factor assessment by

performing hysterosonography, documents ovulation by

follicular scanning and finally, replaces the need for

hormonal monitoring (estradiol) during ovarian stimulation

by measuring the endometrial thickness [54]. Monitoring of

follicular development in an IVF cycle, as well as the timing

of hCG administration, can be done using sonographic

criteria with basic inexpensive ultrasound equipment,

thereby avoiding the need for expensive endocrine investi-

gations [55, 56].

When the results of a standard infertility evaluation are

normal, practitioners assign a diagnosis of unexplained

infertility. Although estimates vary, the likelihood that all

such test results for an infertile couple are normal (ie, that

the couple has unexplained infertility) is approximately 15%

to 30% [57].

In the algorithm proposed by N. Gleicher, in level 1, CC

is given for 3 cycles without monitoring ( ovulation kits may

be used ).As previously mentioned, in the study assessing

reliability of ovulation tests in infertile women conducted by

Guermandi E., et al. in 2001, it was concluded that urinary

LH was accurate in predicting ovulation. In another study

conducted by Luciano AA et al. [58], the temporal relation-

ship and reliability of the clinical, hormonal, and ultrasono-

graphic indices of ovulation in infertile women were

assessed. Urine LH testing correlated well with the serum

LH peak, particularly in the evening urine, and predicted

ovulation in all patients. In addition, the use of urinary LH

surge for the timing of intrauterine insemination (IUI) in

CC-IUI cycles resulted in a higher pregnancy rate compared

with hCG-induced ovulation [59]. Lastly, it remains to

be mentioned that the average cost of the ovulation kits is

approximately $0.5-0.8, which highlights its cost effective-

ness.

A prospective multicenter randomized trial compared in a

parallel design the efficacy of CC with rFSH for ovarian

hyperstimulation in an IUI program for couples with

unexplained or male subfertility of at least 24 months. There

was no significant difference in live birth rates and multiple

pregnancy rates between the two groups. It was concluded

that unless larger studies demonstrate otherwise, for econo-

mic reasons, CC should still be the drug of choice for

ovarian stimulation in IUI cycles [60].

Patients who fail to conceive after level 1, despite

adequate ovulation (unexplained infertility) or due to failure

of ovulation with CC, should proceed to level 2 where they

will be given gonadotrophins for 3 cycles based on the

assumption that the efficacy of gonadotrophins decreases

after 2-4 cycles [61].

A. M. Case, in the Table 1, compared the cost of various

treatment regimens for infertility and their success rates. It is

clear that the more complicated and expensive treatments are

more successful although they may be not be as cost-

effective [62].

In another comparison of the costs of infertility

treatments, IUI, CC-IUI, and hMG-IUI had a similar cost per

delivery of between $7,800 and $10,300. All 3 of these

treatments were more cost-effective than IVF-ET, which had

a cost per delivery of $37,000. The use of IVF in women

with blocked fallopian tubes was more cost-effective than

tubal surgery via laparotomy, which had a cost per delivery

of $76,000 [67]. This study seems to support the proposed

algorithm, previously described in Fig. (1); i.e.the use of IUI,

CC-IUI, and hMG-IUI before IVF in women with open

fallopian tubes. For women with blocked fallopian tubes,

IVF-ET appears to be the best treatment from a cost-

effectiveness standpoint.

In a recent review by J. Collins on the current best

evidence for the advanced treatment of unexplained

subfertility, he concluded that IVF is superior to FSH/IUI

treatment, but this benefit is achieved only at considerable

cost, and the evidence is not robust, comprising only a few

trials. The small increase in effectiveness with IVF over

FSH/IUI treatment is achieved only at considerable

incremental cost, whether it is measured per cycle or per

couple. Current best evidence is consistent with a

progression from low-tech to high-tech treatment, but it is

not convincing enough to support a rigid management

protocol; thus a large multi-center factorial trial is needed to


evaluate the relative value of existing empiric treatments for

unexplained infertility [68].

In agreement with this, another study assessing

conventional treatment in normogonadotrophic anovulatory

infertility (WHO 2) (CC followed by exogenous

gonadotrophins [FSH] and IVF), showed that using CC ›

FSH ›IVF compared with FSH › IVF generated more

pregnancies against lower costs but when compared with CC

›IVF, it also produced more pregnancies, but at higher

costs. The average costs per cycle were 53 ($72), 1108

($1,515), 1830 ($2,502) for CC, FSH and IVF, respectively,

and the costs per ongoing pregnancy were 544($743),

8584($11,737), 7686($10,510) [69].

Recently, the validity of evidence used by the Royal

College of Obstetricians and Gynecologists in recommend-

ing ovarian stimulation with IUI as an effective treatment for

couples with unexplained infertility has been questioned, re-

igniting the debate on what the initial treatment for

idiopathic infertility should be. The current best available

evidence, using the results of randomized controlled trials, is

that the initial treatment for idiopathic infertility should be

IUI as opposed to IVF [70]. This was supported by a

prospective, randomized, parallel trial that concluded that in

idiopathic or male subfertility, IUI offers the same likelihood

of successful pregnancy as IVF and is a more cost-effective

approach [71]. Cost-effectiveness studies showed that three

IUIs were as successful, but much cheaper, than one

IVF/ICSI cycle [67,71-75].

THE CONCEPT OF FRIENDLY IVF / NATURAL

CYCLE IVF

Keeping things simple without altering the success rate

of IVF is the idea behind “Friendly IVF”. Friendly IVF aims

to reduce the burden of the IVF procedures and its related

complications, thereby giving a couple the chance to

conceive using procedures that are less costly in terms of

physical, emotional, social and financial costs. The rationale

behind natural cycle IVF (probably the "gold standard" of

friendly IVF) is that it is more nearly natural. The body itself

selects its own "best egg" for that cycle. The ovaries do not

blister full of multiple follicles, and neither the body nor the

endometrium are exposed to supra-physiological levels of

estradiol. Natural cycle IVF is safe and less stressful, results

in fewer multiple births and is cost effective (one–fifth of the

price of the current standard stimulation regimen) [76,84].

In a study conducted by M.J. Janssens, et al., the authors

concluded that Natural IVF is an easy, inexpensive and

realistic method to achieve pregnancy for patients with tubal

infertility. Ongoing pregnancy rates approach 5.3% per

cycle, 6.5% per oocyte retrieval, 11.4% per embryo transfer

and 11.4% per embryo [77].

In 1995, Daya et al. reported that despite the high failure

rate seen with each step in the process, natural cycle IVF was

more cost-effective than stimulated-cycle IVF, which

incurred an incremental cost per live birth of $48,000. The

total cost for one live birth was five times lower with Natural

IVF. In Daya’s study, a pregnancy rate of 12% was

confirmed [78]. Mild approaches to ovarian stimulation

promise to be more science-based and patient-friendly and

they may also help improve the health of the offspring,

through reduced perinatal morbidity, mortality, multiple

pregnancies and the need for fetal reduction. Although a mild

stimulation protocol resulted in a lesser number of embryos

retrieved when compared to a high dose conventional

protocol, it was associated with a significantly higher

proportion of chromosomally normal embryos [79].

A multi-center study published in 2005 by Groen et al., compared the effects and costs of conventional IVF with

those of Manipulated Natural Cycle-(MNC) IVF. Full

treatment costs of MNC-IVF, including costs of pregnancy

and delivery, ranged from 1,329 ($971) to 1,465Euro

($1071) per cycle, depending on the treatment phases com-

pleted and the number of pregnancies achieved. Medication

costs ranged between 265 ($193) and 275 Euro ($201) per

cycle versus 885 Euro ($647) for conventional IVF. The cost

per live birth after three cycles of MNC-IVF was 17,197

Euro ($12,571), which is comparable to the costs per live

birth after a single cycle of conventional IVF. It was

concluded that three cycles of MNC-IVF achieve pregnancy

rates similar to those of conventional IVF but with much

Table 1. Indications, Costs, and Success Rates of Commonly Used Infertility Treatments

Treatment Indication Cost Per Cycle($) Success Rate Per Cycle (%)

CC Oligo-ovulation 50-150 10-15 [63]

CC Unexplained 4-6 [64]

CC & IUI Unexplained 150-300 8-10 [64,65]

SO & IUI Unexplained 750-2000 18-20 [65]

IVF Tubal factor 5000-8000

IVF Male factor 40 ( 30 years ) [66]

IVF Endometriosis 35 (30-35) [66]

IVF Unexplained 25(35-39) [66]

IVF and ICSI Male factor 8000-10000 15 ( 40) [66]

CC- clomiphene citrate, ICSI – intracytoplasmic sperm injection, IUI – intrauterine insemination, IVF – in vitro fertilization, SO – superovulation( using gonadotrophins).


lower twin pregnancy rates. Thus, MNC-IVF may be a cost-

effective alternative for conventional IVF [80]. Alter-

natively, low-dose hCG can be administered in the later

stages of controlled ovarian stimulation. This results in a

significantly reduced dose of recombinant FSH/hMG while

the outcome is comparable to that of traditional Controlled

Ovarian Hyperstimulation (COH) regimens [81,82].

A non-randomized clinical trial of minimal ovary

stimulation compared CC and gonadotropin outcomes and

direct costs to those of a conventional GnRHa-gonadotropin

stimulation protocol for infertile patients undergoing IVF.

The pregnancy rate per oocyte retrieval cycle in the GnRHa-

gonadotropin protocol was similar to the minimal

stimulation protocol (13.1% vs 13.0%). However, the cost

per pregnancy of the minimal stimulation protocol was less

than that of the GnRHa-gonadotropin protocol ($6,021.95 vs.

$10,785.65) [83]. The use of CC stimulation seems to be

superior to natural or minimal stimulation IVF [84,85].

On the other hand, CC may be no better than natural

cycle IVF, which has repeatedly been shown to be inefficient

(<10% clinical pregnancy per cycle) [86-89]. Repeating one

procedure that has a 10% chance of success four times is not

mathematically equivalent to performing a single procedure

with a 40% chance of success. Cumulative pregnancy rates

after three cycles of minimal stimulation have been

disappointingly low, yielding per-cycle success rates of only

8%, similar to the expected rate of CC–IUI rates, limiting its

utility [90].

In a study evaluating the acceptability of stimulated

versus natural cycle IVF among couples attending one

infertility clinic, with respect to cost and pregnancy outcome,

15% (16/107) of the patients who were indicated for IVF

cancelled, mostly due to financial reasons (12/16). Most

patients who completed their IVF treatment (82/91, 90.1%)

believed that the price of the medical service offered was

high, and 68.1% (62/91) accepted the idea of using less

expensive drugs with fewer side effects but with possibly a

lower chance of pregnancy [91].

A policy of elective single embryo transfer (eSET) is the

most efficacious measure of reducing the incidence of

multiple pregnancies in ART [92-98]. This highlights the

importance of natural cycle and minimal stimulation IVF and

the lesser need for the production of many embryos per cycle

in decreasing the burden imposed by multiple pregnancies.

On the other hand, a systematic review of studies looking at

the cost-effectiveness of IVF-SET versus IVF with double

embryo transfer (DET) used in a health economic model

compared three strategies: (1) IVF-SET, (2) IVF-DET, and

(3) IUI with gonadotropin stimulation (sIUI). IVF-DET was

the most cost-effective strategy at $35,144/live birth,

followed by sIUI at $66, 960/live birth, and IVF-SET at

$109,358/live birth. The results were sensitive both to the

cost of IVF cycles and to the probability of live birth [99].

‘‘Patient-friendly’’ IVF must be associated with a healthy

newborn achieved in a safe, cost-effective, and timely

manner. Patients are best served when physicians provide

honest appraisal of treatment techniques and outcomes using

the evidence available from scientific study [100]. The ‘‘less

is better’’ approach has tremendous emotional appeal,

because patients do not like taking medications, viewing

them as unnatural. Minimal stimulation protocols thrive on

that appeal. But a recent review of abstracts presented at the

First World Congress on Natural Cycle/Minimal Stimulation

reports inconclusive supporting evidence and the availability

of procedures that ‘‘might be superior’’[101].

MAKING IVF AFFORDABLE

In 2006, the European Society of Human Reproduction

and Embryology (ESHRE) created a Special Task Force

whose mission was to focus on infertility in developing

countries; the Arusha-project looks for ways to make IVF

affordable for African couples by vastly simplifying

conventional IVF technologies. This task force is also

attempting to: document the problem of infertility in

developing countries; develop and test the effectiveness of a

simplified ‘one-step clinic’ for the diagnosis of infertility;

and develop and test the effectiveness of simplified IVF-

related procedures. It plans to begin offering IVF at clinics in

Cairo and Alexandria, Egypt, for around $360. In the US and

the UK, the price of one round of treatment can cost as much

as $12,000 and £5000 ($8000), respectively, and is rarely

covered by health insurance.

One of the aspects of IVF the task force is looking at is

the stimulation protocol. The recombinant form of FSH can

cause women to release a large number of oocytes per cycle

and thus, some embryos can be frozen. However, this has the

disadvantage of being enormously expensive. On the other

hand, clomiphene costs just $11 for one round of treatment.

It can induce the maturation of up to four viable eggs per

cycle. That is far fewer than seen with the use of FSH. And

because low-cost IVF facilities are unlikely to have the

equipment or liquid nitrogen for freezing extra embryos,

fewer eggs are needed anyway. Using clomiphene, the

ESHRE group plans to transfer no more than two embryos to

the woman's uterus whereas the Low Cost IVF Foundation

(LCIF) initiative plans to transfer only one. As clomiphene

has fewer side effects than recombinant FSH, women may be

more likely try further rounds of IVF if earlier attempts fail.

The ESHRE group estimates this approach will achieve a

pregnancy rate of 15% to 20%, lower than the European rate

of 25% and US rate of 35%. The ESHRE group plans to

transfer the embryo on the first or second day after

fertilization [102].

Another aspect of assisted reproduction that is being

assessed is cutting down on the incubator expenses. Simple

portable table-top incubators cost less than $1000. LCIF is

counting on the use of warm water baths to incubate

embryos. The use of a ‘humidicrib’, a plastic box that is

commonly used for keeping newborns snug, instead of

an expensive laminar flow hood, has also been proposed

[103, 104]. Others argue that incubators can be avoided

completely since women themselves can act as a natural one.

Intravaginal culture was described approximately 20 years

ago [105-108]. A tube filled with 3 ml of culture medium

containing 1–5 oocytes with 10 000–20 000 washed

spermatozoa per millilitre was hermetically closed and

placed in the vagina. It was held in place by a diaphragm for

incubation for 44–50 h. Comparable success rates with

conventional IVF were reported [106].


The INVOcell is a small plastic capsule into which

fertilized eggs are placed together with culture media. The

capsule, encased in a protective shell, is then inserted into a

woman's vagina for three days, which keeps the embryos at

the desired temperature. Fertilization of the oocyte(s) and

early embryo development occur in the INVOcell, which is

placed into the maternal vaginal cavity for incubation. The

vaginal cavity replaces the complex IVF laboratory. After

removal, the two best embryos are selected and transferred to

the woman's uterus. It costs between $85 in Africa and $185

in Europe and can cut the cost of IVF by half. The INVOcell

overcomes the disadvantages of the

previously used

prototype and makes the procedure simpler and reproducible.

Over 800 cycles have been published worldwide that showed

a clinical pregnancy rate of 19.6%. The INVO technology

can be performed in an office setting with minor capital

equipment. INVO is a simple low-cost procedure that can be

available almost everywhere [109].

Bicarbonate-free media can be used to maintain the pH,

obviating the need for cylinders of CO2, which are expensive

and unnecessary if an embryo is incubated for only one or

two days. Also, the need for CO2 cylinders can be overcome

simply by exhaling across the culture medium before sealing

it in a plastic bag. This bag, containing the Petri dish with the

embryos, can be dropped into a warm bath without the need

for expensive incubators. This technique has been

successfully used for more than 10 years for cow embryos in

veterinary IVF [110,111].

Less expensive microscopes for confirming cell division

can be easily adapted for a minimal cost, as can portable

digital ultrasound machines that sell for less than $5000 - far

below the typical $400,000 price tag for machines used in

western IVF clinics [102].

CONCLUSIONS

In an era of evidence-based medicine, we often fail to

specify the best cost-effective regimen for an infertile

couple. Setting a predetermined algorithm, though inefficient

in some cases, can help simplify the management approach.

The value of prevention and education should not be

underestimated. Our goal should be to offer not necessarily a

low-cost approach, but rather a cost-effective one that does

not compromise success rates--a balance that is difficult to

achieve. This can be done by making “wise choices”

(evidence-based choices) amongst investigatory tools and

treatment options.

The availability and implementation of low-cost,

effective infertility management protocols is needed in

developed countries as much as it is needed in developing

countries. Many European countries are experiencing long-

term downtrends in fertility, and there is increasing pressure

on governments to enhance their baby-friendly policies as a

measure to reverse future reductions in fertility.

The idea of a “patient- friendly” treatment regimen

sounds appealing, but it should not necessarily be confused

with “minimal stimulation IVF” because in order to provide

the best medical care for patients, it should be evidence-

based and without any personal bias. The ESHRE Task

Force experience in developing countries will probably be a

first step in tackling the challenge of providing a cost-

effective simplified assisted reproduction program.

However, studies on a wide scale must be a part of that

experience.

FIVE YEAR REVIEW

Infertility is a major problem in low-resource countries

and causes extensive social and psychological suffering.

Providing infertility treatment in resource-poor countries

should be part of an integrated reproductive care program

that includes family planning and motherhood care. Access

to preventive treatment in terms of detection and treatments

of STIs is an important preventative aspect, and it should be

available to all patients in developing economies. Patients in

low-resource and developing countries have a right to

infertility treatment including ART.

KEY POINTS

1. The incidence, severity and the gravity of infertility is

highest in many low-resource countries.

2. The most common cause of infertility is tubal damage,

which is preventable through early detection and

treatment of STIs.

3. In practicing medicine, we should not fail to specify the

best cost-effective regimen for our patients. Evidence-

based choices can be made without compromising

success rates.

4. Setting a predetermined algorithm, though inefficient in

some cases, helps to simplify the management approach.

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Received: January 10, 2010 Revised: February 08, 2010 Accepted: April 15, 2010



Female Infertility and Antioxidants

Lucky H. Sekhon, Sajal Gupta, Yesul Kim and Ashok Agarwal*

Center for Reproductive Medicine, Glickman Urological & Kidney Institute and Ob/Gyn& Women’s Health Institute,

Cleveland Clinic 9500 Euclid Avenue, Desk A19.1, Cleveland, OH 44195, USA

Abstract: Aim: Many studies have implicated oxidative stress in the pathogenesis of infertility causing diseases of the fe-

male reproductive tract. The aim of this study was to review the current literature on the effects of antioxidant therapy and

to elucidate whether antioxidant supplementation is useful to prevent and/or treat infertility and poor pregnancy

outcomes related to various obstetric and gynecologic conditions.

Methods: Review of recent publications through Pubmed and the Cochrane data base.

Results: Antioxidant supplementation has been shown to improve insulin sensitivity and restore redox balance in patients

with PCOS. Supplementation with RU486, Curcuma longa, melatonin, caffeic acid phenethyl ester (CAPE) and catechins

may induce remission and halt disease progression in endometriosis. Selenium therapy may improve pregnancy rates

in unexplained infertility. Currently there is no evidence to substantiate the use of antioxidants to prevent or treat

preeclampsia. Up to 50-60% of recurrent pregnancy loss may be attributable to oxidative stress. Observational studies

have confirmed a link between antioxidant-poor diet and recurrent pregnancy loss.

Conclusion: Although many advances are being made in the field of antioxidants therapy, there is a need for further

investigation using randomized controlled trials within a larger population to determine the efficacy and safety of

antioxidant supplementation.

Keywords: Oxidative stress, antioxidants, polycystic ovarian syndrome (PCOS), endometriosis, unexplained infertility, preeclampsia,

spontaneous abortion.

INTRODUCTION

Reactive oxygen species (ROS) can modulate cellular

functions, and oxidative stress (OS) can impair the intracel-

lular milieu, resulting in diseased cells or endangered cell

survival. Reproductive cells and tissues remain stable when

free radical production and the scavenging antioxidants re-

main in balance. The role of ROS in various diseases of the

female reproductive tract has been investigated. ROS can

affect a variety of physiological functions in the reproductive

tract, and excessive levels can result in precipitous patholo-

gies affecting female reproduction. The oxidant status can

influence early embryo development by modifying the key

transcription factors, hence modifying gene expression.

The review will focus on ROS homeostasis and genera-

tion of OS in the female reproductive processes. Our review

elucidates the role of ROS in physiological processes such as

folliculogenesis, oocyte maturation, endometrial cycle, lute-

olysis, implantation, and embryogenesis and the role of anti-

oxidants in various reproductive pathologies. This review

encapsulates the role of OS, which is becoming increasingly

important as new evidence of its role in conditions such as

polycystic ovarian disease and abortions is discovered. The

review highlights how OS modulates natural and assisted

*Address correspondence to this author at the Professor & Director, Center

for Reproductive Medicine, Glickman Urological & Kidney Institute and

Ob/Gyn & Women’s Health Institute, Cleveland Clinic, 9500 Euclid

Avenue, Desk A19.1, Cleveland, OH 44195, USA; Tel: (216) 444-9485;

Fax: (216) 445-6049; E-mail: [email protected]

fertility and the importance of antioxidant strategies to inter-

cept OS to overcome its adverse effects.

WHAT IS OXIDATIVE STRESS?

Oxidative stress arises from an imbalance between pro-

oxidant molecules generated from aerobic metabolism and

protective antioxidants. OS influences the entire reproduc-

tive lifespan of a woman. Reactive oxygen species may act

as key signalling molecules in physiological processes but

at excess, uncontrolled levels they may also mediate patho-

logical processes involving the female reproductive tract.

There is a body of literature providing clinical evidence that

substantiates the link between OS and female infertility.

Pro-Oxidants

Under physiological conditions, biomolecules are com-

prised of stable bonds formed by paired electrons. Weak-

ened, disrupted bonds allow for the generation of free radi-

cals- unstable and highly reactive species with one or more

unpaired electrons. They gain stability by acquiring electrons

from nearby nucleic acids, lipids, proteins, and carbohy-

drates, initiating a cascade of chain reactions that may result

in cellular damage and disease [1-4].

Reactive oxygen species are formed endogenously during

aerobic metabolism and as a result of various metabolic

pathways of oocytes and embryos or as part of the body’s

defense mechanisms. ROS also can arise from exogenous

sources, such as alcohol, tobacco, and various environmental

Female Infertility and Antioxidants Current Women’s Health Reviews, 2010, Vol. 6, No. 2 85

pollutants. ROS include hydroxyl radicals, superoxide anion,

hydrogen peroxide, and nitric oxide (NO) [5]. Several bio-

markers indicative of redox status, including superoxide

dismutase (SOD), glutathione peroxidase (GSH-Px), lipid

peroxides, and nitric oxide, have been identified within the

ovary, endometrium, fallopian tubes, embryo, placenta, and

the peritoneal fluid of women. At controlled levels, free

radicals are capable of exerting physiological effects and

mediating processes such as tissue remodelling, hormone

signalling, oocyte maturation, folliculogenesis, tubal func-

tion, ovarian steroidogenesis, cyclical endometrial changes,

and germ cell function [6, 7]. However, when ROS increase

to pathological levels they are capable of inflicting signifi-

cant damage to cell structures.

Antioxidants

Under normal conditions, antioxidants act to oppose ROS

production, scavenge existing free radicals, and promote the

repair of ROS-induced damage to cell structures [8]. Non-

enzymatic antioxidants include vitamin C, vitamin E, sele-

nium, zinc, beta carotene, carotene, taurine, hypotaurine,

cysteamine, and glutathione. Enzymatic antioxidants include

SOD, catalase, GSH-Px, glutaredoxin and glutathione reduc-

tase [5]. The degree of antioxidant defense present is often

expressed as total antioxidant capacity (TAC) [6].

A disruption in the delicate balance between antioxidants

and pro-oxidant molecules can result in OS. OS arises when

the generation of reactive oxygen species and other radical

species overrides the scavenging capacity by antioxidants,

either due to the excessive production of ROS or an inade-

quate availability of antioxidants. Thus, oral antioxidant

supplementation may serve to prevent and alleviate OS and

its contribution to the pathogenesis of obstetrical disease

such as preeclampsia and recurrent pregnancy loss and gyne-

cological disorders such as polycystic ovarian syndrome

(PCOS) and endometriosis.

OS IN THE FEMALE REPRODUCTIVE TRACT –

PHYSIOLOGICAL ROLE OF OS

Follicle

The expression of various markers of OS has been

demonstrated in normally cycling ovaries [9, 10]. The

follicular fluid microenvironment contains leukocytes,

macrophages, and cytokines, all of which are known sources

of ROS. ROS within the follicular fluid plays a role in

modulating oocyte maturation, folliculogenesis, ovarian

steroidogenesis, and luteolysis [11]. Follicular development

involves the progression of small primordial follicles into

large pre-ovulatory follicles. Studies have implicated the

nitric oxide radical in the follicular growth and programmed

follicular cell death that occur during folliculogenesis [12,

13]. Moderate OS levels are required for ovulation. The final

stages of oocyte maturation are associated with fluctuations

in cytokines, prostaglandins, proteolytic enzymes, nitric

oxide, and steroids, which increase the level of ROS,

influencing ovarian blood flow and eventually facilitating

follicle rupture [14]. A degree of oxidative enzyme activity

is exhibited by thecal cells, granulosa lutein cells, and hilus

cells, illustrating the role of OS in ovarian steroidogenesis

[11].

ROS is controlled and kept at physiological levels within

the ovary by various antioxidant systems, including catalase,

vitamin E, glutathione and carotenoids [4]. SOD, a metal-

containing enzymatic antioxidant that catalyzes the

decomposition of superoxide into hydrogen peroxide and

oxygen, has been characterized in the theca interna cells in

the antral follicles. Therefore, the theca interna cells may

protect the oocyte from excess ROS during its maturation

[15]. Another antioxidant factor important for healthy

follicle development is transferrin, an iron-chelating glyco-

protein that suppresses ROS generation [16]. Vitamin C also

is known to have a protective effect within the follicle as

vitamin C deficiency has been reported to result in ovarian

atrophy, extensive follicular atresia, and premature resump-

tion of meiosis [15].

The overall ROS scavenging ability of antioxidants

within the follicular fluid microenvironment may diminish

with reproductive aging. Carbone et al. demonstrated

decreased levels of follicular fluid catalase and SOD in older

women, whose oocytes were seen to exhibit lower

fertilization rates and decreased blastocyst development

compared with oocytes of younger women [17]. Therefore,

the redox status of the follicle is closely related to oocyte

quality and fertilization capacity.

Endometrium

The relationship between OS and cyclical changes in the

endometrium is well-established. OS-promoting alterations

in ROS and SOD levels have been demonstrated just prior to

menstruation, during the late-secretory phase [18]. Estrogen

and progesterone withdrawal in endometrial cells in vitro has

been associated with a decrease in SOD activity, resulting in

the unopposed activity of ROS [18]. Elevated lipid peroxide

and decreased SOD in the endometrium during the late-

secretory phase may modulate endometrial breakdown,

leading to menstruation. NO is known to regulate the

endometrial microvasculature and is produced by endothelial

NO synthase (NOS), which is distributed in the glandular

surface epithelial cells of the endometrium [19]. NO is

thought to mediate endometrial decidualization and

menstruation as endothelial NOS mRNA expression has

been detected in the mid-secretory and late-secretory phase.

Endothelial NOS is also implicated in the changes seen in

the endometrium in preparation for implantation [20]. ROS

may mediate the physiological processes of shedding and

implantation by its activation of nuclear factor B within

the endometrium, leading to increased cyclooxygenase-2

mRNA and prostaglandin F2 synthesis [18].

Infertility

Approximately 1.3 million American couples receive

medical advice or treatment for infertility every year [21].

Infertility is a disease defined as the inability to conceive

following 12 or more months of unprotected sex [22]. In

general, an estimated 84% of couples conceive after 1 year

of intercourse, and 92% of the couples conceive after 2 years

86 Current Women’s Health Reviews, 2010, Vol. 6, No. 2 Sekhon et al.

[23]. A primary diagnosis of male factor infertility is made

in 30% of infertile couples. High levels of ROS biomarkers

have been detected in semen samples of 25-40% of infertile

men [5]. Although ROS have a physiological role in normal

sperm function, mediating the acrosome reaction, hyperacti-

vation, motility, and capacitation of spermatozoa, excessive

levels of ROS may arise from immotile or morphologically

abnormal spermatozoa and leukocytes. Spermatozoa lack

the necessary cytoplasmic antioxidant enzymes and are

vulnerable to OS-induced DNA damage and apoptosis

[5, 24]. Substantial evidence exists that implicates OS in

many causes of male infertility. Oral antioxidant supple-

mentation has become standard practice for male infertility

[5].

Combined female and male factor infertility is responsi-

ble for 20%–30% of cases. If the results of a standard infer-

tility examination are normal, a diagnosis of unexplained

or idiopathic infertility is assigned [25]. OS has a well-

established role in pathogenesis of unexplained infertility,

which is seen to affect 15% of couples [25]. Although the

frequency and origin of different forms of infertility varies,

40%–50% of the etiology of infertility studied is due to

female causes [26].

OS induces infertility in women through a variety of

mechanisms. Excess ROS in the follicle may overwhelm

follicular fluid antioxidant defense and directly damage oo-

cytes. The DNA of oocytes and spermatozoa may be dam-

aged, leading to defective fertilization when the peritoneal

cavity microenvironment is plagued with severe OS. Even

when fertilization is achieved, OS-induced apoptosis may

result in embryo fragmentation, implantation failure, abor-

tion, impaired placentation, and congenital abnormalities

[27]. Excess ROS may hinder the endometrium, which nor-

mally functions to support the embryo and its development

[28]. OS may induce luteal regression and insufficient luteal

hormonal support for the continuation of a pregnancy [8].

The association of OS with various gynecologic and obstet-

ric conditions related to infertility suggests a potential role

for oral antioxidant supplementation (Fig. 1). Additional

research is needed to determine whether such supplementa-

tion can ensure successful fertilization and pregnancy by

controlling the OS experienced by patients with endometri-

osis, PCOS, unexplained infertility, preeclampsia, and recur-

rent pregnancy loss.

THE USE OF ANTIOXIDANTS IN TREATMENT OF

GYNECOLOGICAL CONDITIONS

Polycystic Ovarian Syndrome

PCOS is an anovulatory cause of infertility affecting 6-

10% of premenopausal women [29-32]. PCOS often can be

characterized by hyperandrogenism, hirsutism, and oligo-

menorrhea or amenorrhea. Metabolic, endocrinologic, and

cardiovascular disorders may also coexist. Oxidative stress

has been implicated in mediating the insulin resistance and

increase in androgens seen in these patients [33].

A recent study by Kuscu et al. demonstrated increased

MDA levels and upregulated SOD activity in patients with

PCOS compared to controls. MDA levels were highest in

patients who exhibited insulin resistance [34]. Insulin

resistance and hyperglycemia are established as factors that

increase oxidative stress. Fulghesu et al. evaluated the effect

of N-acetyl-cysteine (NAC), known to replenish stores of the

anti-oxidant glutathione, on insulin secretion and peripheral

insulin resistance in subjects with PCOS. Patients were

treated for 5-6 weeks with a 1.8g oral NAC per day.

Massively obese patients were given a higher dose of 3g per

day. NAC treatment was found to improve parameters of

glucose control in hyperinsulinemic patients. Insulin levels

were reduced, with increased peripheral insulin sensitivity.

Therefore, the anti-oxidant effects of NAC may serve as a

therapeutic strategy to improve the level of circulating

insulin and insulin sensitivity in PCOS patients with

hyperinsulinemia [35].

Non-obese PCOS patients without insulin resistance also

have been reported to have elevated total oxidant and anti-

Fig. (1). The role of oxidative stress in obstetric and gynecologic conditions that contribute to infertility.


oxidant status [36]. Verit et al. demonstrated that total anti-

oxidant status in these types of PCOS patients was correlated

with raised luteinizing hormone levels and free androgen and

dehydroepiandrosterone (DHEAS) levels [36]. Yilmaz et al. studied the effects of 12 weeks of treatment with oral

hypoglycemic agents on OS in lean patients with PCOS [37].

Before treatment, PCOS patients exhibited OS with

significantly raised serum MDA and homocysteine and

significantly decreased serum TAS. PCOS patients treated

with rosiglitazone showed an increase in TAS and a decrease

in MDA levels, compared with a metformin-administered

patient group in which these parameters did not change [37].

Therefore, rosiglitazone may be useful in combating OS in

hyperinsulinemic PCOS patients.

Zhang et al. used methods of chemicalorimetry to

measure and compare levels of serum lipid peroxides (LPO),

MDA, SOD, vitamin E, and vitamin C in patients with

PCOS and normal women [38]. Levels of serum LPO and

MDA in patients with PCOS were significantly higher than

those found in normal women. Levels of vitamin E, vitamin

C, and SOD were lower in patients with PCOS than in the

control group. After 3 months of therapy with oral

ethinylestradiol and cyproterone acetate tablets (Diane-35®

,

Merck, Whitehouse Station, N.J.), an anti-androgenic oral

contraceptive often used to treat hirsutism associated with

PCOS, MDA and LPO levels decreased, while vitamin E,

vitamin C, and SOD levels increased in patients with PCOS

[38]. Therefore, this therapy may alleviate the symptoms of

PCOS through both its anti-androgenic and anti-oxidant

actions.

Endometriosis

Severe cases of endometriosis are thought to render a

woman infertile by mechanical hindrance of the sperm-egg

union by adhesions, endometriomata, and pelvic anatomy

malformations. However, in women with mild-to-moderate

forms of endometriosis and no pelvic anatomical distortion,

the mechanism by which their fertility is reduced is poorly

understood.

ROS production may be amplified in the setting of en-

dometriosis due to menstrual reflux, which subjects the peri-

toneal cavity to pro-inflammatory hemoglobin and heme

molecules released from transplanted erythrocyte debris.

Peritoneal fluid containing ROS-generating iron, macro-

phages, and environmental contaminants such as polychlori-

nated biphenyls may disrupt the prooxidant/antioxidant bal-

ance, resulting in increased proliferation of tissue and adhe-

sions [39-42]. ROS are thought to promote the growth and

adhesion of endometrial cells in the peritoneal cavity, con-

tributing to the pelvic anatomical distortion known to cause

infertility in endometriosis [43]. OS may have a role in pro-

moting angiogenesis in ectopic endometrial implants by

increasing vascular endothelial growth factor (VEGF) produc-

tion [44]. This effect is partly mediated by glycodelin,

a glycoprotein whose expression is stimulated by OS.

Glycodelin may act as an autocrine factor within ectopic

endometrial tissue by augmenting VEGF expression [44].

Altered molecular genetic pathways may contribute to

the effects of OS in the pathogenesis of endometriosis and

endometriosis-associated infertility. Differential gene ex-

pression of ectopic and normal endometrial tissue has been

identified, including differential gene expression of glu-

tathione-S-transferase, an enzyme in the metabolism of the

potent antioxidant glutathione [45]. This suggests that altered

molecular genetic pathways may determine the development

of OS and its ability to induce cellular proliferation and an-

giogenesis in women with endometriosis.

Peritoneal fluid of women with endometriosis has been

reported to exhibit increased ROS generation by activated

peritoneal macrophages [46]. Increased macrophage activity

is accompanied by the release of cytokines and other im-

mune mediators such as NO. NO is a pro-inflammatory free

radical that exerts deleterious effects on fertility by increas-

ing the amount of OS in the peritoneal fluid, an environment

that hosts the processes of ovulation, gamete transportation,

sperm-oocyte interaction, fertilization, and early embryonic

development [2, 47, 48]. However, the results of further

studies with large patient numbers failed to confirm an anti-

oxidant or oxidant imbalance as ROS levels in peritoneal

fluid of patients with endometriosis were not reported to be

significantly higher than controls [49, 50].

After adjusting for confounding factors such as age,

BMI, gravidity, serum vitamin E, and serum lipid levels,

Jackson et al. reported a weak relationship of elevated levels

of thiobarbituric acid reactive substances (TBARS), an over-

all measure of OS, in women with endometriosis [51]. In-

creased NO production and lipid peroxidation have been

reported in the endometrium of women with endometriosis

[2, 52]. However, several studies failed to find significant

differences in the peritoneal fluid levels of NO, lipid perox-

ide, and ROS in women with and without endometriosis-

associated infertility.

The failure of some studies to confirm alterations in peri-

toneal fluid NO, lipid peroxide and antioxidant status in

women with endometriosis may be explained by the fact that

OS may occur locally, without affecting total peritoneal fluid

ROS concentration. Also, markers of OS may be transient

and not detected at the time endometriosis is diagnosed.

An imbalance between ROS and antioxidant levels may

play an important role in the pathogenesis of endometriosis-

associated infertility. Increased concentrations of oviductal

fluid ROS may adversely affect oocyte and spermatozoa

viability and the process of fertilization and embryo implan-

tation. Also, pro-inflammatory macrophages and activated

neutrophils in the oviductal fluid may significantly amplify

ROS production by endometriotic foci [43]. Increased ROS

production may inflict oxidative damage to the sperm plasma

and acrosomal membranes, resulting in a loss of motility and

decreased spermatozoal ability to bind and penetrate the oo-

cyte. The various possible consequences of OS-induced

DNA damage include failed fertilization, reduced embryo

quality, pregnancy failure, and spontaneous abortion.

Modest levels of OS have been shown to induce the pro-

liferation of endometrial stromal cells in vitro, which has

been shown to be inhibited by antioxidants [53]. Several

studies have shown that the peritoneal fluid of women with

endometriosis-associated infertility have insufficient antioxi-


dant defense, with lower total antioxidant capacity (TAC)

and significantly reduced SOD levels [2, 47, 54].

An early study used a simple rabbit model to demonstrate

the beneficial effect of antioxidant therapy in halting pro-

gression of the disease [55]. SOD and catalase were instilled

in the rabbit peritoneal cavity and were shown to signifi-

cantly reduce the formation of intraperitoneal adhesions at

endometriosis sites by blocking the toxic effects of the su-

peroxide anion and hydrogen peroxide radicals [55]. More

recently, RU486- a potent antiprogestational agent with anti-

oxidant activity, has been shown to decrease the proliferation

of epithelial and stromal cells in endometriosis [56].

Another drug being investigated for its potential use in

the treatment of endometriosis-associated infertility is pen-

toxifylline, a 3’,5’-nucleotide phosphodiesterase inhibitor.

Pentoxifylline has potent immunomodulatory properties and

has been shown to significantly reduce the embryotoxic ef-

fects of hydrogen peroxide [57]. Zhang et al. conducted a

recent randomized control trial in which pentoxifylline

treatment failed to demonstrate significant reduction in en-

dometriosis-associated symptoms such as pain. Furthermore,

there was no evidence of an increase in the clinical preg-

nancy rates in the pentoxifylline group compared with pla-

cebo [58]. Currently, there is not enough evidence to warrant

the use of pentoxifylline in the management of premeno-

pausal women with endometriosis-associated pain and infer-

tility.

Curcumin is a polyphenol derived from turmeric

(Curcuma longa) with antioxidant, anti-inflammatory, and

antiproliferative properties. This compound has been shown

to have an anti-endometriotic effect by targeting aberrant

matrix remodelling in a mouse model. Matrix metalloprote-

inase-9 (MMP-9) has been shown to correlate with severity

of endometriosis. In randomized controlled trials, curcumin

treatment was seen to reverse MMP-9 activity in endometri-

otic implants near to control values. Furthermore, the anti-

inflammatory property of curcumin was evidenced by the

fact that the attenuation of MMP-9 was accompanied by a

reduction in cytokine release. Decreased expression of tumor

necrosis factor alpha (TNF- ) was demonstrated during re-

gression and healing of endometriotic lesions within the

mouse model. Pretreatment of endometriotic lesions with

curcumin was shown to prevent lipid peroxidation and pro-

tein oxidation within the experimental tissue, attesting to its

therapeutic potential to provide antioxidant defense against

OS-mediated infertility in endometriosis [59].

MMP-9 also was identified as a therapeutic target in the

treatment of OS-mediated endometriosis in another study

evaluating the effectiveness of melatonin in treating experi-

mental endometriosis in a mouse model [60]. Melatonin is a

major secretory product of the pineal gland with anti-oxidant

properties. Melatonin was shown to arrest lipid peroxidation

and protein oxidation, while downregulating MMP-9 activity

and expression in a time- and dose-dependent manner. Tis-

sue inhibitors of metalloproteinase (TIMP)-1 were found to

be elevated. Regression of peritoneal endometriotic lesions

was seen to accompany the alteration in metalloproteinase

expression [60]. Guney et al. confirmed these findings in

that treatment with melatonin was also shown to cause re-

gression and atrophy of endometriotic lesions in rats [61].

Endometrial lesions treated with melatonin demonstrated

lower MDA levels and significantly increased SOD and cata-

lase activity [61], corroborating the usefulness of this hor-

mone in neutralizing OS.

Guney et al. conducted another study that evaluated the

effects of antioxidant and anti-inflammatory caffeic acid

phenethyl ester (CAPE) on experimental endometriosis in a

rat model, and the levels of peritoneal SOD and catalase ac-

tivity, and MDA [62]. Treatment with CAPE was seen to

decrease peritoneal MDA levels and antioxidant enzyme

activity in rats. Endometriotic lesions treated with CAPE

were histologically demonstrated to undergo atrophy and

regression, compared with untreated controls [62].

As previously mentioned, OS stimulates factors that in-

crease VEGF expression and promote angiogenesis of en-

dometriotic lesions. The green tea-containing compound,

epigallocatechin gallate (EGCG) has been evaluated as a

treatment for endometriosis due to its powerful antioxidant

and anti-angiogenic properties. Xu et al. conducted a study

in which eutopic endometrium transplanted subcutaneously

into a mouse model was used to compare the effects of

EGCG treatment on endometriotic implants to the effects

seen with vitamin E treatment or untreated controls [63].

Lesions treated with EGCG exhibited significantly down-

regulated VEGF-A mRNA. While the control endometrial

implants exhibited newly developed blood vessels with

proliferating glandular epithelium, the EGCG group demon-

strated significantly smaller endometriotic lesions and

smaller and more eccentrically distributed glandular epithe-

lium. Despite its widely studied benefits as a potent antioxi-

dant in the treatment of female infertility, vitamin E was

not shown to control or decrease angiogenesis compared

with baseline controls [63]. As EGCG was shown to signifi-

cantly inhibit the development of experimental endometriotic

lesions in a mouse model, its effectiveness as an oral

supplement in female patients to limit progression and

induce remission of their endometriosis should be further

investigated.

A recent study by Mier-Cabrera et al. utilized question-

naires to compare the dietary intake of antioxidant vitamins

and minerals by women with and without endometriosis.

Relative to healthy control subjects, women with endometri-

osis were found to have a significantly lower intake of vita-

mins A, C, E, zinc, and copper. However, intake of selenium

was not significantly different between the two groups stud-

ied [64]. A randomized control trial in which the effect of

antioxidant supplementation was studied revealed a signifi-

cant increase in the concentrations of serum retinol, alpha-

tocopherol, leukocytes, and plasma ascorbate after 2 months

of treatment. Antioxidant supplementation was also observed

to increase the activity of antioxidant enzymes (SOD and

GPx), while decreasing markers of oxidative stress such as

malondialdehyde and lipid peroxides [64]. These effects

were not observed in the control group, suggesting a role for

antioxidant supplementation in decreasing the levels of oxi-

dative stress afflicting patients with endometriosis-associated

infertility.


Unexplained Infertility

Elevated levels of ROS that disturb the redox balance

within the body may be the root cause of infertility in

women who do not have any other obvious cause. The ovum

released from the ovary, the zygote or embryo, and sper-

matozoa are very vulnerable to damage inflicted by OS [8].

Wang et al. compared ROS levels in peritoneal fluid be-

tween women undergoing laparoscopy for infertility evalua-

tion and fertile women undergoing tubal ligation and demon-

strated that higher levels of ROS exist in the peritoneal fluid

aspirated from patients with unexplained infertility compared

to that measured within the peritoneal fluid of fertile women

[65]. Polak et al. analyzed peritoneal fluid samples obtained

at laparoscopy and found that women with unexplained

infertility had increased MDA concentrations and TAS,

implicating the role of redox imbalance in its pathogenesis

[66].

Elevated ROS levels in patients with unexplained infertil-

ity implies exhausted antioxidant defense, resulting in the

inability to scavenge ROS and neutralize their toxic effects

[65]. This was substantiated by the results of a study in

which antioxidant concentrations were seen to be signifi-

cantly lower in the peritoneal fluid of patients with unex-

plained infertility compared with antioxidant levels in fertile

patients [47]. The link between decreased antioxidant status

and lowered fecundity suggests a potential use for antioxi-

dant supplementation to treat the high levels of ROS seen in

patients with idiopathic infertility.

Howard et al. described a group of patients with a history

of unexplained infertility and abnormal red blood cell mag-

nesium (RBC-Mg) levels. These patients’ RBC-Mg levels

were unresponsive to oral magnesium supplementation and

shown to be associated with deficient red blood cell glu-

tathione peroxidase (RBC-GSH-Px) activity [67]. Treatment

with 200 μg of oral selenium as selenomethionine and oral

magnesium for a period of 2 months was shown to normalize

RBC-Mg and RBC-GPx levels. This correlated with 100%

of previously infertile women in the treatment group

successfully achieving clinical pregnancies within 8 months

of normalizing their RBC-Mg [67].

Badawy et al. conducted a prospective, randomized,

double-blind, controlled trial comparing the effects of using

clomiphene citrate combined with glutathione-replenishing

N-acetyl cysteine versus clomiphene citrate alone in induc-

ing ovulation in women with unexplained infertility [68].

Despite the proposed benefits of strengthening the antioxi-

dant defense of women with unexplained infertility, no dif-

ference was seen in the rates of successful pregnancy be-

tween both groups [69]. Therefore, the use of N-acetylcysteine

to improve outcome during ovulation induction in women

with unexplained infertility is not justified.

THE USE OF ANTIOXIDANTS TO PROMOTE

HEALTHY PREGNANCY

Preeclampsia

Preeclampsia complicates 5% of all pregnancies and 11%

of first pregnancies and is associated with high maternal and

fetal morbidity and mortality [70]. Although the exact

mechanism by which preeclampsia develops is not known,

there is increasing evidence that corroborates the role of

OS in its etiopathogenesis. Reduced antioxidant response

[71, 72], reduced levels of antioxidant nutrients [73], and

increased lipid peroxidation [72, 73] have been observed in

patients with preeclampsia.

Preeclampsia is associated with defective placentation, in

which the dislodging of extravillous trophoblast plugs in the

maternal spiral arteries leads to the onset of blood flow into

the intervillous space, causing an oxidative burst that gener-

ates ROS. Abnormal placentation leads to reduced fetopla-

cental circulation secondary to decreased NO-mediated

vascular relaxation. Placental ischemia and hypoxia leads to

ischemic reperfusion injury to the placenta in which there is

release of cytokines and prostaglandins, which triggers the

endothelial cell dysfunction seen in preeclampsia. Hypoxia

and reperfusion injury leads to increased expression of

xanthine oxidase and NADPH oxidase and increased genera-

tion of SOD.

Poorly perfused placental tissue, abnormal lipid metabo-

lism, and resultant lipid peroxidation and redox imbalance

are established factors that promote the development of

preeclampsia. Numerous studies have demonstrated insuffi-

cient antioxidant defenses and overwhelming degrees of

ROS in women with preeclampsia [73]. Oxidative stress has

been evaluated by measuring elevated lipid peroxidation in

patients with preeclampsia, as well as elevated protein car-

bonyl concentrations, plasma MDA levels, and SOD activity.

Placental oxidative stress has been proposed as a promoter of

lipid peroxidation and endothelial cell dysfunction [74-78].

Increased lipid peroxidation may result in the consumption

of antioxidants and depletion of vitamin A, C, and E, eryth-

rocyte thiol, glutathione, and SOD.

There currently is no accepted method of preventing the

development of preeclampsia. Some trials have evaluated the

use of supplementation with antioxidants vitamin C and

vitamin E for prevention. Early intervention at 16–22 weeks

of pregnancy with supplementation of vitamin E and C re-

sulted in significant reduction of preeclampsia in the treat-

ment group [79]. However, supplementation in women with

established preeclampsia did not yield any benefit [80]. A

recent randomized trial failed to demonstrate any beneficial

effects of vitamin C and E supplementation in preventing

preeclampsia [81]. Poston et al. investigated the use of vita-

min C and E supplementation to reduce OS, limit the injury

of endothelial cells, and prevent or reduce disease severity of

preeclampsia. In this placebo-controlled trial in a diverse

group of high-risk women, antioxidant supplementation was

not associated with a reduction in the preeclampsia risk. In-

stead, treatment was associated with a significantly higher

incidence of complications, including low birth weight, ges-

tational hypertension, and increased need for intravenous

antihypertensive and magnesium sulphate therapy [82].

Although a causal relationship between OS and

preeclampsia is well-established, trials have failed to detect

any risk reduction for preeclampsia with antioxidant sup-

plementation. Trials powered to detect any smaller, more

subtle benefits of antioxidant therapy in preventing placental

pathology must be conducted before the routine use of anti-


oxidant vitamins by nulliparous, pregnant women can be

recommended.

Recurrent Pregnancy Loss

Abnormal placentation has been implicated in the patho-

genesis of both preeclampsia and miscarriage [71]. Recurrent

pregnancy loss is a condition in which three or more con-

secutive, spontaneous abortions occur [83]. It affects 0.5% to

3% of women of reproductive age. Recurrent pregnancy loss

has been associated with several factors, including maternal

age, genetic factors, endocrinologic factors, anatomic prob-

lems, and environmental toxins [83]. Moreover, the etiology

of recurrent pregnancy loss may be linked to chromosomal

abnormalities, uterine anatomic anomalies, immunologic

disorders such as antiphospholipid antibody syndrome, clot-

ting disorders, and sperm DNA fragmentation [6]. However,

50%-60% of recurrent pregnancy losses are considered idio-

pathic [84]. Oxidative stress may be implicated in this sub-

group as placental oxidative stress can lead to recurrent abor-

tions by impairing placental development and causing syn-

cytiotrophoblast degeneration [85]. During pregnancy both

extracellular and intracellular ROS production increases

sharply, originating from the developing embryo [84]. Thus,

the demand for enzymatic antioxidant defense is increased

in embryos and oocytes and their tubal and follicular fluid

microenvironments to successfully support a pregnancy and

the heightened OS it produces.

The increase in peripheral white blood cell count consist-

ing of polymorphonuclear leukocytes (PMNL) accounts for

the normal and natural rise in OS seen with normal preg-

nancy [86]. Fait et al. compared the changes in peripheral

PMNL counts during early pregnancy with the non-pregnant

state and found that in an uncomplicated early pregnancy,

peripheral PMNL and neutrophilia counts were elevated

[86]. The priming of the PMNL is known to cause an in-

creased release of ROS and OS, which occur in early preg-

nancy [86]. This conclusion is also supported by a study by

Safronova et al. that explored the changes in regulation of

oxidase activity of peripheral blood granulocytes in women

with habitual abortion. Researchers found that in the early

stages of pregnancy, the peripheral polymorphonuclear

leukocyte count increases [84].

A successful pregnancy requires a successful embryo

implantation and adequate uteroplacental circulation for ma-

terno-fetal exchange [84,87]. The sharp peak in the expres-

sion of OS markers in the trophoblast in normal pregnancy

may result in damage to protein, lipids, and DNA, which

may ultimately lead to cell death if this oxidative burst be-

comes excessive. Joanne et al. confirmed the contribution of

placental oxidative stress to early pregnancy failure, in dem-

onstrating significant increases in both morphological and

immunohistochemical evidence of syncytial oxidative stress

and damage in miscarried placental tissues. In a miscarriage,

disorganized placental blood flow may lead to hypoxia and

reperfusion injury with a resultant increase in the oxygen

tension within the early placenta [88].

Moreover, the increase in oxygen concentration seen

during normal early pregnancy renders the body more vul-

nerable to ROS formation, particularly within the mitochon-

dria where electron leakage from the enzymes of the respira-

tory chain occurs. This increase in oxygen concentration may

also lead to acute stress in the syncytiotrophoblast, with loss

of function and extensive degeneration [88]. The syn-

cytiotrophoblast is susceptible to OS because of its location

on the villous surface, which makes this tissue first to expe-

rience the increase in intervillous PO2. Also, the syn-

cytiotrophoblast possesses much lower concentrations of the

antioxidant enzymes than other villous tissues during early

gestation [87].

The connection between recurrent pregnancy loss and OS

is not only corroborated by the increase in ROS generation

seen in early pregnancy but also can be related to increased

levels of antioxidants needed to neutralize and scavenge

excessive ROS present in women affected by habitual

abortion. Wang et al. has reported that levels of plasma

vitamin E and lipid peroxides are increased in pregnant

women versus non-pregnant controls [89]. Lipid peroxida-

tion is an oxidative process that normally occurs at low

levels, and antioxidant function has the ability to control the

amount of oxidative stress it induces. However, when there

is a deterioration of the antioxidants’ capacity to neutralize

ROS, peroxidative activity occurs at the expense of polyun-

saturated fatty acids.

Simsek et al. evaluated the outcome of deficient antioxi-

dant defense in women with habitual abortion and demon-

strated elevated lipoperoxides and significantly decreased

vitamin A, E, and beta carotene in this population compared

with the control group. Their findings confirm that OS may

be involved in the pathogenesis of recurrent pregnancy loss

[90]. Sane et al. found that women undergoing induced or

spontaneous abortions exhibited a maximum rise in serum

lipid peroxidase levels immediately before the onset of abor-

tion and significantly depressed levels of serum lipid peroxi-

dase after the abortion was complete [91]. Jenkins et al. stud-

ied changes in antioxidant levels by measuring SOD levels,

which measure the amount of oxygen ion scavenger that may

result in increased ROS production [92]. This study found

that SOD levels were significantly lower in women whose

pregnancies ended in miscarriage than in healthy pregnant

women [92].

The glutathione and glutathione transferase family of

enzymes has been investigated in patients who experience

recurrent pregnancy loss [70, 71]. The glutathione peroxi-

dase reductase antioxidant system is an ROS scavenger, pre-

venting lipid peroxidation in cells and maintaining intracel-

lular homeostasis and redox balance [84]. Studies have

shown glutathione concentration and activity to be signifi-

cantly higher in women with recurrent miscarriage compared

with the glutathione concentration seen in women with nor-

mal pregnancies or in healthy, non-pregnant woman [93].

Red blood cell GSH-Px activity was not seen to differ be-

tween pregnant women and the control group, but were seen

to be significantly deficient in women that had a miscarriage

[93].

The bioavailability of selenium is directly related to the

activity of the GSH-Px system. GSH-Px catalyzes the reduc-

tion of hydrogen peroxide and hydroxyperoxides, acting as a

free radical scavenger and preventing the lipid peroxidation

of cell membranes and [93]. And because GSH-Px is an en-

zyme that is essential in cells to neutralize the effects of free


radicals, selenium concentrations may decrease in those pa-

tients at risk of recurrent miscarriage because selenium is

incorporated into the active site of GSH-Px [94,95]. Al-

Kunani et al. reported significantly lower concentrations of

selenium in the hair samples of women with recurrent preg-

nancy loss compared with controls [96]. Although this study

failed to confirm a difference in the overall blood plasma

selenium concentrations in women who had a miscarriage

compared with those with viable pregnancies, selenium lev-

els were found to be significantly higher in non-pregnant

women [96], confirming that pregnancy in general is accom-

panied by a state of increased OS.

In addition to the various female factors related to recur-

rent pregnancy loss, several male factors can contribute to

OS in these patients. A recent study by Gil-Villa et al. as-

sessed sperm factors possibly involved in early recurrent

pregnancy loss by evaluating and comparing standard sperm

parameters, lipid peroxidation of sperm plasma membranes,

antioxidant capacity of seminal plasma, and sperm chromatin

integrity in ejaculates from partners who have a history of

recurrent pregnancy loss with those from a control group

[97]. Reactive oxygen species in semen from sources such as

seminal leukocytes and morphologically abnormal sper-

matozoa is harmful to the functionality and structure of the

sperm. An increase in sperm DNA damage has been associ-

ated with increased risk of undergoing embryo loss and

augmented time to reach pregnancy [98]. This study success-

fully showed that a larger number of individuals of the recur-

rent pregnancy loss group presented alterations in sperm

concentration, motility, morphology, and thiobarbituric acid-

reactive substance production and lower antioxidant capacity

of seminal plasma than did the individuals in the control

group [97]. These findings may justify the use of antioxidant

therapy in the male partner in couples experiencing recurrent

pregnancy loss [97].

Given the array of evidence implicating OS in the patho-

genesis of recurrent abortion, many studies have focused on

the role of antioxidant supplementation in women affected

by recurrent pregnancy loss [99]. Poor dietary intake of vi-

tamins has been associated with an increased risk of miscar-

riage [100]. For instance, there are a variety of non-

enzymatic antioxidants, including vitamins C, E, and A, ly-

copenes, selenium compounds, lipoic acid, and ubiquinones

[101] that have the ability to scavenge ROS and ultimately

prevent OS and cellular damage [102]. An observational

study demonstrated an association between the risk of spon-

taneous early miscarriage and intake of green vegetables,

fruit, and dairy products [103]. Some evidence suggests that

reduced intake of micronutrients during pregnancy exposes

women to nutritional deficiencies and may affect fetal

growth [104]. Thus, adequate maternal nutrition, particularly

vitamin intake, may be an important factor in preventing

miscarriage [100]. Although the evidence in regards to ex-

actly what vitamin combinations, type, and amount are opti-

mal for a pregnant woman is insufficient, the use of any vi-

tamin supplements in pregnancy needs to be carefully moni-

tored and evaluated [100].

Vitamin C and E are two popular vitamins that may have

a potential role in alleviating the effects of OS in women

affected with miscarriages. Vitamin E’s principal function is

to protect against OS-related damage and thereby serve as an

antioxidant. In a normal pregnancy, vitamin E level naturally

increases, while in an abnormal pregnancy, vitamin E con-

centrations are lower [102]. Moreover, vitamin C levels in-

crease physiologically during pregnancy [102]. These occur-

rences suggest that perhaps vitamins C and E may play a role

in compensating for the oxidative burst during early preg-

nancy, reducing the risk of pregnancy loss [102]. However, it

is necessary to perform an accurate assessment of the appro-

priate type and dosage of vitamins that can be tolerated

without causing deleterious side-effects to the mother and

baby [100].

Homocysteine is a thiol-containing amino acid that is

involved in the sulfurylation and methylation metabolic

pathways and has been proposed to have pro-oxidant effects

[84]. Normally, plasma homocysteine levels fall during a

normal pregnancy. However, Del Banco et al. demonstrated

significantly elevated homocysteine levels in women with a

history of at least two consecutive miscarriages [105].

Quere et al. conducted a study evaluating the effect

of vitamin supplementation on pregnancy outcome in 25

women with recurrent early pregnancy loss and hyperhomo-

cysteinemia in the absence of any folate supplementation

during pregnancy [106]. This study involved hyperhomocys-

teinemic patients. Folic acid supplements are believed to

reduce a woman’s risk for having a baby with a neural-tube

defect. The potential for folic acid to prevent elevated homo-

cysteine levels and OS- induced miscarriage has been the

focus of many investigations. Szymanski et al. found that

women receiving folic acid supplements had better quality

oocytes and a higher degree of mature oocytes compared

with those who did not receive folic acid supplementation

[107]. However, the results of a study by Gindler et al. failed

to confirm that the consumption of folic acid decrease a

woman’s risk for miscarriage [108]. Thus, the role of folic

acid supplementation to prevent recurrent pregnancy loss is

inconclusive and requires further analysis.

Antiphospholipid (aPL) antibody syndrome is a known

autoimmune cause of recurrent pregnancy loss [84]. The

pathophysiology of antibody formation is still not clear;

however, OS has been proposed to have a role in the forma-

tion of these antibodies [84]. Omega-3 supplements have

been used in prevention of recurrent miscarriage with an-

tiphospholipid syndrome [109]. Del Bianco et al. studied the

effects of omega-3 fatty acid supplementation in women

with three or more miscarriages associated with antiphos-

pholipid syndrome [105]. All of the subjects in this trial

achieved successful pregnancy with no further miscarriages

[105]. Although the results of this study are promising, the

safety and efficacy of omega-3 supplementation must be

confirmed by follow-up trials.

Melatonin, a hormone that acts as a powerful agent

against ROS, has been hypothesized to have properties es-

sential for successful pregnancy and prevention of spontane-

ous abortion [110]. Tamura et al. propose that deficient

melatonin production in early pregnancy may be related to

the development of spontaneous abortion as melatonin is a

free-radical scavenger and antioxidant that is known to

physiologically increase to compensate for the oxidative

burst during normal pregnancy [110]. Therefore, the safety


and efficacy of melatonin supplementation to combat OS and

prevent recurrent pregnancy loss should be further investi-

gated.

EXPERT COMMENTARY

The purpose of this article was to discuss the role of

antioxidant supplementation in the treatment of various

gynecological and obstetric conditions known to contribute

to female infertility and poor pregnancy outcome. The

association between high levels of uncontrolled oxidative

stress and polycystic ovarian syndrome, endometriosis,

unexplained infertility, preeclampsia, and recurrent

pregnancy loss has been well established by numerous

studies that have measured various biomarkers of redox

status. As high degrees of reactive oxygen species and low

antioxidant status has been implicated in these diseases,

treatment based on strategies to boost the exhausted

antioxidant defense of the female reproductive micro-

environment are intuitive. This approach seems especially

plausible in light of the fact that oral antioxidant supple-

mentation in males has been proven effective to treat male

infertility and is widely employed in current clinical practice.

However, reports regarding the safety and efficacy of oral

antioxidant supplementation in the treatment of female

infertility are conflicting. Additional studies using double-

blinded, randomized, controlled trials are needed to further

evaluate the potential use of antioxidants to treat female

reproductive disease.

FIVE YEAR VIEW

There is a need for continued investigation of the efficacy

and safety profiles of various oral antioxidant supplements

before this modality of treatment can be relied upon to

modulate the levels of oxidative stress that contribute to

infertility and abnormal pregnancy in women with

obstetrical and gynecologic disease. Observational studies

and randomized control trials have identified several

antioxidant therapies of interest which have demonstrated

striking promise in the prevention and treatment of female

reproductive disease. However, it is still unclear as to what

types or combinations of therapy as well as the amounts and

dosing that are optimal for women, particularly during

pregnancy. It is necessary to conduct further studies to

identify any possibility of deleterious side effects of

antioxidants on mothers and their unborn baby. Despite the

fact that oxidative stress is strongly implicated in the

etiopathogenesis of preeclampsia, the literature fails to show

strong evidence to support the efficacy of antioxidant

supplementation in preventing or treating preeclampsia.

Further investigation with randomized controlled trials

powered to detect subtler effects may reveal any previously

hidden benefits of antioxidant therapy for preeclampsia. In

addition to analyzing the effect of antioxidant supple-

mentation in women to improve fertility and pregnancy

outcome, the benefits of antioxidant supplementation in male

partners of couples with infertility and recurrent pregnancy

loss should be studied.

KEY ISSUES

• Oxidative stress (OS) occurs when the generation of re-

active oxygen species (ROS) and other radical species

overrides the scavenging capacity of antioxidants, either

due to excessive ROS production or an inadequate avail-

ability of antioxidants.

• At controlled levels, OS facilitates the following

physiological female reproductive functions: oocyte

maturation, folliculogenesis, ovarian steroidogenesis,

luteolysis, ovulation, cyclical endometrial changes, and

menstruation.

• At higher levels, OS is implicated in pathological pro-

cesses of the female reproductive tract that contribute to

infertility and poor pregnancy outcome, such as polycystic

ovarian syndrome (PCOS), endometriosis, unexplained

infertility, preeclampsia, and recurrent pregnancy loss.

• Antioxidant treatment of PCOS: N-acetyl cysteine may

improve glucose control and peripheral insulin sensitivity

in hyperinsulinemic patients. Oral hypoglycaemic agent

rosiglitazone and anti-androgenic oral contraceptives

have been shown to reduce parameters of OS in hyper-

insulinemic patients.

• Endometriosis: The antioxidants catalase, RU486,

curcumin, melatonin, and catechins may have anti-pro-

liferative and anti-angiogenic effects capable of halting

disease progression.

• Selenium supplementation of women with unexplained

infertility has been shown to normalize patient’s RBC-

Mg levels and result in clinical pregnancy after 8 months

of treatment.

• Despite the well-established causal relationship between

OS and preeclampsia, studies have failed to detect any

risk reduction for preeclampsia with vitamin C and vita-

min E supplementation.

• The antioxidants folic acid, melatonin, and omega-3 fatty

acids (particularly in women with antiphospholid anti-

body syndrome) have been investigated for their use in

preventing recurrent pregnancy loss. Further studies to

confirm the safety and efficacy of these compounds are

needed.

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Role of Oxidative Stress in Polycystic Ovary Syndrome

Joo Yeon Lee1, Chin-Kun Baw

1, Sajal Gupta

1, Nabil Aziz

2 and Ashok Agarwal

1,*

1Center for Reproductive Medicine, Cleveland Clinic, Cleveland, USA;

2Liverpool Women’s Hospital, Liverpool, UK

Abstract: Polycystic ovary syndrome (PCOS) is a multifactorial disorder affecting many women of reproductive age,

typically due to hyperandrogenemia, hyperinsulinemia, and enigmatic genetic factors. The complex nature of PCOS is

reflected in the broad spectrum of the disorder’s clinical presentation, including metabolic and reproductive disorders. As

a result, while the European Society for Human Reproduction and Embryology and the American Society for Reproduc-

tive Medicine (ESHRE/ASRM) have agreed on a consensus definition of PCOS to help clinical investigators, the condi-

tion is recognized to have multiple clinical phenotypes.

Oxidative stress (OS) occurs when destructive reactive oxygen species (ROS) outbalance antioxidants, causing DNA

damage and/or cell apoptosis. Moreover, reactive nitrogen species (RNS), such as nitrogen oxide (NO) with an unpaired

electron also are highly reactive and toxic. In a quest to delineate the role of OS in the pathogenesis of PCOS, investiga-

tors have examined patients with the disorder for a wide array of OS biomarkers, including malondialdehyde (MDA),

protein carbonyl, total antioxidant capacity (TAC), superoxide dismutase (SOD), glutathione peroxidase (GPx), and

glutathione (GSH).

Keywords: Polycystic ovary syndrome (PCOS), oxidative stress (OS), insulin resistance, hyperandrogenism, reactive oxygen

species (ROS), nitric oxide synthase (NOS).

INTRODUCTION

PCOS is one of the most common endocrinological

pathologies in women during their reproductive years exhib-

iting a wide spectrum of clinical manifestations. PCOS

women commonly have features of hyperandrogenism and

the primary cause of PCOS is probably multifactorial in

origin [1]. Increased insulin resistance is viewed as a central

feature of PCOS irrespective of the body mass index (BMI).

The resulting hyperinsulinemia together with central obesity,

which is frequently encountered in PCOS patients, are com-

ponents of metabolic syndrome. Metabolic syndrome, which

affects one in five people, increases the risk of developing

cardiovascular disease and type II diabetes, and its preva-

lence increases with age. PCOS patients have been reported

to have markers of cardiovascular and endothelial disorders

in addition to the familiar features of hirsutisms, acne, and

anovulatory infertility [2].

Oxidative stress is commonly referred as the imbalance

between oxidants and antioxidants. When the imbalance fa-

vors oxidants, generation of excessive amounts of reactive

oxygen species harm our body in various ways [3] through

the generation of excessive amounts of reactive oxygen spe-

cies. In other words, reproductive cells and tissues will re-

main stable only when antioxidant and oxidant status is in

balance. Oxidative stress, which is generally known to be

present in women with PCOS regardless of whether they are

lean or have metabolic abnormalities, has been documented

in infertile women [4]. The present review study provides an

*Address correspondence to this author at the, Center for Reproductive

Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195,

USA; Tel: 216-444-9485; Fax: 216-445-6049;


overview of current knowledge in PCOS and ROS’ roles in

women during their reproductive years, exhibiting a wide

spectrum of clinical manifestations in PCOS women, which

have been investigated more actively in recent years.

DEFINITION AND DIAGNOSIS OF POLYCYSTIC

OVARY SYNDROME

The definition of PCOS has been controversial and still

remains unclear due to the syndrome’s heterotrophic nature.

Following the first report on women with polycystic ovaries

in 1935, the term “polycystic ovarian syndrome” was estab-

lished as more clinicians noticed the correlations between

hyperinsulinemia, androstenedione, testosterone levels, and

PCOS [5]. However, a wide spectrum of clinical manifesta-

tions, including impaired glucose tolerance [6], prevalence of

type II diabetes [7], increased risk of hypertension and dis-

lipidemia, and elevated endothelial dysfunction [8] further

complicated the debate on defining PCOS. The presence of

clinical or biochemical hyperandrogenism or polycystic ova-

ries with regular cycles was broadly interpreted as PCOS [9,

10]. As a result, there were no widely accepted diagnostic

criteria available until the National Institute of Health (NIH)

criteria were introduced in 1990.

In 1990, the NIH established diagnostic criteria that char-

acterize PCOS as the combination of oligomenorrhea or

amenorrhea and hyperandrogenemia in the absence of non-

classical adrenal hyperplasia, hyperprolactinemia, and thy-

roid dysfunction [11]. These criteria, however, did not in-

clude ultrasound morphology of polycystic ovaries in the

belief that broader clinical diagnostic criteria were in need

for clinicians to accurately diagnose multi-etiologic PCOS.

In Europe, clinicians maintained that the ultrasound appear-

ance of polycystic ovary was an essential criterion to diag-

Role of Oxidative Stress in Polycystic Ovary Syndrome Current Women’s Health Reviews, 2010, Vol. 6, No. 2 97

nose PCOS. As a result of the continued dialogue between

the ESHRE and the ASRM, a consensus document was pro-

duced, commonly referred to as the Rotterdam 2003 criteria

for defining PCOS.

The new definition of PCOS suggested that the diagnosis

of PCOS must be based on the presence of two of the three

following criteria: (i) oligo- and/or anovulation, (ii) clinical

and/or biochemical signs of hyperandrogenism, and (iii)

polycystic ovaries on ultrasonography and exclusion of re-

lated disorders [12, 13]. The ultrasound criteria for polycys-

tic ovaries is defined as the presence of 12 or more follicles

measuring 2 to 9 mm in diameter and /or an increased ovar-

ian volume > 10 cm3 on transvaginal ultrasound scanning.

PCOS is diagnosed even when only one polycystic ovary is

present [14]. However, these criteria do not apply to women

taking oral contraceptive pills since their use modifies ovar-

ian morphology that slightly different biochemical findings

were included in Rotterdam criteria (Table 1) [14]. While

NIH criteria considered total testosterone, free testosterone,

androstenedione, and DHEA as biochemical markers, the

2003 Rotterdam criteria now consider free androgen index,

total testosterone, and DHEA as diagnostic biochemical

markers. Moreover, the Rotterdam criteria recognize the role

of genetics in PCOS and encourage clinicians to take family

histories to identify PCOS individuals more effectively [12,

13]. Compared with the NIH definition, the new definition

introduced two new phenotypes: (i) ovulatory women with

polycystic ovaries and hyperandrogenism, and (ii) oligo-

anovulatory women with polycystic ovaries without hyper-

androgenism. This has stimulated more debate as to where

the boundaries should be set in diagnosing PCOS [1].

Table 1. Comparison of Two Established Diagnostic Criteria

of PCOS

NIH Criteria (1990) Rotterdam Criteria (2003)

(i) Oligomenorrhea or amenrrhea

(ii) Hyperandrogenemia in the

absence of related disorders

(i) Oligo- and/or anovulation

(ii) Clinical and/or biochemical signs

of hyperandrogenism

(iii) Polycystic ovaries on

ultrasonography and exclusion of

related disorders

Both (i) and (ii) must be present Two of three criteria must be satisfied

Diagnostic markers: total

testosterone,free testosterone,

androstenedione and DHEA

Diagnostic markers: free androgen

index, total testosterone, and DHEA

CLINICAL MANIFESTATIONS AND EPIDEMIOL-

OGY OF POLYCYSTIC OVARY SYNDROME

PCOS occurs in 4-8% of women during their repro-

ductive years, and it is the most frequent endocrine disease

in women [8]. Approximately one in 15 women experiences

PCOS [1], and an enlarged ovary is observed on ultrasound

in 22% of women [14] during their reproductive years. Other

common clinical manifestations include oligomenorrhea,

hyperandrogenism, acanthosis nigricans, insulin resistance,

reproductive aberration and obesity (Fig. 1).

Oligomenorrhea

PCOS is an ovarian dysfunction caused by androgens,

which inhibit folliculogenesis and lead to polyfollicular

morphology, which then disturbs the menstrual cycle and

leads to anovulation [15]. Among women experiencing oli-

goanovulation, 65-87% have PCOS [16]. The wide range

may be attributed to the heterogeneous and complex nature

of PCOS as well as the variation in criteria used for diagno-

sis. According to Balen et al. (1995), among women with

PCOS, 47% experience oligomenorrhea [17], defined as six

or fewer menses annually. A majority of women with PCOS

experience irregular menstrual cycles, of which the most

common manifestation is infrequent menstruation related to

anovulation [14]. In a study of 173 women, polycystic ova-

ries were observed on pelvic ultrasound scan in 87% of

women who also suffered from oligomenorrhea [9]. Moreo-

ver, some evidence indicates the presence of oligomenorrhea

to be highly suggestive of PCOS in adolescents [18].

Hyperandrogenism (Hirsutism, Acne, and Male Pattern

Alopecia)

Hypersecretion of androgens is the most widespread bio-

chemical feature in PCOS women [19]. PCOS accounts for

70-80% of hyperandrogenism and is associated with elevated

serum total or free testosterone concentrations [20]. Hyper-

androgenism can manifest as hirsutism, acne, and male pat-

tern alopecia. Whether hyperandrogenemia affects oxidant

and antioxidant status in women with PCOS is unknown.

However, in a human study, ROS generation was demon-

strated to directly correlate with testosterone and andros-

tenedione [21], suggesting that ROS induces OS, which may

consequently contribute to hyperandrogenism in PCOS

women. Plasma testosterone or androstenedione and ROS

generation are associated, suggesting that OS may directly

stimulate hyperandrogenism. In vitro studies have demon-

strated that OS stimulates the androgen-producing ovarian

steroidogenic enzymes, while antioxidants such as statins

suppress these enzymes [22].

PCOS is present in 60-90% of women with hirsutism [16,

17, 23, 24] as increased androgen production leads to hirsu-

tism and acne. Among women with PCOS, 35% have acne,

and 6% express alopoecia [17]. An inflammatory disorder of

the hair follicle, acne is associated mainly with elevated lev-

els of sebaceous secretion [25, 26]. Among women of mixed

ethnicities with androgenic alopecia, 67% had polycystic

ovaries compared with the 27% expressed in the BMI-,

waist-hip-ratio- and age-matched control group [27]. Also,

21% of the women with androgenic alopecia demonstrated

hirsutism, while this is true for only 4% of the BMI-, waist-

hip-ratio- and age-matched control group.

Ovarian invasion by macrophages has been observed in

PCOS women [28]. Moreover, mononuclear cells in the

polycystic ovary activated by glucose can generate OS that

could stimulate a local inflammatory response, which could

in turn induce the generation of ovarian androgen in PCOS

women [29]. More specifically, theca cells in the ovarian

98 Current Women’s Health Reviews, 2010, Vol. 6, No. 2 Lee et al.

tissue overproduce androgens and insulin receptors and lead

to hyperandrogenism [31]. Moreover, some researchers have

investigated genetically programmed androgen secretion by

the ovary during early childhood or puberty, which may con-

tribute to pathophysiology in PCOS women [30].

Acanthosis Nigricans

Acanthosis nigricans, a disorder seen as dark and velvety

skin with hyperpigmentation and papillomatosis, manifests

itself normally in the axillae, skin flexures, and nape of the

neck. Among women with PCOS, only 3% express acantho-

sis nigricans [17], which is associated with insulin resistance

and, consequently, hyperinsulinemia [32].

Insulin Resistance

Increased oxidant status has been shown to correlate with

insulin resistance. Insulin resistance can be found in 25-60%

of women with PCOS [33]. The wide range may be due to

varying diagnostic criteria, the heterogeneous nature of

PCOS, and ethnic variations. Insulin resistance (IR) and hy-

perglycemia both can increase OS levels, although higher

levels of total oxidant and antioxidant status have been dem-

onstrated in non-obese PCOS patients without IR [34]. Hy-

perglycemia has been demonstrated to increase lipid peroxi-

dation and lower antioxidant levels [35]. A significantly

negative correlation between MDA levels, a marker of OS,

and insulin sensitivity, as well as MDA levels and GSH (an-

tioxidant) levels has been demonstrated [4]. This may imply

that insulin resistance decreases antioxidant levels and

increases lipid hydroperoxide (LPO).

Insulin resistance encourages oxidative stress because

hyperglycemia and higher levels of free fatty acids lead to

ROS production. An increase in ROS generation resulting

from hyperglycemia has been observed in women with

PCOS [36], and insulin infusion in obese individuals has

been shown to inhibit ROS production [37]. Thus, insulin

may defend against pro-inflammatory responses to hypergly-

cemia by acting as an anti-inflammatory agent.

Approximately 75% of obese PCOS women have IR and

hyperinsulinemia [38]. However, insulin resistance inde-

pendent of obesity can play a role in PCOS. Young, non-

obese PCOS patients with high triglyceride levels as the only

dyslipidemic feature have demonstrated high oxidative levels

[2]. Furthermore, 20-40% of women with PCOS have im-

paired glucose tolerance [6], and women with PCOS exhibit

higher levels of type II diabetes (T2DM) than non-PCOS

controls (15% vs 2-3% in normal women) [7]. Insulin resis-

tance and hyperinsulinemia also are features of metabolic

syndrome, and women with PCOS exhibit an increased risk

of hypertension, dyslipidemia, elevated plasminogen inhibi-

tor type 1, elevated endothelin, endothelial dysfunction, and

cardiovascular disease similar to the risks associated with

metabolic syndrome [8].

Reproductive Aberration (Irregular Menses, Infertility,

Miscarriage)

PCOS is a known cause of menstrual irregularity as well

as infertility. Most commonly, irregular menstruation is as-

Fig. (1). Schematic description of various pathogenic factors that manifest PCOS in women of reproductive age. Such patients are at risk of

developing a spectrum of disease phenotypes.


sociated with anovulation. Between 30-40% of women with

amenorrhea are found to have PCOS [39].

Among PCOS women, more than 60% manifest infertil-

ity (primary/secondary), and 19% experience amenorrhea

[17]. Moreover, pregnancy in PCOS women is more likely to

be complicated by gestational diabetes, preeclampsia, preg-

nancy hypertension, and preterm labor leading to miscarriage

[40]. Obesity in PCOS further increases resistance to ovula-

tion induction treatment since obesity is associated with a

disturbed pattern of gonadotrophin-releasing hormone pro-

duction resulting in chronic elevation of tonic LH level with

negative consequences on follicular development in the

ovary [40].

Obesity

Obesity is more common in women with PCOS, and it

can lead to severe hyperandrogenism. According to Franks

(1989), 35% of women with PCOS are obese [10]. Increas-

ing visceral adipose tissue and/or its activity may contribute

to androgenic modulation [41]. Androgen excess is a known

contributor to visceral adiposity in women, which provides

high metabolically active tissue that stimulates the ovaries

and adrenal to proceed with androgenization [15]. Both

androgens and IR seem to have a combined effect on upper

body adipose distribution. Obesity contributes to PCOS, as it

affects hyperandrogenism and IR. In fact, the most influen-

tial factor in endocrinologic and metabolic disturbances in

women with PCOS has been shown to be an elevated BMI >

25 [42].

Central obesity is also related to increased oxidant status

[4]. Obesity has been shown to play an important role in ele-

vated oxidative stress, which contributes to IR [43]. PCOS

patients who are obese express higher levels of insulin resis-

tance than lean PCOS patients [8]. The study by González et

al. (2006) shows that compared with lean controls, PCOS

women express higher p47phox

levels independent of obesity.

In oxidative stress, p47phox

plays a role as part of enzymes

that produce the superoxide radical. Increase in p47phox

ex-

pression decreases insulin sensitivity. It also has been shown

to be greater in PCOS women versus controls and in obese

PCOS and non-PCOS women versus lean PCOS women and

non-PCOS women [29]. Thus, increased obesity may deter-

mine ROS-induced OS in obese PCOS women. PCOS also

affects insulin performance, as increase in abdominal fat is

associated with insulin resistance [1]. Slightly reducing the

body weight of anovulatory, obese women was demonstrated

to restore ovulation and increase insulin sensitivity by 71%

[44]. Weight loss also reduces testosterone concentration,

improves menstrual function and conception rates, decreases

the likelihood of miscarriage, and increases sex hormone-

binding globulin (SHBG) concentration [45-48].

Aside from obese PCOS women, lean PCOS women can

express increased levels of abdominal adiposity [21]. In

a study of 16 women with PCOS and 15 women without

PCOS, mononuclear cells produced elevated levels of ROS

in response to hyperglycemia in PCOS women, independent

of obesity [29].

ETIOLOGY OF POLYCYSTIC OVARY SYNDROME

Pathogenesis of PCOS

Women with PCOS manifest a wide spectrum of symp-

toms and clinical features, including hyperandrogenism, ovu-

latory disturbances and polycystic ovaries and metabolic

syndromes (Fig. 1). The latter is linked to insulin resistance

and obesity that are often associated with PCOS [6, 49, 50].

In other words, the heterogeneity of PCOS is reflected in the

multiplicity of factors such as insulin resistance, hyperan-

drogenism, and dysfunctional gonadotrophin dynamics that

must come into play to manifest the disorder, and no single

mechanism accounts for all clinical and biochemical forms

of this syndrome. Moreover, environmental factors such as

diet or stress also can trigger underlying risk factors and

cause the development of PCOS. The most commonly dis-

cussed causes of PCOS can be categorized into three mecha-

nisms: (i) insulin resistance and hyperinsulinemia, (ii) hyper-

androgenemia and (iii) genetic factors.

(i) Insulin Resistance and Hyperinsulinemia

Insulin resistance, in which an abnormally high amount

of insulin (hyperinsulinemia) is required to initiate a cellular

response, is the most commonly encountered clinical disor-

der in both obese and non-obese PCOS women [51]. An oral

glucose tolerance test is recommended for PCOS patients

with BMI greater than 27 kg/m3 [14] because of the high risk

for developing impaired glucose tolerance and diabetes in

obese PCOS women (31% of obese PCOS patients vs.

10.3% of lean PCOS patients and 7.5% of obese PCOS

patients vs. 1.5% of lean PCOS patients, respectively) [6].

Women with IR display increased fasting insulin level com-

pare with controls of similar age and body weight. As a re-

sult, clinical and molecular research has focused on insulin

receptor and post-receptor defects [19]. Some studies have

correlated severity of hyperinsulinemia to the degree of

clinical manifestation.

Insulin signaling, mediated through a protein tyrosine

kinase receptor, has been investigated in PCOS patients.

Dunaif et al. (1997) reported excessive serine phosphoryla-

tion, which inhibits insulin receptortyrosine kinase activity,

of insulin receptors in insulin- resistant PCOS patients.

Moreover, adverse roles of serine phosphorylation in insulin

signaling were further supported by the mechanism of tumor

necrosis factor (TNF)- -mediated insulin resistance in obese

women [53] and P450c17 enzyme activity leading to hyper-

androgenism in PCOS women [54]. Hyperinsulinemia also

potentiates the effects of LH on theca interstitial cells, result-

ing in increased androgen production [19] while arresting the

follicular maturation process [55, 56].

(ii) Hyperandrogenemia

The ovary is the primary source of hyperandrogenism in

PCOS, driven by increased levels of LH hormone as ovarian

dysfunction causes LH insensitivity [57]. The increase in

basal LH level is the result of a disrupted hypothalamic-

pituitary-gonadal axis [58]. Moreover, hyperandrogenemia

impairs progesterone’s ability to slow down the gonadotro-

pin-releasing hormone (GnRH) pulse [58]. As a result,

elevated GnRH pulses further increase LH level and reduce


FSH, which converts excess androgen into estrogens via

aromatase activity in normal women [15]. The elevated LH

level arrests follicular cells and stimulates theca-cell-

mediated androgen synthesis. Consequently, the increased

androgenic environment in the ovary impairs follicular matu-

rations [8].

Some studies have shown hyperandrogenemia and

hypoestrogenemia in PCOS-like conditions as the result of

ovarian steroidogenic enzyme deficiencies such as 3 -

hydroxysteroid dehydrogenase type II and aromatase [59] In

other words, follicles that are unable to change their sur-

roundings from androgen-dominant to estrogen-dominant

environments will not acquire normal follicular growth and

manifest as a polycystic ovary, a characteristic feature of

PCOS. Adrenal steroidogenesis dysfunction also has been

implicated in establishing a state of hyperandrogenemia in

PCOS. When adrenal steroidogenesis dysfunction results in

reduced cortisol production, adrenocorticotrophic hormone

(ACTH) production is increased to maintain normal serum

cortisol level [8]. Increased ACTH production consequently

stimulates adrenal androgen excess [8]. Thus, hyperandro-

genism in PCOS women is caused by synergic aberration in

steroidogenesis of both ovary and adrenal glands.

As stated above, hyperinsulinemia drives increased an-

drogen production by theca cells [60]. Studies have shown

that bilateral oophorectomy, the surgical removal of both

ovaries [61, 62], the administration of GnRH-agonists to

mimic an increased GnRH pulse [63], or antiandrogenic

compounds [64] did not alter hyperinsulinemia and IR in

PCOS women. Evidence supports disordered insulin action

as a predecessor to development of hyperandrogenemia in

PCOS patients.

(iii) Genetic Factors

Given that the incidence of PCOS is 6-8% in the general

population [65], 35% of premenopausal mothers and 40% of

sisters of PCOS women [65] suggests a probable role for

genetics in PCOS. However, no conclusive role for any gene

has been defined. This may be due to the limited selection of

candidate genes, PCOS’s heterogeneous nature, or lack of

knowledge of disease pathophysiology and the role of envi-

ronmental and lifestyle factors such as diet and obesity in

modifying gene expressions [66]. Moreover, lack of univer-

sal male patterns and reliable markers for PCOS in women

further challenge investigations of the syndrome’s genetic

origin. The proposed male phenotypes, such as increased

serum dehydroepiandrosterone sulfate concentrations in

brothers of PCOS women and insulin resistance in fathers

and brothers of PCOS women still require further investiga-

tion for their practical uses [67]. However, more than 100

candidate gene approaches have selected genes based on

their hypothetical roles in PCOS and target four general

areas: (i) steroid biosynthesis and action; (ii) gonadotrophin

synthesis and action; (iii) weight and energy regulation; and

(iv) insulin secretion and action, as well as several areas

added recently such as cardiovascular disease via inflamma-

tion, hypercoagulation, and blood pressure [66]. Of those,

genes involved in steroidogenic abnormalities and insulin

metabolism aberrations have been investigated the most due

to their importance in PCOS’ clinical manifestations.

Hyperandrogenemia in PCOS women is due partially to

intrinsic defects in metabolic pathways. Because hyperan-

drogenism is prevalent among PCOS patients, genes in-

volved in steroidogenesis such as cytochrome P450 17-

hydroxylase/17,20-desmolase (CYP17) and the aromatase

gene (CYP19) have been investigated. Upregulations of 3 -

hydroxysteroid dehydrogenase and17-hydroxylase/17,20-

lyase activities in PCOS women [68] are reflected in in-

creased mRNA expression and an enhanced promoter region

of CYP17 genes of the theca cells in young girls compared

with controls [69]. On the other hand, a functional mutation

of the CYP19 aromatase gene leads to excess circulating

androgens in PCOS women [70-72]. However, family stud-

ies have not yet shown a correlation between CYP19 and

PCOS [73], and more evidence is needed to confirm this

hypothesis.

Genes involved in insulin signal transduction have been

investigated. Variable number tandem repeat (VNTR) poly-

morphism in the promoter region of the insulin gene at 11p15.5

has shown quite confusing results. While Waterworth et al. (1997) [74] found strong correlations between class III

variable number tandem repeats of the insulin gene allele and

PCOS, Urbanek et al. (1999) [75] did not find evidence to

link the class III allele and PCOS. The insulin receptor gene

is another probable candidate gene since it seems to be si-

lenced in molecular studies [19]. However, defective insulin

receptor function is observed in the presence of serine phos-

phorylation instead of tyrosine phosphorylation in insulin

receptors [52], suggesting more studies are required on

downstream targets of the insulin receptor gene [19].

Hormonal Markers in PCOS Patients

Hormonal markers in PCOS women are viewed as a way

to evaluate steroidogenesis. The most commonly encoun-

tered markers include, but are not limited to LH, FSH, estro-

gen, sex hormone-binding globulins (SHBG), insulin-like

growth factor -1 (IGF-1), total/free testosterone, andros-

tenedione, dehydroepiandrosterone (DHEA) and DHEA me-

tabolite DHEAS, anti-Mullerian hormone (AMH), and 17-

hydroxyprogesterone [8, 19, 60, 76].

Testosterone production and high insulin level in PCOS

women directly down-regulate SHBG synthesis by the liver,

which makes a low SHBG level a good indicator of insulin

resistance [77]. SHBG has strong binding affinity to testos-

terone and dihydrotestosterone thus controlling androgen

bioavailability in serum [78]. Reduced SHBG results in

increased levels of bioavailable testosterone. Since serum-

bound testosterone (T) is the most frequent androgen

measured to diagnose hyperandrogenemia, the reduction in

the proportion bound to SHBG makes the assessment some-

what unreliable [76]. As a result, the free androgen index

(FAI=T/SHBG * 100%) or the association constant for

testosterone binding to SHBG and albumin are utilized to

account for these metabolic changes [79]. Free T also may be

measured directly via equilibrium dialysis [76]. Although

other androgens such as androstenedione (A4) or total testos-

terone may also be utilized to diagnose hyperandrogenemia,

no studies have indicated their superiority as surrogate mark-

ers. For example, Knochenhauer et al. (1998) showed that

only 2 out of 11 (18%) PCOS women had abnormally higher


thyroxine (T4) level, which is blunted by high testosterone

level.

Insulin binds to IGF-1 receptors on theca cells with sig-

nificantly higher affinities than IGF-1 [81]. Hepatic IGF-1

binding protein secretion also is inhibited in PCOS women,

leading to excessive free IGF-1, which is suspected to play a

role in the abnormal androgenesis of theca cells along with

high LH [82]. IGF-1 and insulin further increase mRNA of

P450c17, leading to increased androgen biosynthesis in

ovary and adrenal glands [8]. The use of insulin-sensitizing

agents such as metformin has been demonstrated not only to

reduce circulating insulin concentration but also to reduce

ovarian androgen biosynthesis [83].

DHEA secreted from the adrenal zona reticularis is an-

other actively investigated hormonal marker in PCOS

women. However, DHEA has several shortcomings as a sur-

rogate marker due to its diurnal variation, intra-subject varia-

tion and low serum concentration [84]. On the other hand,

DHEAS, DHEA’s sulfate ester, is not subject to these varia-

tions, making it a more preferred marker to assess increased

adrenal androgen production [85]. In clinical studies, ap-

proximately 20-70% of PCOS women manifest excess

DHEAS serum levels [86-88]. However, DHEAS levels de-

crease with age [88], and levels are controlled by the activity

of DHEA sulfotransferase [89]. Moreover, ethnicity also

may affect circulating DHEAS levels with lower circulating

levels of DHEAS is reported in Mexican American group

compared with Caucasian American controls [90]. Conse-

quently, in PCOS patients with high DHEAS measurements,

only 10% will actually have hyperandrogenaemia [76]. Thus,

DHEAS measurements should be interpreted with caution

[76].

AMH is secreted from the Sertoli cells of the fetal testis

to inhibit female Mullerian ducts development in a male em-

bryo. It also is produced by the granulosa cells of small an-

tral and pre-antral follicles to disrupt FSH’s aromatase in-

duction in the ovary [91], compromising normal ovulation in

PCOS women. Studies have shown that AMH levels are sig-

nificantly higher in PCOS women [92] and confirmed that

granulosa cells release more AMH when cultured in vitro

[93]. Moreover, AMH level was positively correlated with

antral follicle counts [94], suggesting that serum AMH

measurements may serve as an alternative diagnostic tool

when ultrasonography is not an option inpatients younger

than 35 (1). While AMH’s role in folliculogenesis is gener-

ally established, its association with circulating androgens is

more controversial. Pigny et al. (2003) [95] found a correla-

tion between AMH and testosterone and androstenedione

only in PCOS women, while Piltonen et al. (2005) [96]

reported AMH levels in both PCOS women and controls

were correlated with both testosterone and androstenedione.

In conclusion, no hormonal marker can be used as the

sole criterion to diagnose PCOS. Hormonal assays may serve

as supplementary diagnostic tools for clinicians and scien-

tists.

INTRODUCTION TO OXIDATIVE STRESS

Unstable and highly reactive, free radicals achieve stabil-

ity by stealing electrons from nucleic acids, proteins, lipids,

carbohydrates, and other nearby molecules [97], thus induc-

ing cellular damage. The two major forms of free radicals are

ROS and RNS. Free electrons typically form reactive oxygen

species during oxygen reduction as a by-product of natural

metabolic pathways [98]. Most of the mitochondrial genera-

tion of ROS occurs at complexes I (where NADH dehydro-

genase acts), and III (where the ubiquinol to ubisemquinone

to ubiquinone conversion occurs) of the electron transport

chain (ETC) [99].

Of inspired oxygen, 98% is reduced during lipolysis and

chemical energy generation, and 2% is incompletely re-

duced, leading to three major forms of ROS [97]. The three

main forms of reactive oxygen species are the superoxide

radical [O2-

], hydrogen peroxide [H2O2], and hydroxyl [HO·].

Superoxide is formed through electron leakage at the elec-

tron transport train. At complex IV, molecular oxygen nor-

mally is converted to water, but it may gain an extra electron

as they are being passed down the ETC during ATP genera-

tion [100]. Hydrogen peroxide is formed from either super-

oxide dismutation or oxidase enzymes. The most reactive

form is the hydroxyl ion, as it has three extra electrons.

Through alteration of purines and pyramidines it can cause

strand breaks and damage DNA. When the balance between

antioxidants and oxidants does not exist, modification of key

transcription factors can occur, which can alter gene expres-

sion (Fig. 2). The superoxide radical can be converted to

hydrogen peroxide by mitochondrial superoxide dismutase 2,

preceding further modification by GSH peroxidase to form

water. Thus, the presence of antioxidants is vital to maintain-

ing redox homeostasis. Decreased amounts of antioxidants to

counteract the production of ROS can lead to cell damage

[99].

ROLE OF ROS IN PCOS

ROS are free radicals with oxygen centers. An unpaired

electron in the outermost shell is an extremely unstable con-

figuration, and free radicals quickly react with other mole-

cules or radicals to achieve the stable configuration of pairs

of electrons in their outermost shells [101]. Several basic

cellular processes lead to the production of ROS within a

cell. Cellular respiration involves the reduction of molecular

oxygen (O2) to water in the electron transport chain. This

reduction occurs through a series of reactions: (i) O2 + e-

O2

-·, (ii) O2

-· + 2H2O 2H2O2, (iii) O2

-· + H2O2 OH

· +

OH- + O2. As mentioned earlier, the superoxide anion radical

(O2

-·), hydrogen peroxide (H2O2), and the hydroxyl radical

(HO·) are three major species of ROS [97].

Role of MDA in PCOS

Unsaturated fatty acid peroxidation is a radical chain

reaction initiated by the abstraction of a hydrogen atom from

a methylene group of the fatty acid chain. The carbon radical

formed by this reaction tends to be stabilized by molecular

rearrangement, leading to conjugated double bonds. By reac-

tion with oxygen, a reactive peroxy radical is generated that

can abstract a hydrogen atom from lipids [102].

Products of lipid peroxidation reactions have been widely

employed as biomarkers for OS. MDA, produced during the

decomposition of polyunsaturated fatty acids, is one of the

stable end products of lipid peroxidation that can serve as a


good biomarker [102]. Several methods are available for

quantification of lipid hydroperoxides and secondary lipid

peroxidation products. MDA is most commonly measured

by a thiobarbituric acid-reactive substances (TBARS) assay

with a simple spectrophotometric method. The amount

of MDA corresponds to the chromogen found from MDA

and thiobarbituric acid (TBA) with a maximum absorption at

532-535 nm. While the assay for MDA is non-specific,

HPLC is a more accurate tool for MDA estimation.

Fig. (2). Oxidative stress occurs when the balance between highly

reactive radicals (oxidants) and antioxidants tips towards the

oxidants; it negatively contributes to reproductive processes.

Ku çu et al. (2009) compared PCOS patients (n=31,

mean age 23.8 years and mean BMI 21.8) with healthy con-

trols. Blood MDA level, not specified as measured from se-

rum or erythrocyte, was found to be significantly higher in

the PCOS group (0.12±0.03 vs 0.10±0.03, p=0.01). This

study demonstrated that PCOS subjects had significantly

elevated concentration of plasma MDA independent of obe-

sity. PCOS patients in this study were further divided into

two subgroups in terms of insulin resistance, IR- and IR+.

The results showed that MDA level is significantly higher in

young, non-obese PCOS patients even in the absence of IR

when compared with controls (0.125±0.03 vs 0.101±0.03,

p=0.03) (2).

Sabuncu et al. (2001) compared PCOS patients (n=27,

mean BMI 31.4 and mean age 26.7 years) with BMI- and

age-matched controls. They demonstrated that higher levels

of erythrocyte MDA were seen in PCOS patients (mean=70.9

mol/mol Hb) compared with controls (p=0.009). Signifi-

cantly higher levels of MDA in PCOS patients compared

with controls also were also found by Palacio et al. (2006)

[103].

Zhang et al. (2008) demonstrated that serum MDA levels

in PCOS patients (n=30) were significantly higher than those

of controls (12.313±2.512 vs 6.932±1.663 mol/L, P<0.05)

(104). A negative point of this study was that some of the

important patient characteristics, such as BMI and age, were

not recorded.

However, Karadeniz et al. (2008) [105] found MDA levels

in PCOS patients (n=58) were similar to those of controls

(5.38±2.47 vs 4.475±2.06, p>0.05) (105). Furthermore,

MDA levels were found to be similar in a PCOS patient

group where the homeostatic model assessment (HOMA)-IR

was below and above the cutoff value of 1.75. This observa-

tion suggests that the presence of insulin resistance in PCOS

patients has no effect on MDA levels. In addition, Dursun

et al. studied PCOS patients (n=23, mean BMI 23.0 and

mean age 24.4 years) and found serum MDA levels in PCOS

patients were similar to those of BMI- and smoking status-

matched controls (3.60±1.22 vs 3.53±1.0 mol/l) [106].

Role of Protein Carbonyl

Protein oxidation status often is assessed with a col-

orimetric assay that measures protein carbonyl (PC) content,

after reacting the serum with dinitrophenylhydrazine. Fenkci

et al. (2007) demonstrated that the PC level was significantly

higher in PCOS patients with normal BMI compared with

controls (18.01±0.80 vs 14.19±0.40 nmol/L, p=0.001). This

observation of higher protein oxidation suggested that free

radicals damage proteins in PCOS patients [107]. Further-

more, protein carbonyls were shown to have a positive corre-

lation with fasting insulin, suggesting a strong association

between insulin resistance and protein oxidation in PCOS

[107].

Role of NOS in PCOS

RNS are free radicals with nitrogen centers. The two

major examples of RNS are nitric oxide (NO) and nitrogen

dioxide (NO2). NO is specifically synthesized by NOS dur-

ing the conversion of L-arginine to L-citrulline [97]. Under

normal physiological process, NO acts in a variety of tissues

to regulate normal cell functions, but excess of NO can be

toxic [101]. NO, with an unpaired electron, is highly reactive

and can damage proteins, carbohydrates, nucleotides and

lipids. RNS have been associated with asthma, ischemic/

reperfusion injury, septic shock, and atherosclerosis [108].

Role of NO

Measuring plasma concentration of NO3

- and NO2

-

assesses NO concentration. The sum of NO3

- and NO2

- is

assumed as the best index of total NO. NO contents are

assessed by a two-step process consisting of the conversion

of nitrate to nitrite first, followed by spectrophotometric

detection of total nitrite at 540 nm [109].

Nácul et al. (2007) reported that NO levels in PCOS pa-

tients (n=31, mean age 22.4±7.1 years and mean BMI

26.7±10.1) were similar to that of age- and BMI-matched

controls (NO mean value 11.5 vs 10.2 mol/L, p>0.05).

Moreover, a significantly negative correlation was observed


between NO and fasting insulin levels (r=-0.39, p=0.03) and

HOMA (r=-0.41, p=0.02) (84). These data suggested that

NO was related to the presence of insulin resistance in PCOS

patients, although further studies are needed to clarify the

role of NO in PCOS.

ROLE OF ANTIOXIDANTS IN PCOS

Antioxidants scavenge excess ROS to counteract poten-

tial for significant cell damage by excess ROS. Antioxidants

help create a balance between beneficial oxidant generation

(frequently act as cell signaling molecules) and damaging

oxidative stress. There are two categories of antioxidants:

enzymatic and non-enzymatic. Enzymatic antioxidants in-

clude SOD, catalase, and GPx. Non-enzymatic antioxidants

include GSH, -tocopherol (vitamin E), -carotene, ascor-

bate (vitamine C), taurine, L-carnitine, coenzyme Q10, etc

(97). There are three SOD isoforms in eukaryotes: manga-

nese SOD (Mn-SOD), copper/zinc SOD (Cu/Zn-SOD), and

extracellular SOD (EC-SOD)1.

Antioxidants that prevent or limit the damaging effects of

oxygen radicals have been reported to have important roles

in the female reproductive system and in the pathogenesis of

female infertility.2 Changes in antioxidant concentrations in

serum and peritoneal fluid have been studied in idiopathic

infertility, tubal infertility, and endometriosis patients [111,

112]. Results indicate that investigation of antioxidant con-

centrations in PCOS patients is promising. Various studies

have measured antioxidant markers to correlate OS and

PCOS and the diverse clinical manifestations of metabolic

syndrome including diabetes, obesity, and cardiovascular

diseases.

Role of TAC in PCOS

Total antioxidant capacity is the ability of serum to

quench free radical production, protecting the cell structure

from molecular damage. Various detection assays for TAC

have been described, one of which is the spectrophotometric

assay in which long-lived 2,2’-azino-di-[3-ethylbenzthia-

zoline sulfonate] (ABTS) radical cation is measured. ABTS

radical is formed by the incubation of ABTS with a peroxi-

dase (metmyoglobin) and hydrogen peroxide. The principle

of the assay is to measure the ability of aqueous and lipid

antioxidants to inhibit the oxidation of ABTS to ABTS+

[113]. The capacity of the antioxidants to prevent ABTS

oxidation was compared with that of standard Trolox, a

brand name for 6-hydroxy-2,5,7,8-tetramethylchroman-2-

carboxylic acid, a water-soluble derivative of vitamin E. This

1 Mn-SOD, which contains a manganese prosthetic group, resides in the mitochondria.

It is thought to protect mitochondrial membranes, proteins, and DNA from O2

-· gener-

ated as a result of the electron transport chain. The Cu/Zn-SOD, which contains copper

and zinc prosthetic groups, often resides in cytosol. EC-SOD, is secreted and binds to

the elements of the extracellular matrix. All forms of SODs are thought to reduce O2

-·

to form O2 via the oxidation of the prosthetic group [110].

2 The production of H2O2 within cells may lead to the production of HO

· and subse-

quent cellular damage. Thus, it is important to remove H2O2. Catalase functions to

rapidly transform H2O2 to water and oxygen via the redox reactions achieved by its

manganese or heme group. Catalase resides mainly in peroxisomes, mitochondria and

the cytosol [110].

assay measures the combined antioxidant capacity of all its

components including vitamins, proteins, lipids, glutathione,

uric acid, etc. [113].

Another method to measure TAC is through the produc-

tion of hydroxyl radical via Fenton reaction. It is initiated by

the hydroxyl radical, and the brown-colored dianisidinyl

radical cations are produced in the reaction medium of the

assay [114]. Antioxidant capacity of the added sample

against these colored potent free-radical reactions is meas-

ured as a whole to represent TAC. The results also were

expressed as millimoles of Trolox equivalent per liter [34].

Fenkci et al. (2003) demonstrated that TAC was signifi-

cantly lower in PCOS patients (n=30 mean age 25.80±0.63

years and mean BMI 24.3±1.1) compared with the age-,

BMI-, and smoking status-matched controls (1.15±0.01 vs

1.30±0.02 mmol/L, p=0.001) [115]. This observation sug-

gested that the oxidative status imbalance in PCOS women

might contribute to their increased risk of cardiovascular

diseases. Moreover, there was a negative correlation between

fasting insulin level and TAC, suggesting that that IR may

have a detrimental effect on antioxidant defense system in

PCOS.

However, Verit et al. (2008) reported that TAC levels

were significantly higher in PCOS patients (n=63 mean age

24.4±4.1 years and mean BMI 21.2±1.8) compared with age-

and BMI-matched controls (1.8±0.5 vs 1.1±0.2 mmol Trolox

Eq/L, p<0.0001). This study demonstrated that TAC was

increased in non-obese, normoinsulinemic PCOS patients

(fasting insulin 10.7±5.0 IU/mL, no significant difference

compared with controls). High levels of antioxidants in

PCOS are thus suggested to have detrimental effects. This

result was inconsistent with other studies in the literature.

Although the complete mechanism of this elevation is un-

known, it is proposed that TAC was increased as to compen-

sate for the increase in total oxidative stress (19.1±7.6 vs

12.3±4.8 mol H2O2 Eq/L, p<0.0001) [34].

Although results of studies about antioxidant levels are

conflicting, it is possible to conclude that an imbalance be-

tween oxidants and antioxidants occurs in PCOS. Further

studies of oxidative stress defenses in PCOS are needed to

clarify the association between antioxidants and PCOS.

Role of SOD in PCOS

SOD induces the conversion of superoxide to H2O2, a

toxic substance that is converted to water by GPx. High SOD

levels may explain the absence of endothelial dysfunction

markers. Generation of an adequate antioxidant response

against such an intrinsic oxidative load may provide proper

functioning of vascular system.

Ku çu et al. (2009) demonstrated that SOD levels were

significantly higher in a PCOS group compared with a con-

trol group (8.0±0.7 vs 7.28±0.8, p=0.001). In this study the

PCOS patients were further divided into two subgroups: IR-

and IR+. SOD levels were significantly higher in both sub-

groups compared with the control (7.99±0.7 vs 8.22±0.8 vs

7.28±0.8, p=0.009 and 0.03, respectively). This elevation

may have been due to the body’s defense mechanisms. Sub-

jects used in this study were relatively young (mean age


23.8±4.37 years) with greater ability to cope with higher

levels of ROS production.

Sabuncu et al. (2001) demonstrated elevated SOD levels

(mean value 94.62 MU/mol Hb) in a group of PCOS patients

with mean BMI 31.4 (p<0.05). They proposed that the

increase in SOD levels might be due to a compensatory

response to OS.

Zhang et al. (2008) demonstrated that the serum SOD

level in PCOS patients (n=30) was significantly lower

than that in the control group (67.316±12.463 vs 113.815±

13.003 U/mL, P<0.05) [104]. However, the study did not

capture other patients’ characteristics, making it difficult to

comment as to why SOD level was lower in this selected

PCOS group.

Role of GPx

Sabuncu et al. (2001) demonstrated that GPx did not dif-

fer between a PCOS group and a healthy control group

(2.88±0.52 vs 2.98±0.54 MU/mol Hb). In an environment

with increased H2O2, an increase in GPx is to be expected.

However, the fact that GPx activity did not increase in PCOS

women might result from the low amount of GSH, which is

the substrate of GPx [4].

Role of GSH

GSH was often determined by adding 5,5’-dithiobis(2-

nitro-benzoic acid), which is a disulfide chromogen that is

readily reduced by sulfhydryl compounds, to an intensely

yellow compound. Reduced chromogen absorbance is meas-

ured at 412 nm and is directly proportional to GSH concen-

tration [116, 117].

Sabuncu et al. (2001) demonstrated that GSH was sig-

nificantly lower in the PCOS patient group than in the con-

trol group (0.39±0.07 vs 0.44±0.07 mol/mol Hb, p=0.03).

Low levels of GSH may have been partly related to IR. In-

creased ROS and peroxides may also have led to GSH deple-

tion.

In accordance with the findings of Sabuncu et al. (2001),

Dincer et al. (2005) also found GSH levels to be signifi-

cantly lower in women with PCOS than in the control group

(5.03±0.96 vs 5.59±0.82 mol/gHb, p<0.05) [118]. They

proposed that GSH depletion might have resulted from in-

creased production of ROS in PCOS patients.

CONCLUSION

In this review we documented the burgeoning interest in

the relationship between OS and PCOS, evidenced by a rap-

idly increasing body of literature. The discussion has in-

cluded multiple biomarkers of both ROS and antioxidants in

various PCOS patient groups. Cumulative studies to date do

not yield a definitive conclusion regarding the association

between OS and PCOS. Measurement of biomarkers of OS

also is known to be a controversial issue. Units of measure-

ment in published studies are not consistent. Standardized

measurement units of each biomarker should be used in the

future to facilitate comparison across studies. Additional

studies are recommended to examine the association and

mechanism of OS on PCOS.

KEY POINTS

• PCOS is the most common female endocrinological ab-

normality, affecting 4-8% of women in their reproductive

years.

• Clinical PCOS is diagnosed in women based on presence

of at least two of the following criteria a) oligo- or

anovulation, b) biochemical and/or clinical features of

hyperandrogenism, c) polycystic ovary appearance on ul-

trasound scanning.

• The condition is multifactorial, but insulin resistance

appears to be a central feature that explains many of the

manifestations of the syndrome and the increased risk of

developing type II diabetes.

• Components of metabolic syndrome, particularly hyper-

insulinemia and central obesity (visceral adiposity), are

frequently encountered in PCOS.

• Risk markers for cardiovascular disease, endothelial

dysfunction, and dyslipedemia are increased in PCOS

• Oxidative stress seems to be involved in altered steroi-

dogenesis in the ovaries, thus contributing to increased

androgen production, disturbed follicular development,

and, ultimately, infertility.

EXPERT COMMENTARY

There is mounting evidence to substantiate the etiological

relationship between PCOS and metabolic syndrome. How-

ever, epidemiological research thus far has failed to demon-

strate that the markers of cardiovascular disease, endothelial

dysfunction, and dyslipedemia in PCOS are associated with

increased mortality. The role of oxidative stress in the patho-

genesis of PCOS is not fully understood, and the evidence is

conflicting. The current evidence merely points towards an

association between the oxidative microenvironment of the

ovarian tissue and ovarian steriodogenesis and follicular de-

velopment. Whether oxidative stress is the cause or the result

of the metabolic disturbances encountered in PCOS remains

to be elucidated. However, a strong relationship among hy-

perinsulinemia, hyperlipaedemia, and oxidative stress is rec-

ognized.

FIVE-YEAR VIEW

Research is underway to determine whether reducing

visceral adiposity in PCOS patient is associated with reduced

markers of cardiovascular risk, improved insulin resistance,

and the amelioration of the clinical symptoms of PCOS.

Health economic constraints mean that issues associated

with PCOS should be addressed in a radical way to modify

the associated health risks. A prominent example of this is

the increased adoption of systems in which the availability of

fertility treatment is restricted for overweight PCOS patients

because of poor treatment outcome. In the next few years

clinical trials will determine the role of exercise, diet, and

other life style modifications, as well as pharmacological

intervention, on improving fertility outcomes and reducing

health risks in these patients.


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Polycystic Ovary Syndrome in Adolescents

Mohamed Yahya Abdelrahmana,c

, Mohamed A. Bedaiwya,b

, Elizabeth A. Kiracofed and

Marjorie Greenfielda,*

aDepartment of Obstetrics and Gynecology, University Hospitals Case Medical Center, Case Western Reserve

University, Cleveland, OH 44106, USA

bDepartment of Obstetrics and Gynecology, Assiut University Hospitals, Egypt

cDepartment of Obestetrics and Gynecology, Sohag University Hospitals, Egypt

dCase Western Reserve University School of Medicine, Cleveland, OH 44106, USA

Abstract: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, typically presenting with

menstrual irregularities and signs of androgen excess. Approximately 4-10% of reproductive aged women have PCOS.

The fact that PCOS often presents in adolescence and the chance of long-term adverse health consequences indicate the

need for early diagnosis and intervention. Menstrual dysfunction and hyperandrogenism are key features of the diagnosis

of PCOS in reproductive aged women. Diagnosis can be challenging, however, in adolescent girls. The etiology of PCOS

is complex and incompletely understood. Therapy should focus on alleviating symptoms and preventing adverse health

consequences.

Keywords: Polycystic ovary syndrome, polycystic ovaries, adolescence, diagnosis, management.

INTRODUCTION

Polycystic ovary syndrome (PCOS) is the most common

endocrinopathy in women, and typically presents with signs

of androgen excess and menstrual irregularities Approxi-

mately 4-10% of reproductive aged women have PCOS [1].

The prevalence in adolescent girls may be higher when com-

pared to other cohorts; as high as 9% in girls with regular

cycles, 28% with irregular cycles, and 45% with oligomenor-

rhea [2]. The incidence varies with the definition of PCOS

being used.

PCOS is a major risk factor for a number of chronic

health problems including type 2 diabetes mellitus (DM

type 2), cardiovascular disease, infertility, and endometrial

carcinoma. Early diagnosis and treatment are mandatory

to improve quality of life and prevent progression towards

serious health problems. This review will address the patho-

physiologic mechanisms and current guidelines in the diag-

nosis and management of PCOS in adolescence.

ETIOLOGY

The etiology of PCOS is complex and incompletely un-

derstood. It is clear from twin studies that a significant ge-

netic component contributes to the pathogenesis of PCOS.

Environmental factors, principally dietary, are also likely to

be involved in the modulation of the phenotypic expression


Gynecology, University Hospitals Case Medical Center, Case Western

Reserve University School of Medicine, 11100 Euclid Ave, Cleveland, OH

44106, OH 44106, USA; Tel: 216-844-8551; Fax: 216-201-4239;


of PCOS through the effects of obesity. Strong data suggest

that PCOS can be inherited [3]. Studies on monozygotic and

dizygotic twin sisters from the Netherlands twin registry

showed a high correlation of heritability between monozy-

gotic and dizygotic twins [4].

The fact that PCOS often presents in adolescence sug-

gests that the underlying predisposition to the typical ovarian

abnormalities originates before puberty. Franks et al. pro-

posed that the ovary is genetically predisposed to hyper-

secretion of androgens, perhaps as early as intrauterine life,

but certainly during the activation of the hypothalamic-

pituitary-ovarian axis that occurs transiently in infancy and

in a sustained manner at puberty. This predisposition to hy-

perandrogenism was shown to be associated with luteinizing

hormone (LH) abnormalities and amplification of the so-

called physiologic insulin resistance of puberty. Higher than

normal concentrations of LH and insulin further enhance

ovarian androgen production and may contribute to the

mechanism of anovulation [3].

Many genes have been investigated as possible suscepti-

bility loci but the effect of any one gene is likely small. One

candidate gene is a locus on chromosome 19 (p13.2), which

is close to the insulin receptor gene. Its function remains

uncertain [5, 6]. Large family-based case-control studies are

needed.

The clinical and biochemical abnormalities seen in PCOS

are amplified by obesity. In a series of 350 women with

PCOS, an increase in body mass index (BMI) seemed to

negatively affect metabolic indices [7]. Many studies report

that calorie restriction and lifestyle modification with as little

Polycystic Ovary Syndrome in Adolescents Current Women’s Health Reviews, 2010, Vol. 6, No. 2 109

as a 5% reduction in body weight in obese women with

PCOS improve metabolic indices and infertility [8, 9].

In utero androgen exposure has also been proposed to

influence the phenotypic expression of PCOS. In fact, in

nonhuman primates, fetal exposure to high levels of andro-

gen during early intrauterine development is associated with

defects in insulin secretion and action in adult life. Prenatally

androgenized female rhesus monkeys exhibit glucoregula-

tory deficits similar to those seen in adult women with PCOS

[10]. However, a recent prospective human study failed to

find a relationship between prenatal androgen exposure and

PCOS in adolescence [11].

PATHOGENESIS

Altered Gonadotropins Secretion

One of the well-described features of PCOS is an in-

crease in LH levels and a relative decrease in follicle stimu-

lating hormone (FSH) levels [12]. The relative decrease in

FSH could be the chief cause of PCOS-associated anovula-

tion. The pulsatile secretion of LH from the pituitary gland is

increased in amplitude and frequency in PCOS [13]. In addi-

tion, the pituitary in women with PCOS exhibits a greater

response to gonadotropin releasing hormone (GnRH) than

the pituitary in typical women [13,14]. This eventually leads

to an abnormal circulating LH- to- FSH ratio in some women

with PCOS. Overall, these data suggest the presence of a

defect in the hypothalamic-pituitary axis in PCOS.

Obesity, Insulin Resistance and Androgen Excess

Obesity is commonly associated with PCOS. More than

50% of women with PCOS are obese, which is defined as a

BMI >30 kg/m2 [15]. In many cases, obesity is believed to

cause the hormonal abnormalities that lead to PCOS, as dis-

cussed below. However, the fact that PCOS can be diag-

nosed in women of normal weight indicates that obesity is

not the only cause of PCOS.

The link between PCOS and obesity is often insulin resis-

tance (IR) [16]. IR can be defined as a state in which a

greater than normal amount of insulin is required to facilitate

glucose transport into cells. Early in the IR disease process,

pancreatic beta cells increase insulin secretion; compensa-

tory hyperinsulinemia maintains plasma glucose levels in the

normal range. If the ability of the pancreas to secrete insulin

declines or the degree of IR becomes greater than can be

compensated for by hyperinsulinemia, impaired glucose tol-

erance (IGT) or frank Type 2 diabetes develops, both of

which are manifested by abnormally elevated plasma glucose

levels [17]. Impaired fasting glucose is a relatively late ab-

normality that develops in patients with IR. Therefore, so

fasting glucose is not recommended as a screening test for

diabetes in the PCOS population.

Androgen excess in women with IR is believed to be the

result of insulin’s stimulatory effect on androgen production

by ovarian theca cells [18]. Approximately 70% of women

with PCOS have elevated serum androgen levels and 25%

have high concentrations of dehydroepiandrosterone sul-

phate (DHEAS) [19]. This has led investigators to suggest

that uncontrolled steroidogenesis may be the primary ab-

normality in this disorder [20]. These increased circulating

androgens are believed to be associated with LH abnormali-

ties. In Rhesus monkeys, positive feedback driven by in-

creased levels of LH increase androgen secretion by theca

cells. [The result is often PCOS with anovulation, signs of

androgen excess and polycystic ovaries.] The central role of

elevated insulin in many cases of PCOS is evidenced by

studies that show that lowering insulin levels in women with

IR using oral insulin sensitizers often results in spontaneous

ovulation [21].

Compensatory hyperinsulinemia may contribute to

anovulation directly by interfering with follicular develop-

ment, causing premature follicular atresia and follicular ar-

rest, and indirectly, by diminishing gonadotropins’ effects on

the follicles [22]. On the other hand, increased insulin binds

to insulin growth factor-I receptors (IGF-I), enhancing the

theca cell production of androgen in response to LH stimula-

tion [22].

Insulin may increase the cytochrome P450 17 activity, a

key enzyme in the biosynthesis of ovarian and adrenal an-

drogens. In ovarian theca cells, the 17 -hydroxylase activity

converts progesterone to 17 -hydroxyprogesterone, whereas

its 17, 20 lyase activity converts 17 -hydroxyprogesterone

to androstenedione. Androstenedione is then converted to

testosterone by the enzyme 17 -reductase. Thus, the increase

in P450c17 activity is accompanied by an increase in the

serum testosterone concentration. In this regard, this abnor-

mality may be responsible for exaggerating the 17-

hydroxyprogesterone response to stimulation by GnRH ana-

logs [23].

Excess insulin has a major impact at the hepatic level.

Hyperinsulinemia inhibits the synthesis of sex hormone

binding globulin (SHBG), increasing free androgens and

consequently peripheral androgen action. At the same time,

hyperinsulinemia inhibits the hepatic secretion of the insulin

growth factor binding protein (IGFBP 1), leading to in-

creased bioactivity of IGF-I and IGF-II. Eventually, this will

augment ovarian androgen production from theca cells by

stimulating IGF-I receptors [22].

DIAGNOSIS

PCOS is a syndrome, not a disease, and it may have sev-

eral different etiologies with a final common pathway. Even

the definition and diagnosis are still controversial.

PCOS was first described by Stein and Leventhal in 1935

[24]. They made their diagnosis of PCOS when patients with

amenorrhea and infertility were seen to have enlarged ova-

ries at surgery.

In 1990, a National Institutes of Health (NIH) conference

led to diagnostic criteria based on a majority opinion of con-

ference participants [25]. The criteria included: hyperandro-

genism and/or hyperandrogenemia, chronic anovulation, and

exclusion of other similar disorders. The NIH criteria did not

comment on ovarian morphology. At a PCOS consensus

workshop in Rotterdam, both the European Society of Re-

production and Embryology (ESHRE) and American Society

of Reproductive Medicine (ASRM) revised the diagnostic

criteria for PCOS. Their revised criteria state that PCOS re-

110 Current Women’s Health Reviews, 2010, Vol. 6, No. 2 Abdelrahman et al.

mains a diagnosis of exclusion, and diagnosis is complete in

women found to have at least two of the following condi-

tions: 1) ovulation dysfunction as evidenced by oligo or ame-

norrhea, 2) hyperandrogenism, determined either clinically

or biochemically, and 3) polycystic ovaries demonstrated

ultrasonographically [26].

However, the Androgen Excess and PCOS Society (AE -

PCOS Society) disputes this definition. They claim that

PCOS is a hyperandrogenic disorder, meaning that hyperan-

drogenism, either clinical or biochemical, is the cornerstone

of the diagnosis. Diagnosing a woman with PCOS implies

that there is an increased risk for many health conditions [27]

associated with the hyperandrogenism. The AE - PCOS So-

ciety suggests the following criteria for diagnosis; 1) hyper-

androgenism: either hirsutism or hyperandrogenemia, 2)

ovarian dysfunction: oligo-ovulation and/or polycystic ova-

ries and 3) exclusion of other causes of androgen excess or

related conditions [28] (Table 1).

Table 1. Definition of PCOS by Different Organizations

NIH Criteria (Both 1 and 2)*

1- Chronic anovulation.

2- Hyperandrogenism (Clinical or biochemical)

Rotterdam Criteria (2 out of the following 3)*

1- Chronic anovulation.


3- Polycystic appearance of the ovaries.

Androgen Excess and PCOS Society (Both 1 and 2)*


2- Ovarian dysfunction (Oligo-anovulation and/or polycystic

ovaries)

*After exclusion of other related disorders.

Adoption of any of the above criteria in diagnosing

PCOS is challenging in adolescent girls. For two to three

years after menarche, adolescents exhibit a transient phase of

anovulation [29], during which the menstrual cycle can be

irregular. The difficulty of diagnosing PCOS in adolescence

is not only due to the physiologic anovulation, but also to

transient hyperactivity of the hypothalamic-pituitary-gonadal

axis leading to increased androgen production [29] and

relative insulin resistance related to growth hormone levels.

More stringent criteria have been proposed to diagnose

PCOS in adolescents. These include four out of the five cri-

teria shown in (Table 2) [30].

CLINICAL FEATURES

PCOS presents as a spectrum of clinical disorders with

at the extreme hyperandrogenism, ovulatory dysfunction,

obesity, and insulin resistance.

Hyperandrogenism

Clinical signs of androgen excess are the most constant

and prominent components of PCOS. Approximately 72% of

women with PCOS will exhibit hirsutism, defined as the

presence of excessive thick, pigmented (terminal) hair in

androgen-dependent body areas such as the lip, chin, side-

burn area, neck, abdomen, and inner thighs [31]. As stated

by DeUgrate et al., degrees of hirsutism vary greatly in dif-

ferent ethnic populations (e.g. it is rare in Asian women

[32]), so the threshold of defining hirsutism should be set

based on the population [33].

Table 2. Proposed Criteria for Diagnosis of PCOS in Adoles-

cents: Four of Five Criteria [30]

Oligomenorrhea or amenorrhea, two years after menarche

Clinical hyperandrogenism: persistent acne, severe hirsutism

Biologic hyperandrogenism: plasma testosterone >50 ng/

dl, or increased LH/FSH ratio >2

Insulin resistance/hyperinsulinemia: acanthosis nigricans,

abdominal obesity, glucose intolerance

Polycystic ovaries on ultrasound scan: enlarged ovaries,

peripheral microcysts, increased stroma

Another sign of androgen excess is acne, which will be

found in 15-25% of women with PCOS. However, it is un-

clear whether the prevalence of acne is significantly in-

creased in PCOS over that observed in the general popula-

tion [34]. The present recommendation regarding acne and

alopecia is to consider them as unreliable clinical signs of

hyperandrogenism, particularly if they are the only diagnos-

tic features [27].

Approximately 70% of women with PCOS will be found

to have mildly elevated serum androgen levels, and 20-30%

will have mildly elevated dehydroepiandrosterone sulfate

(DHEAS) levels [19]. Marked elevations of total testoster-

one, DHEAS, or 17 hydroxyprogesterone may indicate un-

derlying pathology that is mimicking PCOS such as an ovar-

ian or adrenal tumor (especially if these elevations are asso-

ciated with symptoms and signs of rapid onset virilization),

or non-classical congenital adrenal hyperplasia [35].

Serum analysis may fail to identify biochemical hyperan-

drogenism in 20-40% of patients [36]. Even semi-

quantitative measurements, such as the Ferriman-Gallwey

score for hirsutism [37], may underestimate clinical hyper-

androgenism [33].

Most commercial assays for total testosterone are not

designed or validated for use in women [38], raising con-

cerns about their diagnostic value. Moreover, the range that

is regarded as healthy for women by commercial laboratories

is very broad and may fail to diagnose hyperandrogenemia

even in some women with severe hirsutism [39]. An alterna-

tive explanation for the disparity between normal serum

androgens and the presence of clinically significant hirsutism

is the fact that some individuals may have different hair fol-

licle sensitivity to androgens (idiopathic hirsutism). This

patient category will still benefit from suppression of their

normal levels of androgens, however. Another issue to be

considered is that women with asymptomatic polycystic ova-

ries who have normal baseline serum androgens on repeated

testing may have occult androgen excess [40].


Although controversial, many investigators believe that

failure to detect biochemical or clinical hyperandrogenism

should not exclude diagnosis of PCOS in the presence of

other clinical signs [41]. This is supported by the Rotterdam

criteria, which allow the diagnosis of PCOS in patients with-

out androgen excess.

Laboratory Criteria for Androgen Excess

Biochemically, hyperandrogenemia is most commonly

assessed by measuring serum total testosterone (T) and sex

hormone binding globulin (SHBG), followed by calculation

of the free fraction by the free androgen index (Testoster-

one/Sex Hormone Binding Globulin 100) or the mass

action equation [38, 42]. [The mass action equation, which

utilizes Testosterone, Sex Hormone Binding Globulin, Al-

bumin, and the association constants for the interactions of T

with SHBG and albumin, is regarded as the method of

choice to calculate free serum testosterone, if reliable assays

are used and normative data specific to each assay are avail-

able.] Radioimmunoassays that claim to directly measure

free testosterone are widely available, but the results are

highly unreliable and should be interpreted carefully [38,

43]. The concentrations of other serum androgens, such as

androstenedione or adrenal androgen dehydroepiandroster-

one sulfate (DHEAS) are often high in women with PCOS,

but their measurement is of little value in the average clinical

setting.

Ovulation Dysfunction

Ovulation dysfunction is the most common cause of fe-

male infertility and is diagnosed in 70-80% of infertile

women with PCOS [27]. The most frequent sign of ovulation

dysfunction is irregular menses. The irregularity may be in

amount, duration, or frequency. It occurs in 75% of PCOS

patients, and is often one of the earliest symptoms [7]. How-

ever, using menstrual irregularity to diagnose PCOS in ado-

lescence is difficult because irregular cycles may be normal

in the first few years after menarche [44].

Anovulation in adult women with PCOS is attributed to

the disturbance of folliculogenesis that characterizes the

syndrome. The follicular defect in PCOS consists of acceler-

ated early follicular growth and interference with the selec-

tion of the dominant follicle [45]. Accelerated early follicular

growth is mainly due to androgen excess and increased

insulin that induces LH receptor expression and premature

luteinization of granulosa cells. Excess amounts of insulin

and LH further enhance ovarian androgen production [3].

Ultrasonographic Criteria for Polycystic Ovaries

Significant advances in ultrasonography made in the last

decade, especially coupled with use of the transvaginal ap-

proach, have made evaluation of the ovaries more accurate

and detailed. Polycystic ovaries are defined by the Rotter-

dam Criteria as “the presence of at least 1 ovary, using a

transvaginal probe, featuring 12 or more follicles having a

mean diameter 2 to 9 mm, irrespective of location, and/or a

total ovarian volume > 10 ml.” This definition is applied to

the follicular phase ovary (one that lacks follicles larger than

10mm in diameter) [46].

Imaging for polycystic ovaries in virginal adolescent

girls, if desired, can be done by transabdominal ultrasound.

The ovarian volume may be the only parameter that should

be measured, because the follicle criteria are much less reli-

able by the abdominal route, especially in obese individuals

[47]. The transperineal or transrectal route may be an alter-

native when abdominal ultrasonography is not conclusive. A

combination of abdominal and three-dimensional transrectal

ultrasound revealed accurate and reliable results in adoles-

cent girls in one study [48].

Measurement of serum anti-Mullerian hormone (AMH)

is emerging as a potential surrogate for ultrasonography;

values correlated closely to the antral follicle count in pilot

investigations [49]. This assay may facilitate the diagnosis of

PCOS when transvaginal ultrasonography is not appropriate.

Other Phenotypes

Although obesity and IR are common in women with

PCOS, their presence is not necessary to make the diagnosis.

Their presence, however, increases the risk of metabolic

syndrome and other health consequences [3].

LONG TERM RISKS OF PCOS

Pregnancy, Infertility, and Miscarriage

Girls with PCOS and their parents may worry about their

future fertility. PCOS is the most common cause of anovula-

tory infertility so it is important to reassure adolescent girls

that if they do have difficulty conceiving in the future, they

can be treated with medications and/or assisted reproductive

technologies. However, obese patients should be warned of

the pregnancy complications associated with obesity. Preg-

nancy complications (gestational diabetes, preeclampsia, and

macrosomia) are significantly increased in morbidly obese

individuals [50-52]. In addition, the risk of first trimester

miscarriage is reported to be significantly higher for patients

with PCOS--possibly as high as 30% [53].

Diabetes Mellitus

Women with PCOS are at increased risk for glucose in-

tolerance, manifesting as either impaired glucose tolerance

(IGT) or Type 2 diabetes mellitus (DM) [54]. This increased

risk is related to the association of PCOS with obesity and

IR; both are risk factors for glucose intolerance. The inci-

dence of IGT and type 2 DM was reported as 10% and 5%,

respectively, in a cohort of adolescents with PCOS [55].

Women with PCOS and baseline normal glucose toler-

ance have a 16% conversion rate per year to DM type 2 [56],

whereas by the age of 30 years, 30-50% of obese women

with PCOS develop IGT or overt DM type 2. This is a 3-7

fold greater risk than that for an age-comparable population

[17].

The mechanisms underlying the association between

PCOS and glucose metabolism impairment are still un-

known. During fetal life, growth restriction, low birth

weight, and/or small size for gestational age followed by

catch-up weight gain during infancy may lead to hyperinsu-

linemia, IR, obesity, PCOS, and DM type 2 in later life [57,

58].


Evidence suggests that insulin resistance may play a ma-

jor pathophysiological role in the development of glucose

intolerance [59]. There is also a subset of women with PCOS

who are not obese, but have IR because of some molecular

abnormality, such as an insulin receptor defect [60]. Because

of the strong association of PCOS and DM type 2, effective

DM screening of PCOS patients is imperative.

Metabolic Syndrome and Cardiovascular Risks

Metabolic syndrome (MtS) is a cluster of cardiovascular

risk factors, including diabetes or prediabetes, central (ab-

dominal) obesity, atherogenic dyslipidemia, and hyperten-

sion [61]. Adult women with PCOS were found to have an

11-fold increased risk of MtS when compared to that of

healthy controls [61]. Thirty seven percent of adolescent

girls with PCOS have been shown to have MtS, compared

with 5% of the general population [62].

The World Health Organization (WHO) defines the MtS

as the presence of IGT or IR, with at least two of the follow-

ing: hypertension, dyslipidemia, obesity and microalbuminu-

ria [63]. Many revisions have been made to that definition

[64,65], although most are difficult to use in everyday prac-

tice or clinical studies. The most commonly used definition

for diagnosing MtS is the updated Adult treatment Panel III

criteria [66,67] (Table 3).

Table 3. Updated Adult Treatment Panel III for diagnosis of

Metabolic Syndrome*

• Fasting glucose 6.1 mmol/L [110 mg/dL]

• HDL-C <1.3 mmol/L [50 mg/dL]

• Triglycerides 1.7 mmol/L [150 mg/dL]

• Obesity BMI > 30 kg/m2

• Waist circumference 88 cm

• Hypertension 130/ 85 mm Hg

*Three or more criteria required for the diagnosis

(HDL-C: High Density Lipoprotein Cholesterol).

PCOS and metabolic syndrome are related conditions.

Adult women with MtS are at a greater risk of developing

cardiovascular disease; women with PCOS also appear to

carry an increased risk in their postmenopausal life. Women

with MtS may also experience reproductive disturbances

more commonly than their counterparts from the general

population [68].

Gynecologic symptoms may be the earliest manifestation

of MtS in young women. Early presentation affords a clini-

cian the opportunity for diagnosis, counseling, and treatment

to alter the risk profile for the development of MtS and car-

diovascular disease later in life.

Endometrial Cancer

Endometrial hyperplasia is a consequence of unopposed

estrogen stimulation of the endometrium. Adolescents and

women with PCOS are at increased risk because chronic

anovulation results in this dysfunction. Untreated endo-

metrial hyperplasia can lead to adenocarcinoma. Recent

meta-analysis suggests that women with PCOS have a more

than 2-fold risk of developing cancer of the endometrium

compared to the general population [69].

DIFFERENTIAL DIAGNOSIS

Some disorders may mimic PCOS (Table 4). These

disorders must be ruled out before making the diagnosis of

PCOS [27, 46, 70].

Table 4. Differential Diagnosis of PCOS

• Congenital Adrenal Hyperplasia

• Androgen-secreting neoplasm

• Cushing Syndrome

• Thyroid Disease

• Prolactin-secreting tumor

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is a group of auto-

somal recessive disorders resulting from mutations in the

genes coding for steroidogenic enzymes. In these disorders, a

block in cortisol biosynthesis leads to loss of negative feed-

back inhibition, increased adrenocroticotropic hormone

(ACTH) secretion, and subsequent excessive adrenal andro-

gen secretion [71]. The most common form of CAH is 21-

hydroxylase deficiency, which accounts for 90 to 95% of

patients with CAH [71]. 11 -hydroxylase deficiency and 3

-hydroxysteroid deficiency represent 5 to 10% of CAH

[72,73]. “Late onset” non-classical congenital adrenal hyper-

plasia can present in adulthood.

Androgen-Secreting Tumors

Androgen-secreting tumors, although rare, may initially

mimic the hyperandrogenism and menstrual dysfunction

seen in PCOS. However, they tend to present with rapidly

progressive hyperandrogenism and early development of

frank virilization. Sertoli Lydig cell tumors are the most

common virilizing ovarian tumor and account for 0.5% of all

ovarian neoplasms [74]. Androgen-secreting adrenal neo-

plasms are less common than ovarian neoplasms [35]. They

usually present with a mixed picture of Cushing syndrome

and virilization [75].

Cushing Syndrome

Cushing Syndrome, caused by excess cortisol, is charac-

terized by moon face, buffalo hump, obesity, hypertension,

and dyslipidemia. The most common cause of Cushing phe-

notypes is exogenous glucocorticoids. Endogenous Cushing

syndrome may be dependent on ACTH secretion or may be

due to autonomous cortisol secretion by the adrenal gland

[76]. Excess ACTH secretion results in androgen secretion

and then hirsutism in a slowly progressive fashion. If a pa-

tient with Cushing syndrome presents with rapid hair

growth, an adrenal tumor is more likely [77]. Although

Cushing syndrome is a rare etiology of hirsutism, excess

facial and body hair are present in approximately 81% of

patients with Cushing’s [78].


SUGGESTED EVALUATION OF ADOLESCENTS WITH FEATURES OF PCOS

History

A detailed menstrual history should be obtained. Ap-

proximately one half of menstrual cycles during the first 2

years after menarche are anovulatory [79], and bleeding pat-

terns may be slightly irregular. By five years after menarche,

80% of cycles are ovulatory. During the history, the patient

should be questioned about chronic illness, weight changes,

unwanted hair growth, drug use, and a family history of

endocrine malfunction, including dysfunctional bleeding,

infertility, diabetes, and MtS. Depression is common in

adolescents with hirsutism and obesity.

Physical

A focused physical examination is essential in the

evaluation of adolescents suspected of having PCOS. The

clinician should document the blood pressure, BMI, and

waist circumference to determine body fat distribution. A

BMI > 30 defines obesity and waist circumference greater

than 35 inches is considered abnormal and suggests MtS

[70]. Stigmata of hyperandrogenism include acne, hirsutism,

and (rarely) androgenic alopecia. Acanthosis nigricans, a

velvety hyperpigmentation usually seen around the neck,

correlates with insulin resistance.

The gynecologic examination should include inspection

of the external genitalia for clitorimegaly. If bimanual ex-

amination to exclude adnexal masses can not be tolerated,

ultrasound can be performed if necessary. In the context of

fairly normal testosterone levels, examination of the ovaries

for tumor is not imperative.

LABORATORY

Testosterone

The current criteria for the diagnosis of PCOS permit

hirsutism to serve as a surrogate marker for biochemical evi-

dence of androgen excess. However, total testosterone must

be measured to exclude the presence of androgen-secreting

tumors. A total testosterone level greater than 90 ng/dl usu-

ally indicates the presence of androgen excess [80] while

levels of serum testosterone greater than 200 ng/dl are

strongly suggestive of virilizing tumors [81].

Although free testosterone is the best single indicator of

androgen excess, there is no standardization of the test, and

measured free testosterone levels are unreliable [42]. For

research purposes, utilization of the free androgen index

(Testosterone/Sex Hormone Binding Globulin 100) is rec-

ommended. Values greater than 5 are diagnostic of androgen

excess [41].

Dehydroepiandrosterone Sulfate (DHEAS)

DHEAS is exclusively secreted by the adrenal glands,

making it a good marker for adrenal androgen production. It

may be elevated in anovulation [82] with approximately 20-

30% of women with PCOS having elevated DHEAS levels

[19]. DHEAS values above 700 ng/dl suggest adrenal neo-

plasm [83]. If serum testosterone is not exceedingly elevated,

DHEAS measurements are not necessary in the workup of

hirsutism or PCOS.

17 Hydroxy Progesterone

17 hydroxyprogesterone (17-OH-P) is a byproduct of

cortisol synthesis in congenital adrenal hyperplasia. A morn-

ing serum level of 17-OH-P during the follicular phase of the

cycle that is less than 3 ng/dl can be used to exclude non-

classical CAH. In a patient with irregular cycles, is often

helpful to draw a serum progesterone level simultaneously,

to establish that the patient is not in the luteal phase. If the

17-OH-P level is elevated (greater than 2 ng/ml), a cortico-

tropin stimulation test can help establish the diagnosis. Intra-

venous injection of 250 ug of synthetic corticotropin, fol-

lowed by measuring 17-OH-P after 60 minutes, is used. A

level above 10 ng/dL is diagnostic for non-classic adrenal

hyperplasia [84]

24 Hour Urine Free Cortisol

Adolescents with clinical evidence of Cushing syndrome

(moon face, buffalo hump, obesity, hypertension, and dyslip-

idemia) should undergo a 24 hour urine free cortisol test,

which has a sensitivity of 95 -100% and a specificity of 98%

[85] in the diagnosis of Cushing Syndrome. The 24 hour

urine free cortisol test has virtually no false negative results.

False-positive results may be attributable to conditions such

as depression, chronic active alcoholism, and glucocorticoid

resistance [86]. The dexamethasone stimulation test and

midnight salivary test may be helpful if the 24 urinary free

cortisol result is suspected of being falsely positive.

Prolactin

It is not uncommon to detect mild elevations of prolactin

(30-100 g/L) in women with PCOS. If serum prolactin is

found to be elevated, then thyroid function should be as-

sessed. Magnetic resonance imaging (MRI) of the pituitary

should be obtained to exclude pituitary tumor if prolactin

levels exceed 100 g/L.

Thyroid Stimulating Hormone

Hypothyroidism and hyperthyroidism should be excluded

before making the diagnosis of PCOS. Subclinical thyroid

dysfunction may be the cause of anovulation and menstrual

irregularities. Thyroid stimulating hormone (TSH) is the

screening test of choice, particularly in patients with irregu-

lar cycles [83].

Oral Glucose Tolerance Test (OGTT)

The 75 gram glucose, two hour OGTT has been recom-

mended by many organizations for both initial and periodic

screening for IGT and DM in women with PCOS [26, 70, 87,

88] (Table 5).

Recently, both the American Diabetes Association

(ADA) and the endocrine society encouraged clinicians to

use glycosylated hemoglobin testing when screening for and

diagnosing Type 2 diabetes mellitus in the general popula-

tion [50,89]. No recent published data addressing the use of

glycosylated hemoglobin in adults or adolescents with PCOS


are available. Currently, the OGTT is the gold standard for

screening for IGT and diabetes in patients with PCOS.

Table 5. American Diabetic Association Criteria for Hyper-

glycemia

2 Hour GTT Fasting Glucose

Normal < 140 mg/dl < 100 mg/dl*

Impaired 140-199 mg/dl 100-125 mg/dl**

Diabetes 200 mg/dl 126 mg/dl

* WHO defines normal fasting glucose < 110 mg%

** WHO defines impaired fasting glucose from 110 mg% to 125 mg%

Fasting Lipid and Lipoprotein Levels

Patients with PCOS should be screened for cardiovascu-

lar risk using fasting lipids and lipoprotein levels. A high

density lipoprotein cholesterol (HDL) level less than or equal

to 50 mg/dl and a triglyceride level greater than or equal to

150 mg/dl are considered abnormal [90].

IMAGING STUDIES

Ultrasonography

Ultrasonography is a useful tool in evaluating both the

ovaries and the adrenal glands [91], and ovarian characteris-

tics are included in some diagnostic criteria for PCOS. Ultra-

sonography is imperative if serum androgen levels are in

tumor range. If a mass is found, computed tomography (CT)

and MRI should be used as they are more accurate in distin-

guishing between benign and malignant neoplasms [92].

CT Scan and MRI

CT and MRI are indicated if there is a strong suspicion of

adrenal neoplasm. CT can diagnose an adrenal nodule of less

than 5 mm [75]. MRI provides a clear discrimination of tu-

mor invasion into the blood vessels. Recent CT and MRI

techniques allow accurate differentiation between adenomas

and malignant nodules of the adrenal gland [93].

TREATMENT

Treatment of the adolescent with PCOS should be started

as soon as the diagnosis has been made. Early intervention

will help not only to alleviate the distressing symptoms and

progression of hirsutism but also to prevent long-term health

consequences retard mental health consultation may be

needed in adolescents with marked emotional distress.

Treatment of Hirsutism

The majority of adolescent girls with PCOS seek medical

advice due to cosmetic issues related to hirsutism. Many of

these patients may have considerable emotional distress and

psychological morbidity with symptoms of anxiety and de-

pression mental health referral should be considered in girls

who exhibit significant distress.

NON-SYSTEMIC TREATMENTS

Many women are familiar with different hair removal

methods like shaving, waxing, and using depilatory creams.

They are all easy, safe, and inexpensive. However mild skin

irritation, either due to local trauma or chemical reaction,

may occur [94]. Women using these methods can be reas-

sured that they do not increase future hair growth, but they

will not prevent progression of hirsutism related to hyperan-

drogenemia. Combining one of these local measures with

systemic treatment may help achieve rapid response and

adequate patient satisfaction.

Laser Hair Removal

Laser hair removal reduced the number of hairs by 50%

over six months in a systematic review of 11 trials, but

the long-term efficacy of these treatments is not well estab-

lished [95]. Laser targets the pigmented hair at the base

of the hair follicle, and is most effective in light-skinned

individuals. Most patients experience 2 to 6 months of

growth delay after a single treatment, while some have

permanent resolution of excess hair growth after multiple

sessions. Despite the lack of evidence of efficacy, laser

hair removal is frequently asked for by patients who choose

permanent hair removal therapy once their androgens are

under control [96].

Electrolysis

Electrolysis is a procedure by which a fine needle is in-

troduced into the hair shaft and an electric current is applied

to destroy the hair follicle. In comparison to laser treatment,

electrolysis is less expensive, but laser therapy has been

shown to be more effective, less painful, and time-saving

[97].

Topical Creams

Eflornithine is a topical cream used in many countries for

the treatment of hirsutism. It does not remove the hair, but

decreases the rate of growth by inhibiting ornithine decar-

boxylase, an important enzyme for hair growth [98]. Eflor-

nithine will limit the rate of hair growth after 6-8 weeks of

therapy [99].

SYSTEMIC TREATMENTS

First Line Therapy

Combined Oral Contraceptives

Combined oral contraceptive pills (COCs) are the first

line treatment for the majority of patients with hirsutism who

do not wish to become pregnant. COCs decrease androgen

levels by several mechanisms. First, they inhibit gonadotro-

pin secretion from the pituitary, leading to decreased andro-

gen secretion by the ovary. Second, they increase SHBG

levels, which decrease free circulating androgens. Theoreti-

cally, pills with the least androgenic progestins may be of

most therapeutic benefit; however, all COCs suppress ovar-

ian androgens and raise SHBG levels and therefore can be

used for treatment [100]. The contraceptive ring provides a

similar combination of estrogen and progestin and can be

used interchangeably with COCs for girls who are willing to

use a vaginal route of administration.

Oral contraceptive pills that contain antiandrogenic pro-

gestins (cyproterone acetate and drospirenone) have theoreti-


cal benefits over other oral contraceptives in the treatment

of hirsutism. In women treated with drospirenone over 12

cycles, hirsutism scores improved from the sixth cycle of

treatment more significantly than those after treatment with

placebo [101]. The effects of other oral contraceptives on

hirsutism have not been studied.

Women being treated for hirsutism may have relative

contraindications to COC use, including hypertension. The

usual exclusion criteria for oral contraceptives apply in this

population [102].

Antiandrogens

Antiandrogens are another group of agents used as a first

line therapy for hirsutism. However, the teratogenic potential

of these drugs means that they should be used in conjunction

with adequate contraception in women of reproductive age.

Spironolactone, an aldosterone antagonist, competes with

testosterone and dihydrotestosterone at the androgen recep-

tor. Although it is primarily used as a diuretic, a dose of 50-

200 mg/day will reduce facial hair growth in the majority of

patients after 6 cycles of treatment [103]. Concurrent use of

spironolactone with oral contraceptive pills has been shown

to significantly improve hirsutism and reduce serum andro-

gen levels [104]. For patients with hirsutism that is refractory

to oral contraceptives after 6 months, adding spironolactone

may be effective.

Flutamide is an anti androgen used for the treatment of

prostate cancer. It is more effective in treating hirsutism than

spironolactone [105]. However, a recent study concluded

that although flutamide is very effective in treating hirsu-

tism, it is associated with frequent side effects and low long-

term compliance [117]. Hepatic cell damage, the major com-

plication of flutamide, may be fatal [106]. Consequently,

flutamide is not approved by the FDA for treatment of hirsu-

tism.

Cyproterone acetate is an anti androgen as well as a pro-

gestin. In one systematic review, cyproterone acetate (2mg)

was more effective than placebo, but not better than any

other anti androgen [107] in the treatment of hirsutism. It is

also available in an oral contraceptive pill, as cyproterone

acetate (2mg) with 35 ug ethinyl estradiol, which has been

shown to be well tolerated. This drug is not currently avail-

able in the United States.

Fenasteride, also an anti androgen, inhibits only the type

2 isoenzyme of 5 -reductase. It is anticipated that the effect

of fenasteride may be partial. Whether it is equally effective

or less effective than spironolactone is controversial [108,

109]. The FDA has not approved fenasteride for treatment of

hirsutism.

Insulin Sensitizing Agents

Hyperinsulinemia has been shown to increase ovarian

androgen production [110] and decrease SHBG production

[111]. Consequently, reducing insulin levels with insulin

sensitizing agents such as metformin should lower total and

free androgen levels. However, the effects on hirsutism are

not clearly better than if oral contraceptives are used; some

studies have shown insulin sensitizing agents to improve

hirsutism and others have not [112-115]. One systematic

review and one meta-analysis of 8 trials collectively found

no significant difference in hirsutism scores between COCs

and metformin [116, 117]. On the other hand, antiandrogen

drugs (spironolactone, cyproterone acetate, and flutamide)

have been found to significantly reduce hirsutism scores

when compared to metformin in a recent meta-analysis

[116].

Troglitazone was withdrawn from the market due to

hepatotoxicity, and rosiglitazone (thiazolidinediones) may

increase the risk of cardiovascular events in patients at

risk of or having diabetes mellitus [118]. Metformin is a

category B drug that can be used for patients with PCOS

desiring pregnancy, but its effects on hirsutism may not be

significant.

Second Line Therapies

Glucocorticoids and gonadotropin releasing hormone

agonists (GnRHa) can be used as a second line therapy for

treatment of hirsutism in patients with PCOS. They may be

useful in patients with severe hirsutism who do not respond

to first line therapy [119].

Glucocorticoids

Glucocorticoids are known to decrease adrenal androgen

secretion. They produce long-term suppression of the adrenal

glands [120]. Unfortunately, even in women with non-

classical congenital adrenal hyperplasia, the results of treat-

ment of hirsutism with glucorticoids are disappointing.

Cyproterone acetate has been shown to be more effective

than hydrocortisone after one year of use in hirsute women

with late onset adrenal hyperplasia [121]. Moreover, in a

study comparing cyproterone acetate COCs to dexametha-

sone, which has a longer half-life than hydrocortisone, the

hirsutism scores were significantly lower in the former group

(66% versus 31%) [122]. Of note, glucocorticoids are effec-

tive in maintaining ovulation and improving fertility out-

comes for patients with non-classic adrenal hyperplasia

[123].

Gonadotropin Releasing Hormone Agonist (GnRHa)

GnRH is a hypothalamic hormone released in a pulsatile

manner that regulates the production of FSH and LH from

the anterior pituitary in a permissive fashion. Exogenous use

of a GnRHa in a non-pulsatile manner results in suppression

of gonadotropin secretion (FSH and LH) [124]. GnRHa ther-

apy has been tried in uncontrolled and controlled trials [120,

125, 126]. Although weak evidence suggests that GnRHa

therapy is more effective than placebo or no therapy for

hirsutism, it appears to have no therapeutic advantage when

compared with other available agents such as COCs and anti

androgens. Furthermore, GnRH agonists are expensive and

may have undesirable side effects. The current recommenda-

tion suggests that use of a GnRHa for most women with

hirsutism should be avoided [96].

TREATMENT OF MENSTRUAL IRREGULARITY

Oligomenorrhea and Amenorrhea

Menstrual irregularity should be treated in adolescents

with PCOS to prevent prolonged unopposed estrogen stimu-


lation of the endometrium. Although the risk of endometrial

hyperplasia has not been studied in adolescent girls with

PCOS, the risk of endometrial hyperplasia is significantly

correlated with an inter-menstrual interval longer than 3

months and/or endometrial thickness greater than 7 mm in

women with PCOS [127]. In addition, anovulatory bleeding

can be heavy and prolonged, leading to iron deficiency ane-

mia as well as difficulties managing the menstrual flow.

In adolescents with amenorrhea or oligomenorrhea, pro-

gestins have been widely used to induce withdrawal bleed-

ing. Micronized progesterone (100-200 mg daily), me-

droxyprogesterone acetate (5mg/day) or norethindrone ace-

tate (2.5 or 5 mg/day) for 5-10 days is sufficient to induce

withdrawal bleeding. However, 12 days of progestin therapy

every one to three months is necessary to fully oppose the

effects of continuous endogenous estrogen. Progestin-

induced withdrawal bleeds should be considered if sponta-

neous menses occur with a frequency of less than 8 weeks

[128]. Continuous progestin treatment with depot me-

droxyprogesterone acetate or the levonorgestrel-containing

intrauterine device (IUD) can be considered for some ado-

lescents, particularly those who also need a birth control

method.

Treatment of Mild to Moderate Anovulatory Bleeding

Progestins have an important role in the treatment of

the anovulatory dysfunctional uterine bleeding (DUB) often

seen in adolescents with PCOS. For moderate DUB, cyclic

progestins can be administered for 12 days every month to

stabilize the endometrium and prevent the action of unop-

posed estrogen. Low dose oral contraceptives are another

alternative, especially when progestins fail to control the

bleeding. Treatment should be continued for 3-6 months

[129] or until regular ovulation is established. Concurrent

oral iron intake is encouraged if the hemoglobin level is low

or bleeding is excessive.

Severe Anovulatory Bleeding

Hospitalization must be offered in cases of severe DUB.

Immediate resuscitation with intravenous fluids or even

blood transfusion may be necessary to restore hemodynamic

stability. Intravenous conjugated equine estrogens in a dose

of 25 mg every 4 hours until bleeding resolves (the maxi-

mum is four doses) provides excellent control of heavy

bleeding in most cases [130]. To prevent recurrence of

anovulatory hemorrhage, a combination of 2.5 mg conju-

gated equine estrogen and 10 mg medroxyprogesterone ace-

tate for 20-25 days, or oral contraceptive pills, should follow

intravenous therapy [129]. Consideration should be given

to menstrual suppression with continuous oral contraceptive

pills (without placebo) until severe anemia is resolved.

In teens with severe uterine bleeding leading to anemia

requiring transfusion or with bleeding that occurs at the time

of the first menstrual period, workup for coagulopathy is

indicated.

COCs induce regular menstrual periods with a high de-

gree of reliability. In the setting of severe DUB, after estab-

lishing hemodynamic balance, COCs containing 35-50 g

ethinyl estradiol may be taken every 6 hours. After 8 doses

in the first 48 hours, the dose can be tapered over 3 days to

one pill daily. Then the patient should begin a new package

containing the same amount of estrogen for 21 days taking

one pill daily. At the end of that time, withdrawal bleeding

can be allowed, or continuous suppression with pills can be

chosen.

TREATMENT OF OBESITY

Weight loss counseling is an important component of any

treatment provided to obese women with PCOS [131]. A loss

of 5-10% of body weight is enough to greatly improve hirsu-

tism, reduce testosterone, increase sex hormone binding

globulin, resume ovulation and effectively modulate insulin

resistance in a majority of patients [8,132-137]. In light of

the health risks associated with PCOS, including diabetes,

hypertension, heart disease (hypercholesterolemia), and en-

dometrial cancer (unopposed estrogen), patients should be

advised and helped to achieve sustained weight loss.

Regular exercise and behavioral modification programs

are essential for acute and long-term weight management.

Different exercise regimens have been advocated from thirty

minutes three times a week, to ten minutes multiple times a

day, to one hour of exercise most days of the week. The best

program is one that the patient will actually follow [138].

Restricting calories should accompany increased energy ex-

penditure. With an average weight loss of 1b Clark et al. [133] found a 92% ovulation rate and 33% to 45% spontane-

ous pregnancy rate after applying calorie restriction and

exercise to a group of women with PCOS. Unfortunately,

lifestyle modification and weight loss programs require

prolonged patient motivation and are therefore difficult

to achieve beyond the research setting. Advice alone is

typically ineffective at promoting sustained weight loss.

Insulin sensitizing agents have been reported to suppress

the appetite and enhance weight loss. Metformin appears to

have the most utility among insulin sensitizers. A position

statement of the American Association of Clinical Endocri-

nologists recommends the use of metformin in most women

with PCOS, particularly if they are overweight or obese [87].

In a recent meta-analysis of 5 trials [139] in obese children

and adolescents, metformin reduced BMI by 1.42 kg/m2

(95% CI: 0.83-2.02) and insulin resistance scores by 2.01

(95% CI 0.75-3.26) compared with placebo. Another study

found metformin significantly reduced waist circumference

and testosterone levels when used in a dose of 1500 mg/day

over 6 months when compared to lifestyle modification, oral

contraceptives, and placebo [140]. However, no significant

change in BMI was found between the groups. Lifestyle

modification combined with metformin in obese patients

with PCOS may improve long-term outcomes regarding obe-

sity and metabolic consequences [131] than either treatment

alone. This usually requires prolonged treatment, since

weight is often regained after drug therapy is discontinued

[141].

Although controversial, anti-obesity drugs (Orlistat and

Sibutramine) have been proven to be relatively safe and ef-

fective in treating obesity in the general population.

Sibutramine is not approved for use in adolescents. Studies

on adolescents and Orlistat are inconclusive. Gastrointestinal

side effects often limit compliance in teenagers [142].


Bariatric surgery may be the last resort for patients un-

able to lose weight with other strategies. The current recom-

mendation is to offer bariatric surgery for any adult patient

with a BMI of 40 or greater, or for those with BMI of 35 or

greater who have a serious coexisting medical problem

worsened by obesity [143]. The advantages of bariatric sur-

gery include weight loss, improved diabetes, hypertension,

and dyslipidemia, and resumption of normal cycle rhythm

and fertility [144-146]. A recent randomized control trial

reported that 84% of adolescents with BMI >35 kg/m2 who

underwent bariatric surgery lost more than 50% of their

weight versus 12% in the control group. Furthermore, MtS

was eliminated in 100% of participants in the bariatric sur-

gery group compared to 22% in the lifestyle group after 24

months follow up [147]. However, current data are not suffi-

cient to support bariatric surgery for adolescents with PCOS.

Effective strategies, including the use of medications and

surgery, for sustained weight loss in obese adolescents with

PCOS should be evaluated by large long-term randomized

control trials [131].

Insulin Resistance and Metabolic Sequelae

IR is a significant component of the etiology of PCOS

and plays an important role in the risk of type 2 diabetes

mellitus and MtS. Many studies on the treatment of PCOS

address therapies that target IR [148, 149] Insulin sensitizers

have been used in women with PCOS, aiming to reduce in-

sulin resistance and improve lipid profiles. Some studies

report positive effects of metformin on insulin sensitivity and

lipid parameters in women with PCOS [150-152]. Although

the Food and Drug Administration does not approve the use

of metformin for PCOS, many clinical practitioners support

the use of metformin as a protective measure against the

metabolic and cardiovascular effects of insulin resistance

[153] and for the prevention of diabetes.

The Endocrine Society guidelines recommend diet con-

trol and moderate physical activity for 30 minutes 5 days a

week to prevent diabetes before drug therapy is initiated,

even in patients with risk factors for MtS [154]. The

ASRM/ESHRE consensus also reserves drug therapy for

patients who have PCOS with impaired glucose tolerance

[155].

EXPERT COMMENTARY

Polycystic ovary syndrome is a heterogeneous endocri-

nopathy that affects girls and women during their reproduc-

tive years. The exact etiology of PCOS is still unknown.

However, hyperinsulinemia and hyperandrogenism are the

main pathologic features responsible for most of the conse-

quences of the syndrome. In adolescents, the irregular cycles

of PCOS may be hard to distinguish from physiologic

anovulation. However, persistence for more than 2 years

after menarche is a strong predictor of long-term ovulatory

dysfunction. Menstrual irregularity in the context of obesity,

hirsutism, and acanthosis nigricans is likely to represent

PCOS that will be longstanding. Polycystic ovaries may or

may not be present in women and girls with PCOS. Ovarian

size may be used as a surrogate for polycystic ovaries when

abdominal ultrasonography is being used. Although obesity,

acne, and insulin resistance are important phenotypes of

PCOS, they are not required for the diagnosis.

Diagnosis of the syndrome in adolescence provides the

opportunity to alleviate distressing symptoms and prevent or

delay long-term health consequences. Metabolic syndrome,

Type 2 DM, cardiovascular disease, infertility, and endo-

metrial cancer are all potential risks in untreated women.

The diagnosis of PCOS is clinical and can be made only

after ruling out other causes of hyperandrogenism.While the

Rotterdam criteria can be used to make the diagnosis, PCOS

presents along a continuum, and making a strict diagnosis

may not be critical except in a research environment. Time

will often help differentiate an adolescent who is destined to

struggle with PCOS from one who is temporarily suffering

with irregular menses and acne.

Treatment should focus on prevention of medical com-

plications and alleviation of symptoms. Lifestyle modifica-

tion and weight loss are the mainstay of treatment in obese

individuals with PCOS. Oral contraceptives will regulate

menstruation and decrease the chance of endometrial cancer,

and may slow the progression of hirsutism. Metformin is

indicated in the context of IGT or diabetes. Its use in insulin

resistance is controversial, although studies have shown

promise in metformin’s ability to prevent overt diabetes.

More research in adolescent PCOS is needed to guide rec-

ommendations on diagnostic criteria and appropriate phar-

maceutical and surgical management.

FIVE YEAR VIEW

Causes of PCOS

PCOS is a multifactorial syndrome, involving genetic,

endocrinologic, metabolic and environmental factors. Fur-

ther research on the basic pathophysiology of PCOS and the

roles of the different etiologic components will aid in the

understanding of this condition, and help clinicians in their

management of adolescents with PCOS.

PREVENTION OF PCOS

Rates of obesity in the US increased in the 1980s and

1990s and have stabilized in the past decade [156]. On a pub-

lic health level, efforts at improving the rates of overweight

and obesity in the population, if effective, could have the

greatest effect on the incidence of PCOS in adolescents. Na-

tional programs like first lady Michele Obama’s Let’s Move

campaign (http://www.letsmove.gov/) are good first steps

toward systematically addressing the obesity epidemic with

prevention. Research on effective treatments for childhood

and adolescent obesity and programs to support successful

weight loss for individuals are sorely needed.

DIAGNOSTIC CRITERIA

Controversies exist in the diagnosis of PCOS in adoles-

cents. The Rotterdam criteria (Table 1) or Sultan’s criteria

specifically for adolescents (Table 2) are useful but may not

identify all the adolescents who could benefit from sympto-

matic treatment and anticipatory guidance. Population-based

studies to identify diagnostic criteria that would predict


which adolescents will continue to struggle with PCOS as

adults would be most useful.

Management of PCOS

Most recommendations for management of PCOS are

based on expert opinion. Evidence-based recommendations

that encompass the optimal management for symptom con-

trol and the prevention of sequelae would allow a more sci-

entific approach to patient care. For example, although

fourth generation COCs containing drospirenone have the

theoretical advantage of direct anti-androgen effects, they

have not been compared with COCs containing other pro-

gestins in the treatment of PCOS symptoms. Optimum man-

agement of hirsutism is another area for research.

COCs do not treat metabolic features of PCOS including

obesity, insulin resistance, metabolic syndrome and diabetes

mellitus. Metformin is recommended for impaired glucose

tolerance and frank diabetes, although its use in insulin resis-

tance requires further evaluation.

Prevention of Long-Term Sequelae of PCOS

The Oral Glucose Tolerance Test is currently the gold

standard test for diabetes screening in women with PCOS,

and needs to be repeated at undetermined intervals. Glycosy-

lated hemoglobin was recently recommended for screening

and diagnosis of diabetes in general population. We are cur-

rently evaluating the accuracy of glycosylated hemoglobin

compared to the oral glucose tolerance test for diabetes de-

tection in women with PCOS

KEY POINTS

1. PCOS is a complex metabolic derangement involving

insulin resistance, hyperandrogenism, and anovulation.

Genetic, metabolic, endocrinologic and environmental

factors all play a role. Obesity contributes to the devel-

opment of PCOS in most but not all patients.

2. PCOS is a clinical diagnosis made after eliminating other

causes of androgen excess and anovulation (Fig. 1). Sev-

eral organizations have attempted to create strict defini-

tions of PCOS (see Table 1), which are most useful in the

research setting. The varied definitions of PCOS influ-

ence reports of the incidence of this condition.

3. Patients diagnosed with PCOS should be screened for

glucose intolerance and dyslipidemia. Diabetes screening

should be repeated periodically. Fasting glucose is usu-

ally normal in the IGT and diabetes associated with

PCOS. Serum glucose testing two hours after a 75 gram

glucose challenge is the standard for testing.

Fig. (1). Flow Chart showing the evaluation of adolescents with PCOS to exclude other conditions. (TSH=thyroid stimulating hormone;

T=testosterone; DHEAS=dehydroepiandrosterone sulphate; 17 OH-P= 17 hydroxypeogesterone; ACTH=adrenocorticotropic hormone).

*24 hour urinary cortisol is required when Cushing syndrome is suspected. DHEAS screening is optional if total T is normal.


4. Long-term consequences of untreated PCOS include an

increased risk for diabetes, hypertension, heart disease,

infertility and endometrial cancer.

5. Weight loss is the mainstay of treatment for obese

women with PCOS. As little as a 5% weight reduction

can reverse many of the metabolic disturbances of PCOS

and diminish lifetime risks.

6. Other than weight loss, treatment for PCOS is symptom-

specific.

a. Anovulatory cycles pose a short-term risk for excess

bleeding and iron deficiency anemia, and a long-term

risk for endometrial cancer. Treatment with estrogen-

progestin oral contraceptives or long-term progestins

can diminish this risk.

b. Hirsutism can be treated with temporary measures

such as plucking or shaving, or permanent methods

like laser or electrolysis. Progression of hirsutism can

be slowed by decreasing free androgen exposure of

the hair follicle via COCs, systemic anti androgens

like spironolactone, or topical eflornithine.

c. Insulin resistance is best treated with weight loss.

While insulin sensitizing agents like metformin may

prevent diabetes, their use in adolescents is not yet the

standard of care.

d. Dyslipidemia should be identified and treated.

7. Patients with PCOS should be counseled about their

short- and long-term risks. Overweight teens should be

encouraged to lose weight through calorie restriction and

exercise. Symptoms can be distressing and should be ad-

dressed with sensitivity and empathy. Obese adolescents

are often victimized; referral for counseling should be

considered in girls with PCOS who are experiencing

emotional distress.

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Received: January 10, 2010 Revised: March 01, 2010 Accepted: April 15, 2010



Advanced Management Options for Endometriosis

Jashoman Banerjee*, Mona H. Mallikarjunaiah and John M. Murphy

University of Toledo Medical Center, Toledo, OH 43614, USA

Abstract: Endometriosis is a benign disease affecting 10 % of reproductive age females. Approximately 35% of women

with this condition are infertile. The exact cause of the disease is still unknown, but advances in human and animal

research have further elaborated its pathogenesis. Conventional, non-fertility related treatment for endometriosis focuses

on chronic pelvic pain, which is the most common manifestation of this disease. While traditional methods of treatment

have not proven to be completely effective, both medical and surgical therapies still hold some promise in controlling

pain.

Empiric medical therapy is still the most common mode for initiating treatment. Controversies exist regarding fertility

outcomes after surgical treatment. Assisted reproduction holds promise in patients with advanced endometriosis.

New treatment options have arisen in response to advances in research targeting the pathogenesis of the disease. Most

of the newer therapies are still experimental, but results in animal models show promise, which has served as an impetus

for conducting human trials. This article will focus on these new treatment options for endometriosis while also briefly

describing the pathogenesis, diagnosis and controversies of existing treatment modalities.

Keywords: Endometriosis, infertility, angiogenesis, matrix metalloproteinase, SPRM, cytokine, IVF.

INTRODUCTION

Infertility is a growing problem worldwide, which not

only affects individual health issues but also has a significant

social and economical impact [1]. About 10% of reproduc-

tive age females (15 to 45 years) are infertile based on 2002

data from NCHS (National Center for Health Statistics) [2].

The prevalence of female infertility has increased in recent

years due to multiple factors including age, delayed child-

bearing due to career interests, an increased incidence of

sexually transmitted infections, and endometriosis This re-

view will highlight endometriosis, focusing on its patho-

genesis, diagnosis and treatment options.

ENDOMETRIOSIS AND INFERTILITY

Endometriosis is associated with both infertility and

subfertility. Some studies suggest that monthly fecundity

rates (MFR) range from 2-10% in patients with endo-

metriosis compared with 30% in healthy controls [3].

Various factors may cause infertility in patients with endo-

metriosis. Severe endometriosis may induce adhesion forma-

tion in the fallopian tubes, thereby mechanically impairing

tubal function. More recently, evidence suggests that there

is an association between endometriosis and ovulatory

dysfunction [4, 5]. Poor oocyte quality, abnormal folliculo-

genesis [6] , poor implantation [7] and luteal phase defects

have been associated with the presence of endometriosis [8].

Furthermore, in-vitro fertilization studies (IVF) have sug-

gested that endometriosis is a contributing factor to abnormal

sperm parameters [9, 10].

*Address correspondence to this author at the Department of Obstetrics

and Gynecology, University of Toledo Medical Center, Toledo, OH 43614,

USA; Tel: 419-383-4590; Fax: 419-383-3090;


PATHOGENESIS OF ENDOMETRIOSIS

The pathogenesis for endometriosis is somewhat unclear,

though many hypotheses have been proposed. Sampson’s

theory of retrograde menstruation suggests that during

menses, endometrial tissue simultaneously flows in both

anterograde as well as retrograde directions, thereby seeding

the pelvis through the fallopian tubes [11, 12]. While intui-

tive, this theory fails to explain the documented presence

of endometriosis in distant sites not contiguous with the

pelvis. It also does not explain why some women develop

pelvic implants in response to retrograde menstruation while

others do not. Theories such as celomic metaplasia [13, 14]

and lymphatic and vascular dissemination have been

proposed to explain the shortcomings in Sampson’s theory.

Recent research has focused on a potential genetic basis

for the disease with an emphasis on tissue factors and the

possible role of stem cells in the pathogenesis of endometri-

osis [15, 16].

The basic pathogenesis of endometriosis at the cellular

level is quite complicated. It is thought to be an immuno-

inflammatory state [17, 18]. The peritoneal fluid milieu has

been demonstrated to be altered due to multiple factor aris-

ing from this immuno inflammatory state. Cytokines (TNF-

, IL-6,IL-18,TGF- ) [5, 17] and oxidative stress have been

implicated in the causation and progression of this benign

disease [19]. Cytokines, which are mediators of inflamma-

tion, are released by macrophages, which assemble in the

peritoneal environment to defend against foreign endometrial

tissue and thus create the state of inflammation in the perito-

neal cells and fluid [17]. Micro array analyses of peritoneal

fluid have demonstrated that the expression of cytokines in

patients with endometriosis is altered overall and that the

level of expression varies according to the different stages of

the disease [20].

124 Current Women’s Health Reviews, 2010, Vol. 6, No. 2 Banerjee et al.

Pain is the most common symptom, and it has been

correlated in some studies with disease stage (i.e, pain

increases as the disease becomes more widespread) and with

cytokine expression. Although the etiology of endometriotic

pain is still not clear, recent evidence has focused on the

role of prostaglandins and proinflammatory cytokines

released by the endometriotic implants into the peritoneal

cavity [21].

The ultimate fate of the pelvic peritoneum is healing

by scarring. This process can distort the tubal anatomy

indirectly, affecting the tubes’ ability to receive an ovum

and transport it to the uterus [22]. These adhesions at spe-

cific places have also been related to pelvic pain during men-

ses (progressive dysmenorrhoea) and also during intercourse

(deep dysperunia), which is the classical presenting symptom

[23-25].

Peritoneal adhesions are not the only etiology of infertil-

ity. It has been established by in vitro studies that the cytoki-

nes and oxidative stress may affect the oocyte, early embryo

development and sperm qualities by either altering the

morphology or assaulting the nuclear DNA [10, 26].

Apart from cytokines, endometriotic implants in the peri-

toneal fluid have been shown to possess abnormal prote-

olytic and fibrinolytic properties, which may assist their im-

plantation. Plasminogen activator and plasminogen activator

inhibitor have also been studied in the pathogenesis of en-

dometriosis. A state of hypofibrinolysis has been hypothe-

sized which may aid the persistence of endometrial implants.

This may be an indirect result of altered polymorphism in the

genes expressing plasminogen activator inhibitor-1 (PAI-1)

[27, 28]. Newer theories focus on their roles not only in

endometriosis but also in subfertile populations [29].

The role of matrix metalloproteinase (MMPs) has also

been extensively studied as a contributor to the pathogenesis

of endometriosis. These proteolytic enzymes erode the ex-

tracellular matrix and help the endometriotic implants to

grow into peritoneal cells. Under normal circumstances, their

action is kept in check by tissue inhibitors of metalloprotein-

ases (TIMP). The TIMP-MMP balance may be disturbed in

endometriosis, leading to uninhibited MMP expression [30].

The expression of both TIMP and MMP in endometriosis

implants is higher than in normal endometrial tissue [31]. It

has also been found that matrix degrading MMP-1 is ex-

pressed along with its regulator cytokine IL-1 alfa in stroma

of endometrial implants [32, 33].

Oxidative stress has a key role in the pathogenesis of the

disease. This is a state where the balance between pro-

oxidants and anti-oxidants in any cell or tissue is perturbed

in favor of the pro–oxidants which are mainly free oxygen

radicals. This abundance of free radicals can damage cells,

mainly by affecting membrane stability and accelerating

apoptosis [5, 18, 31, 34-36]. Oxidative stress not only affects

the disease directly but also plays synergistic roles in modi-

fying cytokine actions and assisting MMP activity in

the peritoneal cells. Reactive oxygen species have been

demonstrated to activate latent MMPs to their active forms

and also to increase adhesion formation in the peritoneal

cavity [37].

Angiogenesis is a key factor in the survival of ectopic

endometrial issue in the pelvis. Neovascularisation from the

effects of vascular growth factors, tissue factors [16], and

other cytokines allow the implants to remain viable and help

maintain the ectopic endometrium .Studies have shown that

angiogenesis in cancer and endometriosis behave similarly

and that surgery for endometriosis reduces expression of

vascular growth factors in the peritoneal fluid [38-40].

DIAGNOSIS

Diagnosing endometriosis based solely on the clinical

presentation can be difficult, given the non-specific nature of

many of its symptoms and the common occurrence of pelvic

pain in women without endometriosis. Therefore, laboratory

studies, imaging studies and diagnostic laparoscopy are often

necessary [41]. Previous studies have suggested that there is

a significant delay in the diagnosis for many women, with

some studies showing a mean delay of 11.7 years in the

United States [42]. Failure to identify a noninvasive tool or a

serum marker makes clinical examination, imaging and

laparoscopy the most reliable diagnostic tools. A study per-

formed to verify the use of the concomitant serum levels of

CA 125, CA 19-9 and interleukin – 6 with CA 125 alone

concluded that the former did not add significant information

in diagnosing either early or advanced stages of endometri-

osis [43].

Imaging has emerged as an additional tool in the diagno-

sis of endometriosis. Transvaginal ultrasonography (TVUS)

is usually the first imaging modality to be used for further

evaluation of a patient with chronic pelvic pain with sus-

pected endometriosis. TVUS is sensitive in detecting ovarian

endometriomas and other endometriotic plaques located near

the vagina [44]. However, it can not detect pelvic adhesions

or superficial peritoneal foci. A combination of clinical and

vaginal probe ultrasound findings may improve the accuracy

of diagnosis [45]. Abaro et al. and Goncalves et al. state that

TVUS may be more sensitive in detecting rectovaginal deep

endometriosis [46, 47].

MRI is now being used more commonly to diagnose en-

dometriotic lesions. Small nodules may be recognized as

hyperintense lesions on T1-weighted sequences, and plaque

lesions have a similar appearance, with a variable signal on

T2-weighted sequences [48] . Even though MRI is superior

to TVS in detecting small peritoneal lesions, it is recom-

mended in patients with chronic pelvic pain with suspected

adhesions with endometriosis. TVUS seems superior in de-

tecting rectovaginal disease [49, 50].

MANAGEMENT

Endometriosis is a chronic disease marked by acute flare

ups. The condition is generally managed with medical ther-

apy. Surgical treatment is reserved for more problematic

cases. Medical management encompasses the use of tradi-

tional treatments: combined oral contraceptives, GnRH ana-

logues, and progesterone, although the most common medi-

cation used for pain relief is NSAIDs (non steroidal anti in-

flammatory drugs). We will discuss options of surgical

treatment, traditional medical treatment and newer treatment

in this section.

Advanced Management Options for Endometriosis Current Women’s Health Reviews, 2010, Vol. 6, No. 2 125

SURGICAL MANAGEMENT

Laparoscopy is still considered the gold standard in diag-

nosing endometriosis [41, 51, 52]. Recent reviews have

demonstrated that in selected groups of patients, laparo-

scopic surgery improves pelvic pain, irrespective of the

nature of surgery [53, 54].

Various surgical treatments have been utilized to treat

chronic pelvic pain in patients with endometriosis including

lysis of adhesions, laser ablation of implants, and aspiration

and excision of endometriomas [55, 56]. Whether these abla-

tive surgeries compromise ovarian reserve is not currently

known. Multiple authors have concluded that surgery

for endometriosis does not negatively alter IVF outcomes

[57, 58].

Minimally invasive surgery for endometriosis might im-

prove pain in most patients, but the overall debate on

whether surgery is essential to improve fertility outcomes in

patients with endometriosis still prevails. Littman et al. dem-

onstrated that of 29 patients with IVF failure, 22 conceived

after laparoscopic surgery. Fifteen of these pregnancies were

spontaneous and the other 7 were initiated by IVF [59]. Ad-

amson et al. while studying the factors affecting reproduc-

tive outcomes after surgery in patients with endometriosis

stressed the importance of the combination of surgical skills

and proper patient selection for IVF is required to achieve

success [60].

MEDICAL MANAGEMENT

Medical management is largely empirical and based

mostly on clinical findings. Management can be broadly

divided into traditional and newer treatment groups.

TRADITIONAL

NSAIDs

The most commonly used medication for pain in

endometriosis is the NSAID. But its role and efficacy are

doubtful, and the side effect profile is extensive [61].

Oral Contraceptives

With hormone therapy, the goal is to create a pseudo-

pregnancy or a pseudo-menopause state in order to ablate the

active endometriotic deposits. Oral contraceptives may be

used cyclically or continuously. Combined oral contracep-

tive (those containing a combination of an estrogen and

a progestin) decidualizes endometriotic implants, thus reduc-

ing their activity [56], possibly by inducing apoptosis [62].

Contraceptives containing androgenic progestogens are

normally preferred, but those containing desogestrel may

be used with acceptable results [63, 64]. With cyclical OC

therapy, dysmenorrhea can recur during the pill-free period.

In that case, continuous usage might be more beneficial

[65]. The use of combined oral contraceptives did not alter

recurrence rates in post surgical patients with endometriosis

[66].

Gonadotrophin Releasing Hormone Agonists (GnRH)

This is the most commonly used medication to treat en-

dometriosis [67]. It acts by down-regulating the gonadotro-

phin receptors, abolishing the pulsatility in natural secretion

[56]. These drugs include leupreolide, goserelin, nafarelin,

buserelin, and histrelin. The main side effect is the hypoes-

trogenic state that ensues after an initial flare effect. This

hypoestrogenic state can manifest as post menopausal vascu-

lar symptoms and also by bone mineral density loss [68].

These effects can be counteracted by using “add back ther-

apy” either with norethindrone or combined oral contracep-

tives [63, 69]. Disease recurrence is also common after

GnRH therapy is stopped [70].

Danazol

This 17-ethinyl-testosterone derivative has shown to have

similar efficacy when compared with GnRH agonists in re-

lieving pain. It has fallen out of favor secondary to its andro-

genic side effects, which include weight gain, hirsutism, al-

tered lipid profile and abnormal liver enzymes [71].

Progestins

Progesterone treatment creates a pseudo pregnant state.

The exact mechanism of action is unknown but it is believed

that it not only counteracts estrogenic effects on the endo-

metrial cells but also affects MMP activity and prevents an-

giogenesis as seen in animal studies [72]. Murine studies

have also demonstrated the repressive effect of progesterone

on estrogen-induced stroma cell derived factor in endo-

metrial implants, which were unaffected by selective proges-

terone receptor modulators (Asoprisnil) or anti progestogens

(RU486) [73].

Various types of progestins are used for treatment includ-

ing medroxyprogesterone acetate (20-30 mg/day), Depo Me-

droxyprogesterone acetate (DMPA/ Depo-Provera, Pfizer)

and Depo SubQ -104–Provera (Pfizer). These agents have

comparable efficacy with GnRH analogues but have lesser

hypoestrogenic effects on the bone. A recent study con-

ducted in Japan found that a highly selective progesterone

receptor analogue called Dienogest (DNP) had anti-

proliferative and inhibitory effects on cytokines. It has been

shown to be as effective as intranasal buserelin in relieving

pain [74].

The Levonorgestrel (LNG) IUD system may have thera-

peutic implications in patients with endometriosis. One

animal study found that LNG microspheres created a pseudo

pregnancy state in the uterus of a rabbit model [75].

Comparative Studies

GnRH agonists have been compared with Danazol in

randomized studies, and the results showed little if any sig-

nificant difference in pain control [76]. When compared with

COCs in a small randomized trial, goserelin was better able

to alleviate dysmenorrhoea [77] but the combination of trip-

torelin and COC had a better efficacy at 1 year follow up

[78]. Human studies have compared the effects of LNG IUD

with GnRH agonist therapy on endometrial thickness as

evaluated by ultrasonography. This study demonstrated

smaller uterine changes in the LNG arm but similar effects

on endometrial thickness [79].


NEWER TREATMENT METHODS

Advancements in animal and human research exploring

the pathogenesis of endometriosis have opened up newer

avenues of treatment. Medications targeting the disease pa-

thology are being developed. Some of these agents under

investigation include aromatase inhibitors, matrix metallo-

proteinase (MMP) inhibitors, anti-angiogenic agents, anti-

TNF- , selective estrogen receptor modulators (SERMs),

and selective progesterone receptor modulators (SPRM)

(Asoprisnil, Schering and TAP Pharmaceuticals).

Aromatase Inhibitors

Normal endometrial tissue does not express high levels

of aromatase activity whereas endometrial implants do,

secondary to the inflammatory effects of prostaglandins

(PGE) and estradiol. Letrozole and Anastrozole are the two

most commonly used 3rd

generation aromatase inhibitors.

They act by inhibiting aromatase, the enzyme that converts

androstenedione to estrone and testosterone to estradiol by

binding competitively with the heme moiety of the cyto-

chrome P450 subunit. This mainly reduces excess estrogen

and prostaglandin (PGE) production in peripheral tissues,

thus inhibiting the endometrial implants’ ability to prolifer-

ate [80]. A mouse model study demonstrated that aromatase

inhibitors did not prevent implants from becoming estab-

lished in the mouse peritoneum but significantly reduced

their growth when administered on day 1 of the menstrual

cycle. Letrozole also increased apoptosis when started on

day 28. They also reduced vascular endothelial growth factor

(VEGF) and prostaglandin (PGE) production in the perito-

neal fluid [81].

Several studies have shown that aromatase inhibitors may

act singly or in combination with combined oral contracep-

tives or with GnRH agonists in alleviating pain [82, 83]. The

advantage of combining aromatase inhibitors with a GnRH

agonist is that they can prevent the sudden growth of ovarian

cysts due to excess FSH secreted secondary to low estrogen

levels [84]. This combination therapy, however, can pro-

foundly reduce bone mineral density (BMD) immediately

following treatment, which can take 2 years to rebuild after

discontinuing treatment.

Matrix Metalloproteinase Inhibitors

As discussed in the pathogenesis section, a balance be-

tween MMP and TIMP is essential to maintain homeostasis

in peritoneal fluid. In patients with endometriosis, the strict

regulation of MMPs is lost, and TIMP expression declines,

as shown in animal studies [85]. As a result, ectopic endo-

metrial tissue can implant more readily within the pelvic

peritoneum [31].

The role of melatonin as an antioxidant has been docu-

mented in animal studies in relation to MMPs. It has been

shown to reduce the activity of pro- MMP-9 in the peritoneal

cavity [85]. This may be attributed to its anti-oxidant proper-

ties by which it reduces protein oxidation and lipid peroxida-

tion. It can also augment antioxidants such as superoxide

dismutase and catalase and decrease malondialdehyde levels,

as seen in murine studies [86]. The role of melatonin in the

treatment for endometriosis is still experimental and needs

further research.

Anti-Angiogenic Agents

The process of angiogenesis helps keep ectopic endo-

metrial implants biologically active. These implants express

vascular endothelial growth factor-A (VEGF –A) in perito-

neal fluid, which initiates endothelial migration, proliferation

and neovascularisation. This in turn stimulates production of

estrogen and PGE2. VEGF in turn stimulates COX-2 pro-

duction, thus maintaining PGE levels and leading to a vis-

cous cycle of persistent vascular growth [87].

Most anti-angiogenic therapies are currently being used

in patients with advanced cancer. Bevacizumab, a humanized

anti-VEGF antibody (Avastin, Genentec), has been approved

by FDA [88], but no human studies have been performed

using such agents for endometriosis. Many animal studies

have documented that use of a competitive inhibitor, or anti-

bodies to VEGF, may retard implant survival and growth by

preventing new vessel growth [89, 90]. The only drawback

of these studies was that they could not demonstrate whether

the therapy had effect on existing mature vessels. Human

studies have yet to be conducted. Other angiogenesis inhibit-

ing factors, namely TNP-470 [90], endostatin [91], and angi-

nex [90], are still experimental agents.

Recently, vascular-disruptive agents (VDAs) have been

studied in cancer therapy. They have some advantages over

existing angiogenic inhibitors regarding their effect on pre-

existing vasculature and mature vessels. They can be used in

acute treatment and also in advanced disease [92]. VDAs can

be used in advanced endometriosis as they are able to

specifically target the new and existing vessels supplying the

implants better than other anti-angiogenic agents, but no

human studies have been reported to date.

Recent animal research also has targeted tissue factor in

the endothelium of endometriotic implants. A novel agent

called ICON (Immuno Conjugate), designed from Factor

VII-a, has been used to target the tissue factor in the endo-

thelium. ICON binds with the tissue factor and recruits NK

cells to destroy the entire endometriotic lesion [16, 93, 94].

Anti-TNF-

TNF- plays an important role in the pathogenesis of

endometriosis. Targeting this cytokine may help by disrupt

the signaling pathways leading to decreased angiogenesis

and reduced MMP activity. This type of therapy may also

help prevent oocyte and sperm damage.

Animal models mainly the baboon and rat have been

used to demonstrate the effects of monoclonal antibodies on

endometriotic implants. In one study, the size of endometri-

otic lesions decreased, and the efficacy was comparable to

that of GnRH agonists [95]. Randomized trials in humans

with anti- TNF- have not been conducted. Results from a

single case report were not encouraging after long-term use

of Etanarcept and Leflumide. There was no reduction of le-

sion size although the patient was able to conceived with the

help of IVF after 8 years of treatment [96]. Hence, the thera-

peutic role of anti- TNF- agents in established endometri-

osis has yet to be proven.


Selective Estrogen Receptor Modulator (SERM)

Estrogen receptor beta (ERB) binds to SERMS 200 times

more than that of estrogen receptor alfa (ERA).These ligands

(ERB-L) or SERMs have anti-inflammatory properties as

shown in a rat model. They reduce the size of approximately

75% of implants without inhibiting ovulation. Current

human trials are ongoing, and preliminary results suggest

that SERMs do not change the hormone profile. This early

phase II data is encouraging [97].

Selective Progesterone Receptor Modulator (SPRM)

These are progesterone receptor ligands with agonist,

antagonist, and mixed agonist-antagonist activity in various

target tissues. Asoprisnil (Schering and TAC Pharmaceuti-

cals) is the first SPRM manufactured for therapeutic use. It

has tissue specificity and minimal anti-estrogenic side ef-

fects. These agents are also known to reduce PGF2- and

COX-2 synthesis in implants of guinea pigs [98]. Hence,

these agents may also reduce pain in patients with endome-

triosis. Their role in endometriosis is selective inhibition of

endometrium without side effects and reduction of endo-

metrial bleeding secondary to their direct effect on endothe-

lial vasculature [99]. Recently, it was found that SPRM

can cause endometrial hyperplasia after 3 to 4 months of

use [100]. The efficacy and side effect profile should be

established by further human studies.

CONCLUSION

Endometriosis remains an area of great research interest.

New clues to its pathogenesis are leading scientists to ex-

plore new therapies. In the absence of a non-invasive blood

marker, laparoscopy is still the gold standard for diagnosis.

Surgical treatment can help improve pain but controversies

exist regarding its relation to reproductive outcomes in pa-

tients undergoing IVF. In properly selected patients, surgery

might prove to be beneficial. Researchers have explored the

possible use of a new generation of medical therapies, in-

cluding aromatase inhibitors, MMP inhibitors, SPRMs, anti-

TNF- agents, and anti-angiogenesis factors. Most of these

agents have been proven useful in animal studies and in stud-

ies relating to cancer therapy, but major human trials are still

required to establish their efficacy in endometriosis.

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Prevention and Management of Ovarian Hyperstimulation Syndrome

Botros Rizk1,* and Christopher B. Rizk

2

1Department of Obstetrics and Gynecology, University of South Alabama, Mobile, Alabama, USA;

2Rice University,

Houston Texas, USA

Abstract: Ovarian hyperstimulation is an iatrogenic syndrome that presents as the most serious complication of ovarian

induction. This syndrome is characterized by bilateral multiple cysts and third space fluid distribution. While mild forms

have no consequences to the patient, severe forms may result in mortality and severe morbidity. A new classification

of the syndrome is proposed based on the severity. The classification should guide the fertility specialist in determining

the plan of management. OHSS is most prevalent in patients with polycyctic ovarian syndrome. Prediction depends on the

clinical acumen and careful monitoring using ultrasounagraphy and serum estradiol measurements. The most popular

method for prevention is coasting. The role of dopamine agonists has become part of the standard management. The

management of OHSS could be achieved on an outpatient basis in many circumstances. Correction of the circulatory

volume and the prevention of thromboembolism are the two basics that should be achieved by all clinicians involved in

the management of the patient.

Keywords: OHSS, ascites, pleural effusion, thromboembolism, genetics, dopamine agonist.

INTRODUCTION

Ovarian hyperstimulation syndrome (OHSS) is the most

serious iatrogenic complication of ovulation induction [1-

20]. OHSS is characterized by bilateral, multiple follicular

and theca-lutein ovarian cysts (Fig. 1) and an acute shift

in body fluid distribution resulting in ascites (Fig. 2) and

pleural effusion (3) (Fig. 3). Induction of ovulation by

gonadotropins is one of the major advances in the treatment

of infertility in the second half of the 20th

century. Some

degree of ovarian hyperstimulation occurs in all women

who respond to ovulation induction but this should be distin-

guished from the clinical entity of ovarian hyperstimulation

syndrome. Whilst mild OHSS is of no clinical relevance,

severe OHSS, characterized by massive ovarian enlarge-

ment, ascites, pleural effusion, oliguria, hemoconcentration

and thromoembolic phenomena, is a life-threatening compli-

cation. This manuscript is based on our previous publications

and reviews [1-3].

OHSS CLASSIFICATIONS

OHSS may be moderate or severe, early or late in onset

(Fig. 4), and spontaneous or iatrogenic in etiology. Early

OHSS presents 3 to 7 days after the ovulatory dose of HCG,

whereas late OHSS presents 12 to 17 days after HCG. Early

OHSS relates to “excessive” preovulatory response to stimu-

lation. Late OHSS develops only in connection with preg-

nancy, is more likely to be severe and has a low correlation

with pre-ovulatory events. Most cases of OHSS are iatro-

genic following gonadotropin stimulation. Rarely, OHSS

occurs spontaneously as a result of mutations in the follicle

stimulating hormone (FSH) receptor leading to its stimula-


Gynecology, University of South Alabama, Mobile, Alabama 36604-1512,

USA; Tel: (251) 415-8602; E-mail: [email protected]

tion by chorionic gonadotropin, which is abundant in early

pregnancy.

Fig. (1). Bilateral enlarged cystic ovaries Reproduced with

permission from: Rizk B , Rizk CB , Nawar MG, Garcia-Velasco

JA, Sallam HN. Ultrasonography in the prediction and management

of ovarian hyperstimulation syndrome IN: Rizk B, Ed. Ulrasono-

graphy in reproductive medicine and infertility Cambridge, UK:

Cambridge University Press 2010; Chaper 36: 299-312.

There has been no unanimity in classifying OHSS, and

divergent classifications have made comparisons between

studies difficult [2]. Aboulghar and Mansour [6] (2003) re-

viewed the classifications used for OHSS over the last four

decades (Table 1). The most recent classification was intro-

duced in 1999 by Rizk and Aboulghar (1999) [7]. They clas-

sified the syndrome into only two categories, moderate and

severe, with the intent of categorizing patients into more

defined clinical groups that correlate with the syndrome’s

Prevention and Management of Ovarian Hyperstimulation Syndrome Current Women’s Health Reviews, 2010, Vol. 6, No. 2 131

a

b

c

d

e

f

Fig. (2a). Ascites in severe ovarian hyperstimulation syndrome Reproduced with permission from: Rizk B , Rizk CB , Nawar MG, Garcia-

Velasco JA, Sallam HN. Ultrasonography in the prediction and management of ovarian hyperstimulation syndrome In: Rizk B, Ed. Ulrasono-

graphy in reproductive medicine and infertility Cambridge, UK: Cambridge University Press 2010; Chapter 36: 299-312. (2b). Ascites in

severe ovarian hyperstimulation syndrome Reproduced with permission from: Rizk B, Rizk CB, Nawar MG, Garcia-Velasco JA, Sallam

HN. Ultrasonography in the prediction and management of ovarian hyperstimulation syndrome In: Rizk B, Ed. Ulrasonography in reproduc-

tive medicine and infertility, Cambridge, UK: Cambridge University Press 2010; Chapter 36: 299-312. (2c). Ascites in severe ovarian hyper-

stimulation syndrome Reproduced with permission from: Rizk B, Rizk CB, Nawar MG, Garcia-Velasco JA, Sallam HN. Ultrasonography

in the prediction and management of ovarian hyperstimulation syndrome In: Rizk B, Ed. Ulrasonography in reproductive medicine and infer-

tility Cambridge, UK: Cambridge University Press 2010; Chapter 36: 299-312. (2d). Ascites in severe ovarian hyperstimulation syndrome.

Reproduced with permission from: Rizk B, Rizk CB, Nawar MG, Garcia-Velasco JA, Sallam HN. Ultrasonography in the prediction and

132 Current Women’s Health Reviews, 2010, Vol. 6, No. 2 Rizk and Rizk

Fig. (1). contd…..

management of ovarian hyperstimulation syndrome In: Rizk B, Ed. Ulrasonography in reproductive medicine and infertility Cambridge, UK:

Cambridge University Press 2010; Chapter 36: 299-312. (2e). Ascites in severe ovarian hyperstimulation syndrome. Reproduced with per-

mission from: Rizk B, Rizk CB, Nawar MG, Garcia-Velasco JA, Sallam HN. Ultrasonography in the prediction and management of ovarian

hyperstimilation syndrome In: Rizk B, Ed. Ulrasonography in reproductive medicine and infertility Cambridge, UK: Cambridge University

Press 2010; Chaper 36: 299-312. (2f). Ascites in severe ovarian hyperstimulation syndrome. Reproduced with permission from: Rizk B,

Rizk CB, Nawar MG, Garcia-Velasco JA, Sallam HN. Ultrasonography in the prediction and management of ovarian hyperstimulation syn-

drome In: Rizk B, Ed. Ulrasonography in reproductive medicine and infertility Cambridge, UK: Cambridge University Press 2010; Chapter

36: 299-312.

prognosis. Their classifications can be correlated with the

treatment protocol and prognosis.

Fig. (3). Right pleural effusion in OHSS. Reproduced with per-

mission from: Rizk B, Rizk CB, Nawar MG, Garcia-Velasco JA,

Sallam HN. Ultrasonography in the prediction and management of

ovarian hyperstimulation syndrome In: Rizk B, Ed. Ultrasonography

in reproductive medicine and infertility Cambridge, UK: Cam-

bridge University Press 2010; Chapter 36: 299-312.

The new classification omits mild OHSS, used by most

previous authors, as this level of OHSS occurs in the major-

ity of cases of ovarian stimulation and does not require

special treatment. Most cases of OHSS present as moderate

OHSS. In addition to the presence of ascites on ultrasound,

the patient’s complaints usually are limited to mild abdomi-

nal pain and distension and hematological and biochemical

profiles are normal.

MODERATE OHSS

o Abdominal discomfort, pain, nausea, abdominal disten-

sion, ultrasonic evidence of ascites and enlarged ovaries,

normal hematological and biological profiles. Treatable

on an outpatient basis with extreme vigilance.

SEVERE OHSS

o Grade A: Dyspnea, oliguria, nausea, vomiting, diarrhea,

abdominal pain, clinical evidence of ascites plus marked

distension of abdomen or hydrothorax, large ovaries and

marked ascites on ultrasound, normal biochemical pro-

files. Can be treated as inpatient or outpatient depending

on physician’s experience, patient compliance, and medi-

cal facility.

o Grade B: All symptoms of grade A, plus massive tension

ascites, markedly enlarged ovaries, severe dyspnea, and

marked oliguria; biochemical changes, including in-

creased hematocrit, elevated serum creatinine, and liver

dysfunction. Treated as a hospital inpatient hospital

under expert supervision.

o Grade C: OHSS complicated by respiratory distress

syndrome, renal shut-down or venous thrombosis.

Considered critical and should be treated in an intensive

care setting.

Fig. (4). Classification of ovarian hyperstimulation syndrome early and late. Reproduced with permission from: Rizk B, Rizk CB, Nawar

MG, Garcia-Velasco JA, Sallam HN. Ultrasonography in the prediction and management of ovarian hyperstimulation syndrome In: Rizk B,

Ed. Ulrasonography in reproductive medicine and infertility Cambridge, UK: Cambridge University Press 2010; Chapter 36: 299-312.


COMPLICATIONS OF OHSS

Vascular Complications

Cerebrovascular complications are by far the most seri-

ous complications of OHSS. The first cases of severe throm-

boembolic phenomena following human menopausal go-

nadotropin and human chorionic gonadotropin (hMG/hCG)

treatment caused the death of one patient (carotid embolism)

and a limb amputation in the other [2, 3].

Hemoconcentration and increased hematocrit value in the

presence of normal coagulation parameters were found in 9

of 25 patients [2, 3]. Increased levels of factor V, platelets,

fibrinogen, profibrinolysin, fibrinolytic inhibitors, and

thromboplastin generation were observed [2, 3]. Thrombo-

phlebitis occurred in 2 of 25 patients and deep venous

thrombosis has been reported in at least one case of severe

OHSS [2, 3].

Venous compression due to enlarged ovaries and ascites,

together with immobility and a transient change in coagula-

tion were thought to be the main etiological factors in

thromboembolism. Internal jugular vein thrombosis occurred

>6 weeks after ovulation, and a subclavian vein thrombosis

occurred 7 weeks after egg collection for in vitro fertilization

(IVF). Both of these cases suggest a generalized effect on the

coagulation system that may persist for several weeks.

Liver Dysfunction

Hepatic function abnormalities have been recognized

increasingly as a complication in severe OHSS that may per-

sist for >2 months. Liver biopsies typically demonstrate sig-

nificant morphological abnormalities only at the ultrastruc-

tural level [2, 3]. Electron microscopy revealed paracrystal-

line inclusions in the majority of the liver cell mitochondria.

There were prominent membrane-bound bodies containing

Table 1. Classifications of Ovarian Hyperstimulation Syndrome (1967-1999) Reproduced with Permission from Aboulghar MA,

Mansour RT, Ovarian Hyperstimulation Syndrome: Classifications and Critical Analysis of Preventive Measures. Hum

Reprod Update 2003; 9: 275-89

Study Mild Moderate Severe

Rabau etal.

(1967)

Grade 1: estrogen >150 ug and

pregnanediol >10 mg 24 h

Grade 2: + enlarged ovaries and

possibly palpable cysts Grade 1

and 2 were not

included under the title of

mild OHSS

Grade 3: grade 2 +

confirmed palpable

cysts and distended

abdomen

Grade 4: grade 3 +

vomiting and possibly

diarrhoea

Grade 5: grade 4 + ascites and

possibly hydrothorax

Grade 6: grade 5 + changes in

blood volume, viscosity and

coagulation, time

Schenker and

Weinstein

(1978)

Grade 1: estrogen >150 (ig/24 h

and pregnanediol >10 mg 24 h

Grade 2: grade 1+ enlarged

ovaries, sometimes small cysts

Grade 3: grade 2 +

abdominal distension

Grade 4: grade 3 +

nausea, vomiting

and/or diarrhoea

Grade 5: grade 4 + large ovarian cysts,

ascites and/or hydrothorax

Grade 6: marked

haemoconcentration +

increased blood viscosity

and possibly coagulation

abnormalities

Golan et al.

(1989)

Grade 1: abdominal distension

and discomfort

Grade 2: grade 1 + nausea,

vomiting and/or diarrhoea,

enlarged ovaries 5-12 cm

Grade 3: grade 2 +

ultrasound evidence

of ascites

Grade 4: grade 3 + clinical evidence of

ascites and/or hydrothorax and breath-

ing difficulties

Grade 5: grade 4 +

haemoconcentration,

increased blood viscosity,

coagulation abnormality and

diminished renal perfusion

Navot et al.

(1992)

Severe OHSS: variable enlarged ovary;

massive ascites ±

hydrothorax; Hct >45%;

WBC >15 000; oliguria;

creatinine 1.0-1.5; creatinine

clearance >50 ml/min; liver

dysfunction; anasarca

Critical OHSS: variable

enlarged ovary; tense ascites ±

hydrothorax; Hct >55%; WBC

22=25 000; oliguria; creatinine

5=1.6; creatinine clearance <50

ml/min; renal failure; throm-

boembolic phenomena; ARDS

Rizk and

Aboulghar

(1999)

Discomfort, pain,

nausea, distension,

ultrasonic evidence of

ascites and enlarged

ovaries, normal

haematological and

biological profiles

Grade A: Dyspnoea,

oliguria, nausea, vomiting,

diarrhoea, abdominal pain,

clinical evidence of

ascites, marked

distension of abdomen

or hydro¬thorax, US

showing large ovaries and

marked ascites, normal

biochemical profile

Grade B: Grade A

plus massive tension

ascites, markedly

enlarged ovaries,

severe dyspnoea and

marked oliguria,

increased haematocrit,

elevated serum

creatinine and liver

dysfunction

Grade C:

Complications as

respiratory distress

syndrome, renal

shut-down or

venous thrombosis


granular matrix material and interpreted as microbodies or

peroxisomes. The cisternae of the smooth endoplasmic

reticulum were dilated. and focal microvillus proliferation

was present in the region of the canaliculi. No significant

changes in the Golgi apparatus or glycogen granules were

noted. These changes may be related to the increased estro-

gen production induced by hMG. Similar hepatic changes

have been found after the administration of oral contracep-

tives or anabolic steroids. The ultrastructural changes may be

a compensatory morphological change in response to the

increase in demand on the liver enzymes rather than true

pathological alterations.

Respiratory Complications

Respiratory distress, secondary to ascitic fluid accumula-

tion, is common in severe OHSS and is usually relieved by

aspiration of ascitic fluid. Adult respiratory distress syn-

drome was reported in a patient with severe OHSS. A rare

case of pleural effusion as the sole presentation of OHSS and

a similar case after IVF have been described [2, 3].

Gastrointestinal Complications

With the widespread use of ovulation induction for as-

sisted conception, it is mandatory that general practitioners

become aware that gastrointestinal symptoms could be the

initial presentation of ovarian hyperstimulation. One such

case presented with a cerebrovascular accident due to such

symptoms being overlooked [2, 3].

Adnexal Torsion

Adnexal torsion after superovulation is caused primarily

by ovarian enlargement due to the development of multiple

follicular or luteal cysts that make this complication more

common in cases of OHSS [2, 3]. OHSS may worsen during

the pregnancy with the continuing increase in ovarian

size eventually leading to torsion. In a series of 154 patients

hospitalized for severe OHSS, torsion was noted in 16% of

the pregnant patients compared with 2.3% of non-pregnant

patients. Laparoscopic unwinding of twisted ischemic hem-

orrhagic adnexum after IVF was successfully accomplished

[2, 3].

PATHOPHYSIOLOGY OF OHSS

Over the years many substances involved in the regula-

tion of vascular permeability have been implicated as a cause

of OHSS [11], and several of them are still under investiga-

tion. The list of potential mediators includes estradiol; his-

tamines; prostaglandins; the ovarian rennin-angiotensin sys-

tem; interleukin (IL)0-6, IL-2 and IL-8; angiogenin; endo-

thelin-1; insulin; and the ovarian kinin-kallikrein system.

Rizk et al. (1997) and Pellicer et al. (1999) investigated

the role of vascular endothelial growth factor (VEGF) as

a mediator for capillary permeability and fluid leakage

[8] (Figs. 5-7). VEGF production is dependent on human

chorionic gonadotropin stimulation that is administered to

trigger ovulation or during the early phase of pregnancy.

PREDICTION OF OHSS Predicting the risk of OHSS is the cornerstone of preven-

tion. Prediction is based on identifying the characteristics of

patients who are high responders as well as the use of ultra-

sonography and estradiol assessment (Table 2). Rizk et al.

(2010) studied the role of ultrasonography before, during,

and after ovarian stimulation as the key to early prediction

and successful prevention (Figs. 8-11) [3]. Rizk and Aboul-

ghar emphasized the role of estradiol measurement in the

detection of high responders who are at risk for severe OHSS

[7].

Rizk (2009) investigated the role of FSH receptor

(FSHR) mutations and polymorphisms in the development of

OHSS [16]. Mutations in FSH receptors could be either acti-

vated, thus resulting in OHSS, or inactivating, thus resulting

in sterility. To date, 744 single nucleotide polymorphisms

have been identified in the FSH receptor gene. Genetic stud-

ies of FSH receptor mutations have increased the expecta-

tions that OHSS could be predicted based on the FSH recep-

Fig. (5). Pathophysiology of ovarian hyperstimulation syndrome. Reproduced with permission from: Rizk B, Rizk CB, Nawar MG,

Garcia-Velasco JA, Sallam HN. Ultrasonography in the prediction and management of ovarian hyperstimulation syndrome In: Rizk B Ed.

Ulrasonography in reproductive medicine and infertility Cambridge, UK: Cambridge University Press 2010; Chapter 36: 299-312.


tor genotype. The potential association of the S680

allele with

poor responders to ovarian stimulation for IVF led to the

hypothesis that the N680

allele could be associated with the

hyper-responders, i.e., patients at risk of iatrogenic OHSS. In

an elegant study, no statistically significant differences be-

tween the IVF control population and the OHSS patients in

allelic or genotypic frequencies were found. However, a sig-

nificant enrichment in allele 680 was observed as the sever-

ity of OHSS increased (P = 0.034). The results of this study

also suggested that the genotype in position 680 of the FSH

receptor cannot predict which patient will develop OHSS but

could be a predictor of severity of OHSS symptoms in

women who develop the syndrome.

Fig. (6). Vascular endothelial growth factor receptors. Reproduced

with permission from: Rizk B, Rizk CB, Nawar MG, Garcia-

Velasco JA, Sallam HN. Ultrasonography in the prediction and

management of ovarian hyperstimulation syndrome In: Rizk B,

Ed. Ulrasonography in reproductive medicine and infertility

Cambridge, UK: Cambridge University Press 2010; Chapter 36:

299-312.

Bone morphogenetic protein-15 (BMP-15) is an impor-

tant oocyte-derived growth factor which is essential for

normal folliculogenesis and female fertility of mammals.

BMP-15 is a member of the transforming growth factor

(TGF ) superfamily. Within the ovary, BMP-15 mRNA is

found exclusively in the oocyte. In the human, BMP-15 is

detected in the oocytes of primordial follicles and progres-

sively expressed by oocytes in growing follicles through

folliculogenesis [16]. High BMP-15 in follicular fluid is

also associated with high quality ooctyes and subsequent

embryonic development. A genetic association study of

ovarian stimulation outcome in 307 unrelated women with

normal ovarian function who underwent ovarian stimulation

using recombinant FSH was performed. Four single nucleo-

tide polymorphisms located at the BMP-15 gene were ana-

lyzed in order to investigate the role of this gene in relation

to ovarian stimulation outcome. The results support the

hypothesis that BMP-15 alleles predict over-response to

recombinant FSH and ovarian hyperstimulation syndrome in

humans [16].

Fig. (7). Vascular endothelial growth factor receptors and vascular

permeability. Reproduced with permission from: Rizk B, Rizk

CB, Nawar MG, Garcia-Velasco JA, Sallam HN. Ultrasonography

in the prediction and management of ovarian hyperstimulation

syndrome In: Rizk B, Ed. Ulrasonography in reproductive medicine

and infertility Cambridge, UK: Cambridge University Press 2010;

Chapter 36: 299-312.

Table 2. Prediction of OHSS

History and Physical

1. OHSS in a previous cycle

2. Polycystic ovarian syndrome (PCOS)

3. Young age

4. Low body mass index

5. Hyperinsulinism

6. Allergies

During Ovarian Stimulation

1. High serum estradiol, rapid slope of E2 and absolute value

2. Ultrasonography

a. Baseline PCO pattern

b. PCO pattern of response to GnRH before gonadotropins

c. Large number of follicles > 20, on each ovary

3. Doppler low intraovarian vascular resistance

Outcome of ART Cycles

1. Conception cycles

2. Multiple pregnancy


Fig. (8). Polycystic ovaries at the beginning of an IVF cycle. Reproduced with permission from: Rizk B, Rizk CB, Nawar MG, Garcia-

Velasco JA, Sallam HN. Ultrasonography in the prediction and management of ovarian hyperstimulation syndrome In: Rizk B, Ed. Ulrasono-

graphy in reproductive medicine and infertility Cambridge, UK: Cambridge University Press 2010; Chapter 36: 299-312.

PREVENTION OF OVARIAN HYPERSTIMULATION

SYNDROME

Rizk in 1993 [17] suggested a ‘Ten Commandments’ for

the prevention of OHSS. These consisted of identifying pa-

tients at risk, use of treatment of other than gonadotropins

for PCOS patients (such as metformin and ovarian dia-

thermy), and use of low doses and GnRH antagonists when

gonadotropins were necessary (Table 3). A second ‘Ten

Commandments’ addressed the secondary prevention of


OHSS and included withholding or delaying hCG, follicular

aspiration, switching to IVF with cryopreservation of all

embryos, and progesterone for luteal phase support (Table 4)

[10]. Other measures unique to prevention of OHSS are: use

of GnRH antagonists instead of agonists to prevent prema-

ture LH surge, decrease in the dose of hCG, use of LH or

GnRH agonist in place of hCG for triggering ovulation,

administration of albumin, use of glucocorticoids, and

administration of dopaminergic drugs.

Fig. (9). Ascites in moderate ovarian hyperstimulation syndrome in

early pregnancy. Reproduced with permission from: Rizk B,

Rizk CB, Nawar MG, Garcia-Velasco JA, Sallam HN. Ultrasono-

graphy in the prediction and management of ovarian hyperstimula-

tion syndrome In: Rizk B, Ed. Ulrasonography in reproductive

medicine and infertility Cambridge, UK: Cambridge University

Press 2010; Chapter 36: 299-312.

Fig. (10). Twins associated with OHSS. Reproduced with permis-

sion from: Rizk B, Rizk CB, Nawar MG, Garcia-Velasco JA, Sal-

lam HN. Ultrasonography in the prediction and management of

ovarian hyperstimulation syndrome In: Rizk B, Ed. Ulrasonography

in reproductive medicine and infertility Cambridge, UK:

Cambridge University Press 2010; Chapter 36: 299-312.

Fig. (11). Coasting for prevention of ovarian hyperstimulation syn-

drome. Reproduced with permission from: Rizk B, Rizk CB,

Nawar MG, Garcia-Velasco JA, Sallam HN. Ultrasonography in the

prediction and management of ovarian hyperstimulation syndrome

In: Rizk B, Ed. Ulrasonography in reproductive medicine and infer-

tility Cambridge, UK: Cambridge University Press 2010; Chapter

36: 299-312.

Table 3. Primary Prevention of OHSS

The Ten Commandments

1. Prediction of OHSS from history, exam and ultrasound

2. Laparoscopic ovarian drilling in PCOS patients

3. Metformin in PCOS patients

4. Octreotide in PCOS patients

5. Low-dose gonadotropins in PCOS patients

6. GnRH antagonist protocol

7. Recombinant LH to trigger ovulation

8. GnRH agonist to trigger ovulation

9. In vitro maturation of oocytes

10. Replacement of only one embryo

Reproduced with permission from: Rizk B. Ovarian Hyperstimulation Syndrome:

Epidemiology, Prevention and Management. Cambridge, UK, New York, New York.

(2006) Cambridge University Press.

GnRH Antagonist as an Alternative to the Long Agonist Protocol

In a Cochrane review, the efficacy of GnRH antagonist

was compared to the long agonist protocol in assisted con-

ception [18]. In comparison with the long GnRH agonist

protocol, there was no statistically significant reduction in

the occurrence of severe OHSS (RR=0.50; OR=0.79; 95%

CI, 0.22-1.18); however, there were significantly fewer

pregnancies with GnRH antagonist (OR=0.79; 95%CI, 0.63-

0.99). In a review that compared the two GnRH antagonists

Cetrorelix and Ganirelix to the long protocol, a difference

was observed [19]. A significant reduction of OHSS was

observed in Cetrorelix studies (OR=0.2; 95%CI, 0.10-0.54),

but no reduction was observed for Ganirelix, (OR=1.13; 95%

CI, 0.24-5.31). The pregnancy rate in the Cetrorelix studies

was not significantly different from that found in the long


GnRH agonist protocol, (OR=0.91; 95%CI, 0.68-1.22). The

pregnancy rate in the Ganirelix protocols was significantly

lower compared with that in the long GnRH agonist protocol

(OR=0.76; 95%CI, 0.59-0.98). The final word has not been

said in relation to the development of OHSS in GnRH

antagonist cycles. Further studies will clarify this situation.

Table 4. Secondary Prevention of OHSS

The Ten Commandments

1. Withholding HCG +/- continuation of GnRH-a/GnRH

antagonist

2. Coasting or delaying hCG: currently most popular method

3. Use of GnRH-a to trigger ovulation

4. Follicular aspiration

5. Progestesterone for luteal phase

6. Cryopreservation and replacement of frozen-thawed embryos

at a subsequent cycle

7. Dopamine agonist

8. Albumin, administration at time of retrieval

9. Glucocorticoid administration

10. Aromatase inhibitors

Reproduced with permission from: Rizk B. Ovarian Hyperstimulation Syndrome:



Cancelling Cycles to Avoid OHSS

Withholding hCG used to be the most common method

used to prevent OHSS in patients at high risk for developing

the syndrome [11]. The estradiol criteria for withholding

hCG to prevent OHSS ranged from 800 pg/ml to 4000 pg/ml

[11]. Mostly all authorities recommend withholding hCG

when the estradiol level exceeds 4500 pg/mL. Equal or more

important than estradiol levels as criteria for canceling cycles

are the number of 8-10 mm follicles that may have acquired

LH receptors.

Decrease in HCG Dosage

Several clinical trials have been published in the litera-

ture regarding the impact of the dose of hCG on the occur-

rence of OHSS [22, 23]. Tsoumpou et al. elegantly reviewed

the studies in the IVF agonist and antagonist cycles. No de-

finitive conclusions could be made because of the differ-

ences in study design. Only one of the four trials regarding

HCG dose using GnRH agonist was a randomized controlled

and one of the two trials using GnRH antagonist was a ran-

domized controlled trial.

Coasting -- Delaying hCG Administration

Coasting,” also known as a “controlled drift period” is

the postponement of hCG administration to allow serum es-

tradiol levels to drop below a certain threshold.

Coasting is the most popular method among physicians

in the United States or Europe to prevent OHSS in patients

undergoing IVF. Withholding gonadotropins and delaying

the administration of HCG are techniques that have been

employed in ovulation induction since the late 1980s and

early 1990s. Shortly afterwards, coasting was used to prevent

severe OHSS in IVF cycles. Many studies and critical

reviews have evaluated the effect of coasting on OHSS.

Advantages of Coasting

Coasting offers three potential advantages. The first is

that the cycle is rescued and not canceled. Secondly, the

embryos that are generated during the treatment cycle will

be transferred, eliminating the need for cryopreservation.

Thirdly, coasting avoids the need for gonadotropins or other

medications or any supplementary procedures.

How Coasting Works

The association between OHSS and high estradiol levels

is very well established. This certainly does not mean that

high estradiol levels per se result in the manifestations of

increased permeability associated with OHSS.

Coasting may diminish the functional granulosa cell co-

hort, resulting in a gradual decline in circulating estradiol

levels and, more importantly, reduction of the chemical

mediators that augment capillary permeability and fluid re-

tention. VEGF concentration in follicular fluid may depend

on the quality and number of granulosa cells. Coasting acts

through down-regulation of VEGF gene expression and

protein secretion. The fact that medium and small follicles

are more sensitive to undergoing atretic changes is of crucial

relevance in both steroid and vasoactive mediator secretion

When to Initiate Coasting

Three factors should be considered in deciding to initiate

coasting. The first is plasma estradiol concentration, which

reflects the total functional granulose cell population; second

is the number of ovarian follicles, which predicts the poten-

tial for further granulose cell population and estradiol rise;

and third is the diameter of the leading follicles.

Most publications addressing coasting reflect that an es-

tradiol concentration of 3000 pg/ml was the value most

commonly chosen by clinicians. This relatively low thresh-

old for coasting has been shown to reduce the incidence of

OHSS effectively without compromising the cycle outcome.

High cut-off levels of around 6000 pg/ml are associated with

a higher incidence of OHSS and the need for longer periods

of coasting.

After withholding gonadotropins, serum estradiol exhib-

its a subsequent increase for one or more days. When coast-

ing was initiated at a plasma estradiol value of over 3000

pg/ml, the plasma estradiol increased to over 6000 pg/ml

during the coasting period [20]

Timing of hCG and Ending Coasting

Administration of hCG when the estradiol level drops

below 3000 pg/ml has been termed to be effective in lower-

ing the risk of OHSS.

Duration of Coasting

The number of recorded days of coasting has varied be-

tween 1 and 11. The effect of coasting duration has remained


controversial. While some studies suggested that gonadotro-

pins could be withheld for 10 or more days without com-

promising the outcome, others have experienced a decrease

in pregnancy rate when duration exceeds 4 days [20].

How Successful is Coasting in Eliminating OHSS?

From an evidence-based medicine point of view, only

limited data in terms of prospective randomized trials are

available. Ethical considerations make it difficult to subject

a test population to randomization in which one of the

arms would not be coasted and thereby at risk for severe

OHSS. Therefore these studies used a control group of

another modality of OHSS prevention or a group of normo-

responders.

GnRH Agonist as an Alternative to hCG to Trigger Ovulation

Alternatives to hCG to trigger ovulation include GnRH

agonists, native GnRH, and recombinant LH. Although the

incidence of OHSS is lowered, the ongoing pregnancies in

IVF cycles are also reduced when ovulation has been trig-

gered by a GnRH agonist or recombinant LH rather than

urinary or recombinant hCG [7].

Intravenous Albumin

Experience in subjects with different forms of third space

fluid accumulation has shown that albumin is efficacious in

preventing and correcting hemodynamic instability. How-

ever, a series of publications for and against the efficacy of

albumin in preventing OHSS have been published with con-

tradictory results. A multifactorial role of albumin in preven-

tion of OHSS has been proposed. First, it acts to sequester

vasoactive substances released from the corpora lutea. Al-

bumin also serves to sequester any additional substances that

may have been synthesized as a result of OHSS. Finally, the

oncotic properties of albumin serve to maintain intravascular

volume and prevent the ensuing effects of hypovolemia, as-

cites, and hemoconcentration. Aboulghar et al. published, a

Cochrane database review and found albumin to be effective

in preventing OHSS [24]. However, a new Cochrane review

soon to be published, includes new studies and found that

there was no advantage in the use of albumin (Aboulghar,

personal communication).

Hydroxyethyl Starch Solution

Hydroxyethyl starch (HES) is a synthetic colloid, glyco-

gen-like polysacharride derived from amylopectin. It has

been used as an effective volume expander and is available

in several molecular weights with different chemical proper-

ties. Several small studies suggested a beneficial effect of

HES in decreasing OHSS and indicate that HES should be

further investigated [25].

Glucocorticoid Administration

The pathophysiology of OHSS suggests the involvement

of an inflammatory mechanism during the development of

the fluid leakage that is associated with the syndrome. There-

fore, investigators hypothesized that glucocorticoids possibly

could prevent OHSS in patients at high risk. Rizk [2] and

others found no protective effect of intravenous glucocorti-

coids.

Ovarian Electrocautery

Laparoscopic ovarian electrocautery may be effective in

preventing OHSS in selected patients. Although the mecha-

nisms of action are not clear, electrocautery appears to ma-

nipulate the intraovarian endocrine environment through

rupture of androgen-rich cysts, destruction of androgen-

producing stroma, or disruption of the thickened ovarian

capsule. The recommendation is that electrocautery should

be reserved for women who previously have experienced

cancellation of at least cycle due to risk of OHSS.

Fig. (12). Cabergoline and prevention of ovarian hyperstimulation

syndrome. Reproduced with permission from: Rizk B, Rizk CB,

Nawar MG, Garcia-Velasco JA, Sallam HN. Ultrasonography in the

prediction and management of ovarian hyperstimulation syndrome

In: Rizk B, Ed. Ulrasonography in reproductive medicine and infer-

tility Cambridge, UK: Cambridge University Press 2010; Chapter

36: 299-312.

Dopamine Agonists in OHSS Prevention

VEGF secreted by the hyperstimulated ovary acting via

the VEGF receptor 2 (VEGFR-2) is a major cause of OHSS

[26-28]. Dopamine receptor 2 (Dp-r2) agonists, used in the

treatment of human hyperprolactinemia, inhibit VEGFR-2-

dependent vascular permeability (VP) and angiogenesis

when administered at high doses in animals. The dopamine

agonist bromocriptine and, more recently, the Dp-r2 agonist

cabergoline (Dostinex, Pharmacia & Upjohn, Bridgewater,

N.J.) 0.5 mg daily for 8 days beginning the day of hCG ad-

ministration (Fig. 13) have successfully prevented OHSS

symptoms [26].

To test whether VEGFR-2-dependent vascular perme-

ability and angiogenesis could be segregated in a dose-

dependent fashion with cabergoline (Cb2), a well-established

OHSS rat model supplemented with prolactin was used. A

low dose (100 ug/kg) of Cb2 reversed VEGFR-2-dependent

vascular permeability without affecting luteal angiogenesis

through partial inhibition of ovarian VEGFR-2 phosphoryla-

tion levels. No luteolytic effects (no increase in serum pro-


gesterone concentrations or luteal apoptosis) were observed.

Cb2 administration also did not affect VEGF/VEGFR-2

ovarian mRNA concentration.

Fig. (13). Molecular mechanism of dopamine agonist on vascular

permeability. Reproduced with permission from: Rizk B, Rizk

CB, Nawar MG, Garcia-Velasco JA, Sallam HN. Ultrasonography

in the prediction and management of ovarian hyperstimulation syn-

drome In: Rizk B, Ed. Ulrasonography in reproductive medicine

and infertility Cambridge, UK: Cambridge University Press 2010;

Chapter 36: 299-312.

In a recent prospective, double-blind study, more than 20

oocytes were retrieved from 54 donors in whom 20-30 folli-

cles > 12 mm developed. Immediately after hCG administra-

tion, patients were divided into two groups by computer ran-

domization. The study group (n=29) received 0.5 mg oral

Cb2 daily for eight days; the control group (n=25) received

one placebo tablet daily for eight days. Subjects were moni-

tored every 48 hours from the day of hCG (day 0) up to day

8. Hemoconcentration and the presence and volume of as-

citic fluid were significantly reduced in the study group.

OHSS developed in 25 % of women in the study group com-

pared with 65% in the control group.

The frequency of OHSS was reduced by half in the do-

pamine agonist, quinagolide group compared with placebo

[28]. Implantation rates and ongoing pregnancy rates did not

differ. Interestingly, patients who did not become pregnant in

the study cycle experienced more clinical benefits from

treatment than did those women who achieved pregnancy.

This leads to speculation that other vascular permeability

parameters may reduce the effect of dopamine agonists in

women who do become pregnant.

TREATMENT OF OVARIAN HYPERSTIMULATION

SYNDROME

The clinical course of OHSS depends on its severity,

the presence of complications, and whether the woman is

pregnant [27, 28]. Clinical management involves dealing

with electrolytic imbalance, neurohormonal and hemody-

namic changes, pulmonary manifestation, liver dysfunction,

hypoglobulinaemia, febrile morbidity, thromboembolic phe-

nomena, neurological manifestations, and adnexal torsion

(Fig. 14) [7-10]. The general approach should be adapted to

the severity level. Specific approaches such as paracentesis

and pleural puncture should be performed carefully when

indicated.

Fig. (14). Management of OHSS. Reproduced with permission

from: Rizk B, Rizk CB, Nawar MG, Garcia-Velasco JA, Sallam

HN. Ultrasonography in the prediction and management of ovarian

hyperstimulation syndrome In: Rizk B, Ed. Ulrasonography in re-

productive medicine and infertility Cambridge, UK: Cambridge

University Press 2010; Chaper 36: 299-312.

Successful medical management of OHSS requires

familiarity with the disease. Many problems occur due to

a lack of understanding by clinicians of the differences

between OHSS and other medical syndromes that present

with similar symptoms. A better understanding of the under-

lying pathophysiological mechanisms will help in refining

the management of the disease.

Outpatient Management for Moderate OHSS

Based on the classification of Rizk and Aboulghar [7],

moderate OHSS should be followed with regular telephone

calls at least daily and twice weekly office visits. Office as-

sessment includes pelvic ultrasound, a complete blood count,

liver function tests, and a coagulation profile. The patient

should be instructed to report to the hospital if she develops

dyspnea, diminished urine volume, or any unusual symptoms

such as leg swelling, dizziness, numbness, or neurological

problems.

Outpatient Management for Severe OHSS

Whether severe OHSS should be managed on an outpa-

tient basis depends on the classification and definition of

severity, the physician’s level of knowledge and experience

with the disease, and the patient’s willingness to comply

with treatment. OHSS grade A is treatable on an outpatient

basis by aspiration of ascitic fluid, administration of intrave-

nous fluids, and evaluation of all biochemical parameters.

Inpatient Management of Severe OHSS

Patients with severe OHSS grade B and C are admitted to

the hospital for treatment. Indications for hospitalization are

shown in Table 5. Hospitalization should be considered if


one or more of these symptoms or signs are present [29]

Great caution is required in all grades of severe OHSS

because complications can develop suddenly.

Table 5. Indications for Hospitalization of Patients with

Severe OHSS

1. Severe abdominal pain or peritoneal signs

2. Intractable nausea and vomiting that prevents ingestion of food

and adequate fluids

3. Severe oliguria or anuria

4. Tense ascites

5. Dyspnea or tachyspnea

6. Hypotension (relative to baseline), dizziness, or syncope

7. Severe electrolyte imbalance (hypernatremia, hyperkalemia)

reproduced with permission from: Rizk B. Ovarian Hyperstimulation Syndrome:



Inpatient Clinical and Biochemical Monitoring

The patient’s general condition must be assessed regu-

larly, including documentation of vital signs, daily weight

and girth measurement. Strict fluid balance recording is

needed, particularly of urine output.

Biochemical monitoring should include serum and elec-

trolytes, renal and liver function tests, a coagulation profile,

and blood count. Serum and urinary osmolarity and urinary

electrolyte estimation may be required as the disease pro-

gresses in severity. Respiratory compromise and/or signifi-

cant deterioration of renal function require evaluation of

blood gases and acid-base balance. The frequency of these

evaluations depends on the severity of the condition.

Ultrasonographic examination provides accurate assess-

ment of ovarian size and the presence or absence of ascites,

as well as pleural or pericardial effusions. Ultrasound also is

helpful in the diagnosis of intra- or extrauterine pregnancy as

well as multiple or heterotrophic pregnancy. -hCG assay

will help to diagnose pregnancy as early as possible, and a

chest X-ray will provide information on the presence of hy-

drothorax.

Invasive hemodynamic monitoring (central venous pres-

sure and pulmonary artery pressures) may be needed under

certain circumstances in which volume expanders are being

employed.

MEDICAL TREATMENT

Circulatory Volume Correction

The main line of treatment is correction of the circulatory

volume and the electrolyte imbalance. Every effort should be

directed towards restoring a normal intravascular volume and

preserving adequate renal function. Volume replacement

should begin with intravenous crystalloid fluids at 125-150

ml/h. Normal saline and lactated Ringer have been success-

fully used. Plasma colloid expanders may be used if neces-

sary. One concern with using plasma expanders is that the

beneficial effect is transitory before their redistribution into

the extravascular space, further exacerbating ascites forma-

tion. Albumin has been utilized at 200 ml. of 25% albumin

solution. Dextran, mannitol, fresh frozen plasma, and hy-

dryoxyethylstarch (HES) have also been used. HES have the

advantage of being non-biologic in origin and a high mo-

lecular weight (200-1000 kDA vs. 69 kDA for albumin).

HES 6% and 10% have been used successfully, but larger

prospective randomized controlled studies are needed [10].

Electrolyte Replacement

ppropriate solutions will correct electrolyte imbalances.

If hypokalemia is significant, a cation exchange resin may be

needed. Sodium and water restriction have been reported to

be successful by some, but others found no change in the

patient’s weight, abdominal circumference, or peripheral

edema when sodium and water were restricted. With these

inconclusive reports, salt and water restriction are not widely

advocated [10].

Anticoagulant Therapy

Anticoagulant therapy is indicated if there is clinical evi-

dence of thromboembolic complications or laboratory evi-

dence of hypercoagulability [30,31]. Venous thrombosis is

the most common serious complication of OHSS, and pre-

ventative heparin treatment should be used whenever there is

a thromboembolic risk. In cases of severe OHSS, the follow-

ing situations are recognized as indicating an increased risk

of thromboembolism: immobilization, compression of pelvic

vessels by large ovaries or ascites, pregnancy coagulation

abnormalities, and hyperestrogenemia. Prevention using mo-

bilization and antithrombosis stockings is insufficient as

thrombosis may occur at all localizations and may be sys-

temic in nature.

Anticoagulant Prophylaxis

Prophylaxis with heparin remains debatable on the basis

that no randomized studies proving its efficacy in preventing

thromboembolic complications during severe OHSS have

been published. In fact, in some clinical scenarios, throm-

boembolism still occurs despite giving heparin [12]. Despite

these reservations, Rizk [10] recommends giving heparin or

enoxaparin (Lovenox, Sonofi-Aventis, Bridgewater, N.J.) for

patients with severe OHSS. The incidence of deep vein

thrombosis (DVT) is markedly increased in patients with

Factor V Leiden mutation, one of the thrombophilias [32].

The mutation occurs in 4% of Northern European women.

Patients should be questioned about a history of personal or

familial thrombosis, and those with a positive history should

be tested for Factor V Leiden mutation.Patients with Factor

V Leiden mutation who develop OHSS should be placed on

prophylactic heparin. Others risk factors for DVT in OHSS

include protein C and S deficiency and antithrombin III defi-

ciency.

Duration of Anticoagulation

The optimal duration of anticoagulant administration is

undetrmined. Some investigators have reported late throm-

bosis up to 20 weeks post-transfer, and many investigators

favor maintaining heparin therapy for many weeks [4]. The

severity of OHSS must be separated from the risk of throm-


boembolism because intrinsic coagulopathy may trigger

the problem even in moderate cases. However, those who

have followed a more liberal policy for prophylaxis have had

to deal with operating on ruptured ectopic pregnancies in

anticoagulated patients. Therefore, thromboembolism will

remain a more difficult complication to prevent and may

complicate the outcome of OHSS.

Antibiotic Treatment

Infections are not uncommon in the setting of treatment

of OHSS because of frequent catheterizations, venipuncture,

transvaginal aspiration of ascitic fluid, and pleural drainage.

Furthermore, hypoglobulinemia is present in severe cases.

Preoperative antibiotic prophylaxis is highly recommended.

Some authors suggest the administration of immunoglobu-

lins. However, this intervention still awaits further evalua-

tion.

Diuretics

Diuretic therapy without prior volume expansion may

prove detrimental, by further contracting the intravascular

volume, thereby worsening hypotension and its sequelae.

Diuretics will increase blood viscosity and increase the risk

of venous thrombosis. Diuretic use should be restricted to the

management of pulmonary edema.

Dopamine

Dopamine used in oliguric patients with severe OHSS

results in significant improvement in renal function [34,35].

Dopamine produces its renal effect by increasing renal blood

flow and glomerular filtration. Dopamine therapy should be

given cautiously and under strict observation.

In one report, intravenous dopamine 4.32 mg/kg per 24

hours, was administered to 7 patients hospitalized with

severe OHSS following gonadotropin stimulation for IVF or

gamete intra-fallopian transfer (GIFT), beginning within 10

hours of admission [34]. Additional treatment consisted

of bed rest, restriction of fluid intake to 500 ml/day, and

daily monitoring of urine output, abdominal girth, and

weight. Biochemical and hematological clotting factors were

measured daily in the pregnant women. Serum hCG was

measured every 2 days, and patients were given a protein-

and salt-rich diet to increase the oncotic and osmotic blood

pressure. Dopamine treatment was continued until complete

resolution of ascites. In the 5 patients who were pregnant,

dopamine treatment was required for 9 to 22 days. The dura-

tion of treatment was related to the magnitude of the increase

of hCG. The longest duration (18-22 days) was needed in

patients with triplets and the shortest (9-10 days) in patients

with a singleton pregnancy; for patients with twins, treat-

ment duration was intermediate (14 days). In the 2 non-

pregnant women, dopamine was required for only 7 days.

In another report, a 750-mg tablet of docarpamine

(Dostinex) was taken orally every 8 hours by 27 patients

who were hospitalized because of OHSS and refractory to

therapy with intravenous albumin [35]. Clinical symptoms

associated with ascites were gradually improved; no major

adverse effects occurred.

Aspiration of Ascitic Fluid and Pleural Effusion in Severe OHSS

Ascites is the hallmark of OHSS, and symptoms resulting

from ascites are the most common reason for hospitalization.

Aspiration is not indicated in every patient. Paracentesis by

the transabdominal or transvaginal route is indicated for se-

vere abdominal pain, pulmonary compromise as demon-

strated by pulse oximetry, or tachypnea and renal compro-

mise as demonstrated by oliguria and increased creatinine

concentration [36, 37].

Abdominal Paracentesis

Paracentesis is followed by increased urinary output

shortly after the procedure, with a concomitant decrease in

the patient’s weight, leg edema, and abdominal circumfer-

ence. Creatinine clearance rate is increased following the

procedure. Paracentesis offers temporary relief of respiratory

and abdominal distress, but, since the fluid tends to recur,

some patients need repeated paracentesis and drainage of

effusions before spontaneous improvement occurs. The

amount of fluid aspirated can range between 200 and 4000

ml. The risk of injury to ovaries is minimized by ultrasono-

graphic guidance. Monitoring of plasma proteins is essential,

and human albumin should be infused whenever necessary.

Percutaneous placement of a pigtail catheter is a safe and

effective treatment modality for severe OHSS that may rep-

resent an alternative to multiple vaginal or abdominal para-

centesis [10].

Transvaginal Ultrasound-Guided Aspiration

Transvaginal ultrasound-guided aspiration is an effective

and safe procedure. Injury to the ovary is easily avoided by

puncture under ultrasonic visualization. No anesthesia is

required for the procedure, and better drainage of the ascitic

fluid is accomplished because the pouch of Douglas is the

most dependent part.

Autotransfusion of Ascitic Fluid

Transvaginal aspiration of ascitic fluid and autotransfu-

sion of the aspirated fluid has been used in treatment of se-

vere OHSS. The procedure is simple, safe, and straightfor-

ward and shows a striking physiological success in correct-

ing the maldistribution of fluid and proteins without the use

of heterogenous biological material. However, autotransfu-

sion is not recommended because of the possible reinjection

of cytokines into the circulation.

Pleurocentesis and Treatment of Pulmonary Complica-tions

Evaluation and treatment of patients with severe OHSS

complaining of dyspnea includes physical examination, chest

ultrasound and X-ray, and arterial blood gases. An accurate

evaluation of any pulmonary complications that may result

in hypoxia. When a pulmonary embolus is suspected, a CT

scan or ventilation perfusion scan should be performed.

Pulmonary compromise should be treated with oxygen sup-

plementation. Thoracocentesis may be necessary for patients

with significant hydrothorax. However, a dramatic improve-

ment in the clinical status may occur after paracentesis.


Adult Respiratory Distress Syndrome (ARDS)

ARDS is encountered after fluid overload. The impor-

tance of a strict fluid input/output balance in patients with

moderate complications of OHSS is stressed. Optimum man-

agement may require admission to an intensive care unit.

ARDS subsides after 3 to 6 days with fluid restriction, forced

diuresis, and dopamine therapy.

Pericardiocentesis

Pericardial effusion rarely occurs; if it does, drainage by

specialists may be necessary [31].

SURGICAL TREATMENT

Anesthesia Considerations in OHSS Patients

Although surgery is needed only infrequently, when it is

required there are several important considerations for the

anesthesiologist [10]. Careful positioning of patients during

surgery is important as the Trendelenberg position may fur-

ther compromise the residual pulmonary functional capacity.

Establishment of access lines may be necessary in patients

with contracted vascular volume. Drainage of pleural effu-

sions may assist in improving pulmonary status.

Surgery for Ruptured Cysts

Laparotomy, in general, should be avoided in OHSS. If

deemed necessary, in cases of hemorrhage hemorrhagic

ovarian cysts, it should be performed by an experienced gy-

necologist and only hemostatic measures undertaken so as to

preserve the ovaries.

Ovarian Torsion

Ovarian torsion is an infrequent complication of ovula-

tion induction, which, if unrecognized and untreated, results

in the loss of one or both ovaries [38]. Presenting symptoms

are severe unilateral adenexal pain, in a patient with enlarged

ovaries due to ovulation stimulation or with multiple preg-

nancy. Sonography with Doppler flow analysis can be diag-

nostic, but a finding of apparently normal blood flow does

not rule out ovarian torsion [38]. Although the adnexa usu-

ally appear dark, hemorrhagic, and ischemic, they can be

saved by simply unwinding them if a timely diagnosis is

made. This often can be performed as a laparoscopic proce-

dure.

Surgery for Ectopic Pregnancy Associated with OHSS

The combination of OHSS and ectopic pregnancy is not

encountered frequently. Diagnosis of tubal pregnancy by

vaginal ultrasound examination at this stage is not always

possible. The presence of large ovaries filling the pelvis

makes ultrasound scanning of other structures difficult. Fluid

in the cul de sac is of limited diagnostic importance in the

presence of ascites.

Other Surgery

Mesenteric resection after massive arterial infarction has

been reported. Rarely, vascular surgery is required to treat

thromboses that are complicated by recurrent emboli or re-

sistant to medical intervention. Posterolateral thoracotomy

and subclavian arteriotomy and thromboarterectomy by the

Fogarthy technique have been reported. Inferior vena cava

interruption to prevent massive thromboembolism also has

been used [10].

Pregnancy Termination

Pregnancy termination may be performed in extreme

cases and has been reported to improve the clinical picture of

neurological, hematological, and vascular complications [10].

CONCLUSION

OHSS is preventable in the majority of cases. However,

there is a narrow margin in which severe cases may still

occur, and this remains a challenge for the future [40].

EXPERT COMMENTARY

Ovarian hyperstimulation syndrome remains the most

serious complication of ovulation induction. Without under-

standing the pathophysiology, the treatment will remain em-

pirical in nature. Human chorionic gonadotropin is a central

piece that triggers a cascade of events that result in an over-

production of VEGF. Decreasing the dose of gonadotropins

and HCG and utilization of other agents such as dopamine

agonists and metformin will help in the prevention. Success-

ful prediction and active prevention is more helpful than

active treatment.

FIVE YEAR VIEW

OHSS could be successfully prevented over the next five

years if a high index of suspicion is exercised and methodi-

cal steps are taken for the prevention of the syndrome. Iden-

tification of these patients and judicious use of gonadotro-

pins is the beginning of the right path. The use of insulin

sensitizers and dopamine agonists will be more refined.

Newer technologies as in vitro maturation might completely

abolish the syndrome.

KEY POINTS

• Ovarian hyperstimulation syndrome (OHSS) is character-

ized by bilateral cystic ovarian xpe

• Severe OHSS may result in thromboembolism, adult res-

piratory distress syndrome, or kidney failure.

• Human chorionic gonadotropin increases VEGF produc-

tion by granulose cells and endothelial cells, resulting in

increased vascular permeability.

• The cornerstone of successful prevention of OHSS is

accurate risk prediction.

• Previous history of OHSS or polycystic ovary syndrome

is highly predictive of the development of OHSS during

ovarian stimulation.

• Ultrasound is essential for the prediction of OHSS be-

fore, during, and after the treatment cycle.

• Necklace sign, baseline antral follicle count, and ovarian

volume are strongly associated with OHSS.


• The presence of a large number of follicles (>20 per

ovary) and an increase in the number of small and inter-

mediate follicles are associated with an increases risk for

the development of severe OHSS.

• Increased intraovarian blood flow and low intravascular

ovarian resistance are correlated with the severity of

OHSS in patients who develop the syndrome.

• The presence of multiple pregnancy increases the risk of

the severity and duration of OHSS.

• Primary prevention of OHSS can be achieved by the use

of low-dose gonadotropins and, in some cases, ovarian

drilling prior to IVF.

• Secondary prevention of OHSS involves delaying hCG

(coasting) , or, in some cases, cancellation of hCG.

• Medical treatment of OHSS consists of correction of cir-

culatory volume and electrolyte imbalance.

• Ultrasonographic guidance of transvaginal or transab-

dominal aspiration of ascites improves the symptoms of

OHSS.

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Non-Surgical Treatment Options for Symptomatic Uterine Leiomyomas

Julierut Tantibhedhyangkul1,* and Millie A. Behera

2

1Obstetrics, Gynecology and Women's Health Institute, Cleveland Clinic, Cleveland, OH 44195, USA;

2Division of Repro-

ductive Endocrinology and Fertility, Department of Obstetrics and Gynecology, Duke University Medical Center, Dur-

ham, NC, USA

Abstract: Uterine leiomyomas (or uterine fibroids), benign tumors of the uterine smooth muscle cells, can cause signifi-

cant morbidity and impair quality of life in many women. For those who are asymptomatic, watchful waiting constitutes

appropriate management. For women with symptomatic fibroids, hysterectomy and myomectomy are traditionally the

standard treatments. In the last two decades, many alternatives to surgery for the management of fibroids have been

developed. Most of the current medical treatments involve hormone manipulation. Newer treatments such as mifepristone,

asoprisnil and aromatase inhibitors show promising results in fibroid symptom and size reduction; however, larger studies

are needed. A safe and effective therapy as an alternative to hysterectomy is uterine artery embolization (UAE), which

offers shorter recovery times and fewer major complications, though fertility and pregnancy outcomes after a UAE

may be affected. Limited data are available for the efficacy and safety of temporary uterine artery occlusion. Magnetic

resonance-guided focused ultrasound surgery (MRgFUS) is the newest treatment option for uterine fibroids. It also shows

promising results for symptom relief. The degree of symptom relief depends significantly on the amount of fibroid

volume that is non-perfused after treatment and the experience of the physician performing the procedure.

Keywords: Fibroids, hormones, NSAIDs, progestins, oral contraceptives, mifepristone, asoprisnil, gonadotropin-releasing

hormone agonists, uterine artery embolization, selective estrogen receptor modulators, transvaginal temporary uterine artery

occlusion, magnetic resonance-guided focused ultrasound surgery.

INTRODUCTION

Uterine leiomyomas (uterine fibroids) are one of the most

common benign tumors in the female reproductive tract.

African-American women generally have a higher incidence

of fibroids than white women [1]: current estimates indicate

that more than 80% of African-American women and nearly

70% of white women will develop fibroids by the age of 50

[2]. Other risk factors commonly associated with fibroids

include nulliparity, advanced age and obesity [3]. The

growth of fibroids is hormone driven, as demonstrated by

evidence that fibroids develop after puberty, fibroid growth

increases with age, and fibroid size increases during the re-

productive years and regresses after menopause [3]. Leio-

myoma tissues are monoclonal in origin [3, 4]. Many have

non-random chromosomal abnormalities such as deletions,

translocations and duplication. The most common mutations

involve regions in chromosomes 7, 12 and 14, which contain

genes essential in cell proliferation, regulation of transcrip-

tion, or cell cycle control [3, 4].

Fibroids are often discovered incidentally during a physi-

cal or radiological examination. For women who are asymp-

tomatic, watchful waiting is an appropriate treatment option

as fibroids are rarely malignant and pathology results are not

required for the diagnosis. For many other women, however,

uterine fibroids can cause significant morbidity and have a

detrimental effect on their quality of life. The symptoms re

*Address correspondence to this author at the Obstetrics, Gynecology and

Women’s Health Institute, Cleveland Clinic, Mail Code A81, 9500 Euclid

Avenue, Cleveland, OH 44195, USA; Tel: (216) 445-9706; Fax: (216) 445-

5526; E-mail: [email protected]

lated to fibroids include menorrhagia, which leads to iron-

deficiency anemia; pressure-related symptoms such as uri-

nary frequency, pelvic pressure, dyspareunia and difficulty

with urination or defecation; pain; and infertility.

The treatment for patients with fibroids depends on sev-

eral factors such as the size, number and location of the fi-

broids, the severity of the symptoms, and the patient’s child-

bearing concerns (Fig. 1). Medical treatment is often used as

a first line therapy, although many women might later need

surgical intervention. Hysterectomy and myomectomy per-

formed by laparotomy have been the traditional therapies for

women with symptomatic fibroids [5]. Hysterectomy is the

most common procedure because it is the only definitive

option and it eliminates the risk of recurrence. In fact, uterine

fibroid is the most common indication for hysterectomy in

the United States, and each year, more than 250,000 hyster-

ectomies are performed due to symptoms related to fibroids

[6]. Myomectomy is a traditional option for women who

anticipate future child bearing; hysteroscopic myomectomy

is an appropriate treatment for women with submucosal

fibroids; and endometrial ablation is often the treatment

of choice for women with menorrhagia who do not wish to

undergo major surgery and do not desire to bear children.

In the last two decades, many new therapeutic ap-

proaches for symptomatic fibroids have become available

(Table 1). Uterine artery embolization is a non-surgical ap-

proach that has been extensively studied and for which short-

and long-term outcome data are available. New techniques

such as magnetic resonance imaging (MRI)-guided focused

ultrasound and temporary uterine artery occlusion are being

extensively studied and show promising results. Further-

Non-Surgical Treatment Options for Symptomatic Uterine Leiomyomas Current Women’s Health Reviews, 2010, Vol. 6, No. 2 147

more, several new medications are being studied as a poten-

tial long-term treatment for fibroids. The clinical outcomes

of the non-surgical approaches to fibroid treatment will be

reviewed here.

Fig. (1). Fibroid Uterus.

Table 1. Currently Available Treatment Options for Leio-

myomas

Medical Treatments

• NSAIDs

• Combined oral contraceptives and progestins

• Danazol

• GnRH agonists

Surgical Management

• Hysterectomy (abdominal, vaginal, laparoscopic)

• Myomectomy (abdominal, laparoscopic, vaginal, hystero-

scopic)

• Endometrial ablation

• Laparoscopic myolysis

Uterine Artery Occlusion

• Uterine artery embolization

• Laparoscopic uterine artery occlusion

Magnetic resonance-guided focused ultrasound surgery (MRgFUS)

MEDICAL MANAGEMENT

A number of medical therapies are available for fibroid

treatment. Oral contraceptives or non-steroidal anti-

inflammatory drugs are often the first line of therapy to de-

crease pain and bleeding caused by fibroids, but these medi-

cations do not decrease the size of the fibroids. The available

medical options that could decrease the size of the fibroids,

such as GnRH agonists, have multiple side effects, so these

options cannot be used long term. Thus, many patients still

require surgical therapy. However, many new and promising

options for medical treatment are currently being studied for

potential long-term use.

COMBINED ORAL CONTRACEPTIVES AND

PROGESTINS

Combined oral contraceptives have been used effectively

to reduce blood loss in women with idiopathic menorrhagia.

Since it is a non-invasive approach, many physicians pre-

scribe oral contraceptives for women with fibroids and me-

norrhagia before turning to other more invasive options.

There are conflicting reports regarding the effect of com-

bined oral contraceptives on fibroids. A large prospective

study including over 3,000 patients with fibroids found a

positive correlation between fibroid diagnosis and the use of

oral contraceptives at a very young age (prior to 17 years

old) [7]. Other controlled studies, however, did not find any

such relationship [8, 9].

One study found that using combined oral contraceptives

containing a newer generation of progestins did not increase

the size of the fibroids [10]. Progestins are an effective

treatment for idiopathic menorrhagia, but data on the effec-

tiveness of progestins for fibroid treatment is limited. In a

study using GnRH agonists for fibroid treatment, an increase

in uterine size was found in patients who used progestin for

add-back therapy [11]. Another study, however, observed

that progestin decreased fibroid size [12]. Due to the con-

flicting information regarding the effects of estrogen and

progestins on fibroid growth, the uterine and fibroid size

should be closely monitored during the course of treatment

with combined oral contraceptives or progestins [13].

LEVONORGESTREL-RELEASING INTRAUTERINE

SYSTEM

The levonorgestrel-releasing intrauterine system (LNG-

IUS) releases a daily dose of levonorgestrel locally and con-

tinuously into the uterine cavity for at least 7 years. It has

been used effectively to reduce blood loss in women with

menorrhagia, and it is one of the most effective medical

treatments [14]. The studies looking at LNG-IUS for fibroid

treatment are limited to case reports and small case series.

All of the studies have recruited women with fibroids who

had a small uterus (<12 weeks size) and normal uterine cav-

ity [15-20]. LNG-IUS was shown to significantly decrease

the amount of bleeding and improve hematocrit in women

with menorrhagia due to fibroids. The largest study, which

included 46 women with fibroid-related menorrhagia,

showed a significant decrease in menstrual bleeding at 3

months after the IUS insertion in all of the subjects. At 6

months, fifty-six percent of the women in the study had be-

come amenorrhic and 22% were experiencing only spotting

or oligomenorrhea [15] . The rest of the subjects in the study

maintained a normal cycle [15]. No changes, however, in the

fibroids or uterine volume were noted during the treatment

[15, 16].

NON-STEROID ANTI-INFLAMMATORY DRUGS

(NSAIDS)

Non-steroidal anti-inflammatory drugs (NSAIDs) have

been shown to be an effective treatment for idiopathic me-

norrhagia [21]. However, NSAIDs are ineffective in reduc-

ing blood loss in women with fibroid-related menorrhagia

[22]. NSAIDs are often given to patients with fibroids to

148 Current Women’s Health Reviews, 2010, Vol. 6, No. 2 Tantibhedhyangkul and Behera

reduce pain symptoms, although their effectiveness for pain

relief in this population has not been documented [7].

DANAZOL AND GESTRINONE

The androgenic steroids danazol and gestrinone may be

effective treatment options for symptomatic fibroids. Dana-

zol is a derivative of 17 -ethinyltestosterone. It acts primar-

ily by inhibiting the luteinizing hormone (LH) surge, thereby

inhibiting ovulation and inducing amenorrhea. It also inhibits

many of the steroidogenic enzymes and increases free testos-

terone levels. It has been used in the treatment of endometri-

osis and menorrhagia. Because danazol induces amenorrhea,

it might have a role in reducing menorrhagia and anemia due

to fibroids, although data on the effects of danazol on fi-

broids is very limited. A Cochrane review did not find any

reliable evidence from randomized controlled trials showing

either that using danazol is beneficial or harmful in the

treatment of fibroids [23]. The side effects of danazol are

related to its androgenic properties and include weight gain,

muscle cramps, acne, hirsutism, hot flashes, fluid retention,

fatigue, and decreased breast size.

Gestrinone is a 19-nortestosternoe derivative. It has been

used in Europe for the treatment of endometriosis but is not

available in the United States. Gestrinone, starting at a dose

of 2.5 mg three times weekly for 6-24 months, has been

shown to decrease the size of fibroids and uterine volume

[24, 25]. Most of the patients who used gestrinone for 6

months maintained their decreased uterine size (compared

with the pretreatment size) 18 months after discontinuing the

medication [24].

GONADOTROPIN-RELEASING HORMONE AGO-NISTS (GnRH AGONISTS)

GnRH agonists have proven to be effective in the treat-

ment of fibroids, although mainly as short-term therapy for

up to 3-6 months prior to surgery. Long-term use of GnRH

agonists for fibroid treatment is limited because of the hypo-

estrogenic side effects. The continuous administration of a

GnRH agonist causes initial hypersecretion of follicle stimu-

lating hormone (FSH) and LH (flare effect), which lasts ap-

proximately 7-10 days, followed by a significant decrease in

FSH and LH secretion due to pituitary GnRH receptor down

regulation. This in turn causes a reduction in ovarian steroi-

dogenesis and results in a hypoestrogenic state, which is

likely the main mechanism causing the reduction in fibroid

size. GnRH-agonist treatment also causes a reduction in the

expression of several growth factor proteins such as trans-

formal growth factor , epidermal growth factor, insulin-like

growth factor (IGF-I), and IGF II [26]. Microarray analysis

has shown alteration in the expression of several genes

within the myometrium and fibroid tissues after GnRH-

agonist treatment [27, 28].

GnRH agonists have been shown to reduce both fibroid

size and uterine size during the course of treatment, with a

reduction in the fibroid volume of 35% to 65% noted within

the first 3 months of treatment [26, 29]. Fibroid and uterine

volume reductions usually occur during the first 3 months of

treatment [30, 31]. In one randomized controlled trial,

monthly injection of the GnRH agonist depot leuprolide ace-

tate every 4 weeks decreased uterine volume by 36% at 12

weeks and 45% at 24 weeks [30]. Most patients become

amenorrhic during the therapy; thus GnRH agonist treatment

improves the hematocrit level in patients with anemia.

The effects of GnRH agonists are not sustained after the

therapy is discontinued. Although symptomatic improvement

still persists in many women [30, 31], the fibroids return to

the pretreatment size within 4-6 months after therapy [31].

Long-term use of GnRH agonists, however, is limited by

significant side effects, in particular osteoporosis, which may

begin to develop after six months of the therapy. Other side

effects of GnRH agonists include hot flashes, vaginal dry-

ness, headache, arthralgia, myalgia, depression, insomnia,

emotional instability and decreased libido. Nevertheless,

most women who develop side effects during treatment tol-

erate them relatively well and continue with the duration of

treatment.

Add-back therapy with estrogen and progestins has been

used to reduce the side effects of GnRH agonists during

long-term treatment – in particular, to inhibit bone loss. In

one study, patients with symptomatic fibroids were random-

ized to receive add-back therapy with an estrogen-progestin

combination or high-dose progestin after 3 months of injec-

tion treatment with leuprolide acetate, a GnRH agonist. Pa-

tients were continued on leuprolide acetate for a total of 2

years [11]. In both groups, uterine size decreased by 40%

and bone mineral density decreased by 2.6% during the first

3 months of the treatment, but there was no significant

change in bone mineral density at the end of the study. Inter-

estingly, the uterine size in the progestin-only group in-

creased up to 95% of pretreatment size, while there was no

change in the uterine size in the estrogen-progestin group

[11]. These results are likely due to the role of progesterone

as a fibroid growth promoter.

Other medications have also been studied for use as

add-back therapy during GnRH agonist treatment. Tibolone,

a synthetic compound structurally related to 19-nortest-

osterone progestins, has been used to relieve postmenopausal

symptoms and osteoporosis. A small randomized trial

showed that daily tibolone add-back treatment combined

with 6 months of leuprolide acetate treatment reduced vaso-

motor symptoms and prevented bone loss without compro-

mising leuprolide’s ability to reduce fibroid size [32]. An-

other randomized controlled trial using tibolone as an add-

back therapy during 6 months of goserelin treatment found

that patients in the tibolone group had significantly less bone

loss than those in the control group, but there was no signifi-

cant difference in the reduction of fibroid volume in either

group [33]. Long-term use of tibolone and leuprolide acetate

for 2 years has also been found to reduce hot flashes and

prevent bone loss without changing the lipid profile [34]. In

another study, raloxifene, a selective estrogen receptor

modulator, was administered daily during 18 months of le-

uprolide acetate treatment for fibroids [35]. After 18 months

of treatment, a significant reduction in fibroid size was noted

while the bone mineral density and bone metabolic markers

remained unchanged from pretreatment levels.

Pretreatment with a GnRH agonist for 3-4 months prior

to surgery has many benefits. A Cochrane Database Sys-

temic Review evaluated the role of GnRH pretreatment prior


to hysterectomy and myomectomy [36]. Twenty-one trials

were included in the analysis. The review showed signifi-

cantly higher hemoglobin and hematocrit levels prior to

and after the surgery in women who were pretreated with

a GnRH agonist. Patients who used a GnRH agonist prior

to hysterectomy also experienced significantly less blood

loss and a shorter hospital stay than the patients who

received no pretreatment, although there was no difference

in the transfusion rate. Using a GnRH agonist prior to

hysterectomy also allowed many women to undergo vaginal

rather than abdominal hysterectomy due to the decrease

in their uterine size and lead to shorter operating times. In

addition, the decrease in uterine size due to GnRH agonist

treatment allows surgeons to use a transverse incision instead

of a vertical incision in many patients undergoing hysterec-

tomy or myomectomy. The disadvantage of using GnRH-

agonist pretreatment prior to myomectomy is the resulting

increase in the rate of fibroids recurring after surgery, which

is likely because smaller fibroids were not seen or were

ignored during the myomectomy. Results from the Cochrane

review, however, did not have enough data to support this

concept.

GnRH ANTAGONISTS

GnRH antagonists competitively bind to the GnRH

receptor, causing an immediate reduction of gonadotropin

secretion and a reduction of ovarian steroidogenesis without

causing the initial flare effects seen with the use of GnRH

agonists. GnRH antagonists have also been shown to directly

induce apoptosis in uterine leiomyoma cells [37, 38]. A

clinical study using daily subcutaneous injections of geni-

relix, a GnRH antagonist, in 20 women with fibroids showed

a rapid decrease in fibroid and uterine size (median duration

of 19 days, range 1-65 days) [39]. During the first 3 weeks of

treatment, the fibroid size was decreased by 42.7% (14% to

77%) and uterine size was decreased by 46.6% (6% to 78%).

Another study using the GnRH antagonist cetrorelix also

showed a rapid reduction in fibroid size by 16 days of treat-

ment, with a mean fibroid size reduction of 16% [40]. Side

effects of the GnRH antagonists are mainly related to hypo-

estrogenism. GnRH antagonists are usually administered in

daily subcutaneous doses and currently, there are no longer-

acting GnRH antagonists available, which make long-term

usage impractical.

MIFEPRISTONE

Mifepristone (RU486), a selective progesterone receptor

modulator, has been studied for many clinical implications

including fibroids. In the presence of progesterone, mifepris-

tone act as a competitive inhibitor of the progesterone recep-

tor. It also has an antiglucocorticoid property. The first re-

port describing the use of mifepristone for the treatment of

fibroids was authored by Murphy et al. [41]. In the study, 10

patients received 50 mg of mifepristone for 3 months. At the

end of the study, a 49% reduction in fibroid volume was

noted and all of the patients had become amenorrrhic. Sub-

sequent to this study, several smaller studies, with a duration

of 3 months to 1 year, used different dosages of mifepris-

tone, ranging from 5- 50 mg, for fibroid treatment [42-49].

All of the studies revealed a decrease in uterine and fibroid

volume ranging from 26% to 74%. A significant decrease in

blood loss and a high incidence of amenorrhea were reported

in all the studies. A recently study by Eisenger et al. used a

much lower dose of mifepristone – 2.5 mg/day for 6 months

– than in other studies [50]. An 11% reduction in uterine

volume with significant reduction in pain and improvement

in quality of life were noted at the end of the study.

The main side effect of mifepristone is vasomotor symp-

toms. Hot flashes are dose related; no hot flashes have been

reported in patients using a 5 mg dose [46]. Mifepristone has

no effect on bone density, which makes this medication more

attractive than the GnRH agonists. The major concern for

long-term use of mifepristone is the potential risk of endo-

metrial hyperplasia from unopposed estrogen. The rates of

endometrial hyperplasia range from 2% to 28% [43, 44, 46,

and 50]. Two reports on studies using low doses (2.5 and 5

mg) of mifepristone show no evidence of endometrial hyper-

plasia [50]. In contrast, a report from Bavaria et al. using 10

mg revealed a much higher rate of endometrial hyperplasia

(63%) compared with other studies [42]. One patient in the

Bavaria et al. study also had complex hyperplasia. The

available data available suggests that the incidence of endo-

metrial hyperplasia is likely dose dependent. None of the

endometrial biopsies conducted in any of the studies showed

evidence of atypical hyperplasia or cancer.

Few randomized controlled trials using mifepristone for

fibroid treatment are available. A study by Engman et al. randomized 30 women with symptomatic fibroids to receive

50 mg of mifepristone or a placebo every other day for 3

months [43]. Significant fibroid volume reduction averaging

28% was noted in the mifepristone group but not in the con-

trol group. Most of the patients who took mifepristone were

amenorrhic after 4 weeks of treatment. There was no evi-

dence of endometrial hyperplasia reported in this study. A

double blind, randomized controlled trial comparing the use

of 10 mg of mifepristone or a placebo daily for 3 months in

40 women also showed a 26%-32% reduction of uterine vol-

ume with mifepristone [42]. In the mifepristone group, 83%

of the patients showed improvement in dysmenorrhea but

still had other fibroid-related symptoms. As mentioned ear-

lier, this study reported a much higher incidence of endo-

metrial hyperplasia than other studies. A randomized study

conducted by Carbonell Esteve et al. compared the efficacy

of using daily doses of 5 mg and 10 mg mifepristone for 3

months for the reduction of fibroid volume in 100 women

[44]. Both dosages showed comparable reductions in fibroid

volume (57% and 45% in the 5 and 10 mg groups, respec-

tively) and uterine volume (36% and 40% in the 5 and 10 mg

groups, respectively). Only one patient (2%) in this study,

from the 10 mg group, developed endometrial hyperplasia.

Further trials have studied the efficacy of long-term us-

age of mifepristone. A controlled study using 5 mg mifepris-

tone daily for 6 months and a placebo in the control group

showed significant reduction in fibroid volume without evi-

dence of endometrial hyperplasia in the treatment group [45].

Another study comparing the use of 5 mg and 10 mg of

mifepristone for 1 year showed a comparable volume reduc-

tion and amenorrhea rate in both groups [51]. The efficacy of

mifepristone was sustained after treatment for 9 patients in

this study, who maintained reduction of fibroids at 6 months


after treatment [51]. The dosage of mifepristone currently

available in the market is much higher (600 mg) than the

dosage used in the aforementioned studies, thus limiting the

use of this medication for fibroid treatment.

ASOPRISNIL

Asoprisnil is another selective progesterone receptor

modulator that has shown some promising results as a medi-

cal treatment for fibroids. Unlike mifepristone, asoprisnil is

not effective in inducing labor in animals [52]. Asoprisnil

has an antiproliferative effect in the endometrium of both

animals and humans [52]. In vitro, asoprisnil inhibits leio-

myoma cell growth and induces apoptosis but has no effect

on normal myometrial cell growth [53]. It up-regulates the

extracellular matrix metalloproteinase inducer in cultured

leiomyoma cells resulting in down-regulation of collagen

synthesis [54]. It also down-regulates the expression of sev-

eral growth factors, such as EGF, IGF-I and TGF-ß cultured

leiomyoma cells [55].

A very limited number of published studies have reported

on the use of asoprisnil for fibroid therapy in humans. A

phase one randomized trial comparing the use of different

dosages of asoprisnil (5 – 100 mg per day) and a placebo for

28 days showed that asoprisnil delays the onset of the men-

strual cycle and increases the cycle length [56]. This effect

was observed in women using a dose of 10 mg or higher, and

was dose dependent. The largest published study is a phase

two, multi-centered, double-blind, randomized controlled

trial including 129 patients who were randomized to use 3

different dosages of asoprisnil (5, 10, or 25 mg per day) or a

placebo for fibroid treatment for 12 weeks [57]. A 36 % re-

duction in fibroid volume was noted by week 12 in the 25

mg group. A significant decrease in uterine bleeding was

observed in all three asoprisnil treatment groups, with the

greatest effect seen in the 25 mg group. Amenorrhea was

noted in 16%, 36%, and 70% of patients in the 5, 10, and 25

mg groups, respectively. At the same time, significant symp-

toms were noted in the 10 and 25 mg groups. While no evi-

dence of endometrial hyperplasia was noted in any of the

studies, two unique endometrial pathologies called ‘non-

physiologic secretory effects’ and ‘secretory patterns, mixed

type’ were seen in many patients who took asoprisnil [56-

58]. These are characterized by the presence of weak secre-

tory glands with minimal or absent proliferation and variable

effects in the stroma [56].

The side effects of asoprisnil are mild, including bloat-

ing, flatulence, breast pain and vasomotor symptoms. All of

the symptoms were reported as mild and none of the patients

stopped the treatment due to side effects [57]. A decrease in

uterine artery blood flow was seen in another study when

subjects took 25 mg of asoprisnil for 12 weeks [59]. This

might serve as one of the mechanisms by which asoprisnil

reduces uterine and fibroid volume.

SELECTIVE ESTROGEN RECEPTOR MODULA-TORS (SERMS)

Data on the effects of SERMs in the treatment of fibroids

is limited. Raloxifene has been used for fibroid treatment in

several small studies with conflicting results. A study of 70

postmenopausal women with fibroids taking 60 mg/day of

raloxifene for 12 months showed a significant decrease in

mean uterine and fibroid size starting from 6 months of

treatment [60]. Studies in premenopausal women, however,

show conflicting results. A study by Palomba et al. random-

ized 90 premenopausal women with asymptomatic fibroids

into three treatment groups: raloxifine at 60 mg/day, raloxi-

fine at 180 mg/day, or a placebo. During the 6 months of

therapy, no significant changes in uterine or fibroid size or

the amount of uterine bleeding were noted among the three

groups [61]. Another study by Jirecek et al. randomized 25

premenopausal women with fibroids to receive 180 mg/day

of raloxifene (the same dose used in Palomba’s study) or no

treatment for 3 months [62]. Interestingly, after 3 months of

treatment, women in the raloxifene group showed a signifi-

cant decrease in fibroid size when compared with those in

the control group. Jirecek et al. speculated that the difference

in the results of the two studies might be due to the differ-

ence in the average age of the subjects (36 years old and 40

years old in the Palomba and Jirecek studies, respectively)

[61, 62]. A Cochrane Database Systemic Review of this

topic found no evidence that SERMs reduce the size of

fibroids or improve outcomes [63].

In conclusion, there is currently not enough information

to conclude that SERMs have any benefit in fibroid treat-

ment or improve outcomes in premenopausal women.

AROMATASE INHIBITORS

Aromatase, an enzyme that converts androgens to estro-

gen, is very important in the production of estrogen. Aro-

matase activity and its transcripts have been found in leio-

myoma tissues, showing that these tissues can synthesize

estrogen locally and promote their own growth [64]. The

aromatase mRNA level is much higher in leiomyoma tissues

than in normal myometrial tissue, especially in African-

American women [65]. This might account for the higher

prevalence of fibroids seen in African-American women.

Since estrogen plays an important role in the pathophysiol-

ogy of fibroids, and aromatase, which is essential to the pro-

duction of estrogen, is found in fibroid tissues, aromatase

inhibitors are a potential candidate for fibroid treatment.

Published data on aromatase inhibitors and fibroids is

limited to case reports and small trials [66-68]. Two studies

using anastrazole at 1 mg/day for 3 months in women with

fibroids showed an average fibroid volume reduction of be-

tween 9.3% and 55.7% [67, 68], and most patients reported

improvement in their fibroid-related symptoms. One of the

studies noted a significant change in fibroid volume in

women older than 40 years but found no change in women

younger than 40 years. A study comparing fibroid treatment

with letrozole (2.5mg/day) with a GnRH agonist for 3

months revealed comparable effects in the reduction of fi-

broid volume in both groups [66]. No serious side effects

were reported in any of these studies.

In conclusion, aromatase inhibitors are a promising

medication for the treatment of fibroids. However, random-

ized controlled trials are needed to confirm the efficacy of

this medication for this indication. The long-term effects of

this medication in premenopausal women also need to be

studied.


UTERINE ARTERY EMBOLIZATION

Uterine Artery Embolization (UAE) is a minimally inva-

sive procedure performed by interventional radiologists. The

procedure has been used since the 1970’s for the treatment of

obstetric hemorrhage, but it was first utilized as a treatment

for fibroids by Ravina et al. in 1995 [69]. Since then, it is

estimated that more than 200,000 UAEs for fibroid treatment

have been performed worldwide [70].

Of all the minimally invasive treatments for fibroids,

UAE is the most thoroughly studied to date. The procedure

involves passing an angiographic catheter into each uterine

artery through the femoral artery and then injecting the em-

bolization particulate agents to occlude the branches of the

uterine arteries that supply the fibroids [71]. The emboliza-

tion particulate agents normally used include polyvinyl alco-

hol, tris-acryl gelatin microspheres and gelatin sponge parti-

cles [72]. The purpose of the procedure is to significantly

decrease the blood supply to the uterus and fibroids, causing

permanent ischemia and necrosis of the fibroid tissues while

having no permanent effects on normal myometrial tissues

[73, 74]. The treatment causes the global reduction of fibroid

volume and results in the improvement of the symptoms

associated with fibroids. During the procedure, patients nor-

mally receive conscious sedation, although some centers use

epidural or spinal anesthesia instead [72]. After the proce-

dure, most patients experience moderate to severe pelvic

pain for several hours due to ischemia and postembolization

syndrome. Thus, most centers admit the patients overnight

for pain management. Postembolization syndrome is a side

effect generally occurring after the embolization of solid

organs, likely from the immune response related to ischemia

or degeneration [73, 75]. It occurs in up to 40% of patients

who undergo UAE [74]. The symptoms of postembolization

syndrome include diffuse abdominal pain, low grade fever,

malaise, loss of appetite, nausea, vomiting and leukocytosis

[74]. The syndrome is self limiting and lasts from a few

hours to a few days [74, 75]. The treatment for the syndrome

includes supportive management with anti-inflammatory and

antipyretic drugs. Patients usually return to normal activity

within 7 to 14 days [71, 76].

Complications after the procedure are few and mostly

minor and transient. Data from the Fibroid Registry for Out-

come data (FIBROID) registry, the largest prospective regis-

try, which has collected data from more than 3,000 patients

who underwent UAE at 72 sites, reports perioperative com-

plications of 2.7% with a rate of major events of 0.66%.

Those complications include pain, contrast/drug reaction,

urinary retention, groin hematoma, nausea, vessel injury,

device related and non-target embolization [76]. Spies et al. reported perioperative complications of 5% in 400 consecu-

tive patients following UAE [77]. The FIBROID registry

reported adverse events within 30 days after treatment at

26%, with reporting of major events at 4.8 % [76]. The most

common major adverse events were inadequate pain control

requiring an emergency room visit or readmission (2.1%)

and vaginal expulsion of the fibroids (0.7%). Minor adverse

events include hot flashes, vaginal discharge, infection,

bleeding, headache and passing of fibroid tissues [76-78].

Transvaginal expulsion of the fibroid tissues is a common

complication following UAE and sometimes requires sur-

gery [70]. The most serious complication is intrauter-

ine/pelvic infection requiring surgery, which occurs in 2.6%

of patients [79]. There was no death reported in any of the

large clinical trials. There were, however, 2 case reports of

death after UAE due to septicemia [80, 81]. One letter to the

editor reported a death after UAE due to systemic non-target

embolization from an arteriovenous malformation within the

fibroids and patent foramen ovale [82].

Short-term and mid-term outcomes of UAE have been

reported by several large case series. Significant decreases in

fibroid and uterine volume after treatment range from 40%

to 70%. Most patients show improvement in menorrhagia

and pain reduction associated with fibroids after the treat-

ment [75, 78, 83-86], as well as a decrease in emotional and

somatic concerns [87]. Patients who undergo UAE experi-

ence a very high rate of satisfaction (ranging from 85% to

95%) at different time points after the procedure.

Long-term outcomes of UAE are very encouraging. At 3

years after treatment, most patients in the FIBROID registry

continued to have significant improvement in their quality of

life and 85.68% of patients stated that they would recom-

mend UAE to family members or friends [88]. Fourteen per-

cent of the patients in the studies required additional treat-

ments or repeat embolization to further alleviate their symp-

toms. Another study including 200 patients showed that 73%

of the patients continued to have symptom improvement

after 5 years of treatment [89]. If patients do not improve by

1 year or if they have large fibroids, symptoms may still re-

main at 5 years [89].

The Uterine Artery Embolization (UAE) versus Hyster-

ectomy for Uterine Fibroids trial (EMMY)

was a multicenter,

randomized trial in which uterine fibroid embolization was

compared with hysterectomy in 177 patients. At 24 months

after treatment, 24% of the patients in the UAE group un-

derwent hysterectomy [90]. The remaining patients in the

UAE group continued to show improvement in health-

related quality-of-life outcomes. Uterine and fibroid volume

reduction in the UAE patients was 48.2% and 60.5%, respec-

tively [90]. Walker et al. reported long-term clinical out-

comes at 5-7 years after UAE in 172 women [91]. More than

80% of the patients continued to experience improvement in

fibroid-related symptoms. Five percent of the patients moni-

tored in this report became amenorrhic after UAE and 75%

continued to have reduced menstrual flow after surgery.

Overall, most of the patients (86%) remained “very satis-

fied” or “satisfied’ with the procedure. Sixteen percent of the

patients required additional procedures for fibroid treatment.

Eighty-five percent of the patients reported improved quality

of life and 88% of the patients would recommend the proce-

dure to others.

COMPARATIVE STUDIES

A number of studies have compared the outcomes of

UAE with those of surgical procedures. All showed compa-

rable outcomes between UAE and the surgeries, although for

some patients in the UAE group, the therapy failed and they

later required additional treatment for their symptoms.

Most of the large studies have compared the outcomes

between UAE and hysterectomy. A randomized trial by


Pinto et al. assigned 57 women to a UAE or hysterectomy

group for symptomatic fibroid treatment in a ratio of two to

one [92]. The controversial randomized method used by Ze-

len, in which women in the hysterectomy group were not

informed about the study or alternative treatments, was used

in this study. There was also some overlapping in the ran-

domization in that 3 of the patients who underwent hysterec-

tomy had undergone UAE first. The primary outcome of the

study concerned the length of hospital stay. The results

showed that the length of hospital stay for the UAE group

was shorter than for the hysterectomy group by 4.14 days

(1.59 and 5.85 days for the UAE and hysterectomy groups,

respectively). Recovery time was also shorter for patients

who underwent UAE compared with the hysterectomy pa-

tients (9.5 vs. 36.2 days, P<0.001). On the other hand, more

patients in the UAE group developed complications after the

procedure compared with those in the hysterectomy group.

The complications in the UAE group, however, were minor

(PES, pelvic pain, urinary tract infection), whereas the hys-

terectomy group experienced mostly major complications

(surgical incision abscess, intra-abdominal abscess plus

anemia, and urinary retention).

The EMMY trial (The Uterine Artery Embolization

[UAE] versus Hysterectomy for Uterine Fibroids trial)

was a

multicenter, randomized trial that compared UAE and hys-

terectomy for treatment of symptomatic fibroids among 177

patients in the Netherlands [78, 93-97]. The primary end

point of this study was avoidance of a subsequent hysterec-

tomy in at least 75% of patients undergoing UAE. The sec-

ondary end points were symptom improvement in symptoms

and reduction of uterine and fibroid volume. The study met

the primary end point. At two years after UAE, 23.5% of the

patients in the UAE group were required to undergo a hys-

terectomy; thus, 76.5% of these patients avoided hysterec-

tomy [78]. Patients in the UAE group had a shorter hospital

stay than the patients in the hysterectomy group (2.7 vs. 5.1

days in the hospital), and the overall recovery time was

much shorter in the UAE patients [96]. Similar improve-

ments in health-related quality of life were noted in both

groups. At 2 years after treatment, most patients in both

groups reported they were at least “moderately satisfied”

(92% and 90% in UAE and hysterectomy groups, respec-

tively) with their treatments [90].

HOPEFUL (Hysterectomy Or Percutaneous Embolisa-

tion For Uterine Leiomyomata), a multicenter retrospective

study, compared the outcomes for over 1100 women who

underwent UAE or hysterectomy in the UK [75, 79]. All of

the patients were followed up 2 to 5 years postoperatively in

the UAE group and up to 9 years in the hysterectomy group.

At baseline, women in the UAE group were younger and

were more likely to have had prior pelvic surgery than the

hysterectomy cohort (P < 0.001). Obesity, co-morbidity, and

history of pelvic surgery increased the risk of complications

of the UAE. Patients in the UAE group developed fewer

complications than patients who underwent hysterectomy:

the odd ratio was 0.60 (95% CI 0.32–1.15) [75]. Interesting,

although more women in the hysterectomy cohort reported

symptom relief (95% vs. 85%, P < 0.0001), fewer women in

that cohort (85%) said they would recommend the treatment

to a friend, compared with 91% in the UAE group (P=

0.007) [75].

The Randomized Embolization versus Surgical Treat-

ment for Fibroids (REST) trial randomized 157 patients in

the UK in a 2:1 ratio to undergo either UAE or surgery (hys-

terectomy and myomectomy) for symptomatic fibroids [98].

The primary purpose was to compare the quality of life at 12

months after treatment. The study found no significant dif-

ference in health-related quality of life between the two

groups at 12 months, although women in the surgery group

had significantly greater symptom improvement scores than

the UAE group. A high percentage of patients in both groups

said they would recommend their treatment to a friend (93%

and 88% in the surgery and UAE groups, respectively). The

median hospital stay and the recovery time after procedure

were shorter for the UAE group than for the surgery group.

Twenty of the patients in the UAE group required additional

therapy due to continued or recurrent symptoms, whereas

only one patient in the surgery group required additional

treatment.

A few studies have compared the outcomes of UAE and

myomectomy. A study by Goodwin et al. compared the

treatment outcomes of 149 patients who underwent UAE and

60 patients who underwent myomectomy [99]. The primary

endpoint in the study was an improvement of at least 5

points in the uterine fibroid quality-of-life questionnaire

score (UFQoLs) from baseline to 6 months after the proce-

dure. Significant and comparable improvement in UFQoLs,

menstrual bleeding, uterine volume, and overall quality of

life were noted in both groups. Patients in the UAE group,

however, had a shorter hospital stay (23.8 hr vs. 61.6 hr;

P<0.0001) and a shorter recovery time (14.6 days vs. 44.4)

than patients in the myomectomy group (P<0.05). At one

year, only 1.7% of the patients in the UAE group required

additional treatment.

A study by Mara et al. randomized 121 women with fi-

broids who wished to remain fertile into 2 treatment groups,

one to undergo UAE and the other myomectomy [100]. The

aim of the study was to compare the safety, efficacy and re-

productive outcomes between the two treatments. The pa-

tients were followed for 2 years. There were no differences

in the rate of treatment failure (10% in both groups) and

early complications between the two groups. Patients in the

myomectomy group required longer hospital stays than pa-

tients in the UAE group. Safety and efficacy in reducing

symptoms were found to be comparable in the two groups.

However, significantly more patients in the UAE group re-

quired additional intervention (32% vs. 3%), the most com-

mon reason being the persistence of large fibroids > 5 cm.

The reproductive outcomes between the 2 groups also dif-

fered. This result is discussed in detail in the section below

describing reproductive outcomes after UAE .

REPRODUCTIVE OUTCOMES AFTER UTERINE

ARTERY EMBOLIZATION

Significant concerns after uterine artery embolization

include amenorrhea and premature ovarian failure. The inci-

dence of amenorrhea after UAE has been reported to range

from 3% to 7% [86, 89, 101]. Most of the patients who de-

veloped permanent amenorrhea were women who were older

than 45 years at the time of the procedure [86, 101-103]. The

largest available data set comes from the FIBROID registry,


which shows evidence of amenorrhea in 7.3% of UAE pa-

tients [89]. Eighty-six percent of these were women were 45

years of age or older [102]. The potential mechanism by

which UAE causes premature ovarian failure is non-target

embolization of utero-ovarian collateral circulation [71],

which can cause a reduction in the ovarian blood supply,

which in turn results in a decrease in the ovarian reserve or

ovarian failure. To evaluate the effects of UAE on the ovar-

ian reserve, a small number of studies have compared basal

levels of FSH (an ovarian reserve marker) before and after

the procedure [104,105]. All of the studies showed no evi-

dence of a decrease in the ovarian reserve after the proce-

dure, except in patients who were older than 45 years. One

study comparing the FSH level and the antral follicle count

before and after UAE in 20 women aged 33-39 years showed

no difference in the before and after measurements [104].

Another study that compared the difference in FSH levels

before and after UAE in 63 patients found, on the whole, no

difference before and after surgery [105]. However, when

the data were stratified by age, 15% of the patients who were

older than 44 years (4 patients) had FSH in the menopausal

range after surgery. A study by Healey et al. looked at the

ovarian reserve prior to and after UAE and myomectomy and

found no difference in the ovarian reserve prior to or after

either procedure [106].

Data on pregnancy outcomes after UAE are limited to

case reports and case series. Although uncomplicated preg-

nancies have been reported, several studies show an in-

creased risk of pregnancy complications after UAE, such as

miscarriage, malpresentation, postpartum hemorrhage, ab-

normal placentation and cesarean section [75,100,107-115].

In the HOPEFUL study, 27 women achieved 37 pregnancies

after UAE [75]. Among these, 15 miscarriages, 2 ectopic

pregnancies, 1 termination and 19 live births were reported.

In the Ontario multicenter trial, 24 pregnancies occurred, of

which 4 resulted in miscarriages, 14 in full-term deliveries,

and 4 in preterm deliveries [110]. Of the 18 deliveries, 9

were vaginal deliveries and 9 were cesarean sections. Three

patients with abnormal placentation were also noted, and one

of them needed a cesarean hysterectomy because of severe

postpartum hemorrhage.

In a report by Walker et al., 108 out of approximately

1200 women who underwent UAE tried to conceive [109].

Thirty three women became pregnant which resulting in 56

pregnancies. Of these, there were 17 (30.4%) miscarriages, 3

stillbirths and 33 deliveries. The cesarean section rate in this

study was 72.7% and there were 6 cases of postpartum hem-

orrhage. It is difficult to conclude that the complications suf-

fered by these women after UAE were related to the proce-

dure alone, since fibroids themselves constitute a risk factor

for pregnancy complications. Furthermore, many of these

women were in the advance-reproductive age group and their

age could have contributed to an increased risk of miscar-

riage.

A recent systemic review by Homer et al., using the data

available in the existing literature, compared pregnancy out-

comes in women who underwent UAE with pregnancy out-

comes in an age-matched control group of women with un-

treated fibroids [116]. Two hundred and twenty-seven preg-

nancies in the UAE group were compared with over 4000

pregnancies in the control group. The study showed no dif-

ferences in preterm labor, malpresentation, or intrauterine

growth restriction between the two groups. However, the

rates of cesarean section (66% vs. 48.5%) and postpartum

hemorrhage (13.9% vs., 2.5%) were significantly higher in

the UAE group. The miscarriage rate in the UAE group was

also double that of the control group. (35.2% vs. 16.5%, OR

2.8, 95% CR 2.0-3.8) Since this was a retrospective review,

it was difficult to account for confounding factors such as

weight or parity. The patients in the UAE group were more

likely to be symptomatic than patients who had not received

any treatment and might have larger fibroids. Regardless of

these limitations, the authors concluded that early pregnan-

cies are significantly vulnerable after UAE, and their data

supports the recommendation of ACOG that UAE is rela-

tively contraindicated in women who desire future childbear-

ing [117].

Mara et al. compared the reproductive outcomes of

women who underwent myomectomy and UAE [100]. The

patients were followed for up to 2 years after treatment. Of

121 patients in the study, 26 from the UAE group and 40

from the myomectomy group attempted to conceive after

treatment. Thirteen women (50%) from the UAE group and

31 women (78%) from the myomectomy group became

pregnant within 2 years after the procedures. Women who

underwent UAE had a significantly lower pregnancy rate,

lower delivery rate (19% vs. 48%, 6 and 19 patients), and

higher miscarriage rate (64% vs. 23%, 9 and 6 patients) than

women who underwent myomectomy in this study. Although

the number of patients who became pregnant was very small,

the authors concluded that myomectomy is a better choice of

treatment for women who desire future fertility. A retrospec-

tive study by Goldberg et al. using all the data available from

the literature compared pregnancy outcomes between women

who underwent UAE and laparoscopic myomectomy [118].

They found 53 pregnancies after UAE and 139 pregnancies

after laparoscopic myomectomy. The study found a higher

incidence of preterm labor (OR 6.2%; 95% CR 1.4, 27.7)

and malpresentation (OR 4.3%; 95% CR 1.0, 20.5) in the

UAE group. While there was no significant difference in the

rates of postpartum hemorrhage and spontaneous abortion

between the two groups, the rates in both groups were higher

than those found in the general population.

TRANSVAGINAL TEMPORARY UTERINE ARTERY OCCLUSION

Transvaginal temporary uterine artery occlusion, using a

Doppler-Guided Uterine Artery Occlusion Device, is a new

procedure originally developed to decrease blood loss during

gynecologic surgeries. Its use for fibroid treatment has been

described in a very small number of case reports and case

series [119-121]. The procedure is based on the theory that

fibroid tissues undergo necrosis after uterine ischemia--the

same theory that underlies UAE. The device, known as the

FlostatTM system (Vascular Control Systems, San Juan Cap-

istrano, CA, USA – now owned by Johnson & Johnson),

consists of a guiding cervical tenaculum, a transvaginal vas-

cular clamp with integrated Doppler ultrasound crystals, and

a small battery-powered transceiver that generates the Dop-

pler sound. The clamp slides along the guiding tenaculum to


the lateral vaginal fornices at the 3 and 9 o’clock cervical

positions. Using the Doppler ultrasound signal, the right and

left uterine arteries are identified. The clamp then advances

further into the vaginal fornices and displaces the uterine

arteries superior to the point of insertion into the uterus.

When the clamp is closed, it occludes both of the uterine

arteries against the cervix. For the treatment of uterine fi-

broids, the instrument is left in place for 6 hours and then

removed. During the procedure, patients receive a paracervi-

cal block or epidural anesthesia [121]. Minimal pain

has been noted during the procedure, with no pain medica-

tion required after the patient’s discharge from the hospital

[122].

The published data on the use of this system for fibroid

treatment is still preliminary. A case report by Vilos et al. showed a significant decrease in uterine fibroids and uterine

volume of more than 44% in a patient treated with the in-

strument [122]. At three months after treatment, the patient

reported significant improvements in her symptoms. A feasi-

bility study by Hald et al. recruited eight patients for this

procedure [121], of which only 4 patients had successful

occlusion. The authors reported two cases of hydronephrosis,

and 2 of the 4 patients required additional therapy for fibroid

treatment.

This procedure has some advantages over UAE in that

there is no radiation exposure, less pain after the procedure

and no risk of non-target embolization. However, there is

very limited data on both short-term and long-term outcomes

on which to base a recommendation. Because the uterine

arteries are occluded only temporarily using this instrument,

the degree of fibroid ischemia is potentially less than in

UAE. Thus, this treatment might not be favorable to UAE in

the long term for this reason. Furthermore, the potential for

urethral injury noted in the feasibility study needs to be ad-

dressed in larger studies.

MAGNETIC RESONANCE-GUIDED FOCUSED ULTRASOUND SURGERY

Magnetic resonance-guided focused ultrasound surgery

(MRgFUS) has been used in the treatment of uterine fibroids

since 2000. This technique combines the use of high-energy

focused ultrasound technology with real-time MRI guidance.

High-energy focused ultrasound is a thermal ablation proce-

dure in which high-intensity ultrasound waves are transmit-

ted from transducers outside the body to a small area within

the targeted treatment region deep inside the body. Within

seconds, the temperature of the targeted tissues rapidly in-

creases, causing tissue necrosis, while the surrounding areas

remain unaffected. MRI guidance provides accurate imaging

of the tissues and surrounding organs, allowing extreme pre-

cision with planning, monitoring, and treatment. During

treatment, MRI thermal imaging provides real-time tempera-

ture monitoring and thus assures the proper energy exposure

in the target tissues and prevents injury to the surrounding

organs. This technology is currently being used not only for

uterine fibroids, but also for different types of tumors [123].

MRgFUS for the treatment of fibroids is normally done

on an outpatient basis. During the procedure, the patient lies

prone on the MRI table with her abdomen positioned over

the ultrasound transducer. Conscious sedation is usually pro-

vided with intravenous medications given to the patient

throughout the duration of the procedure. The treatment it-

self consists of a series of high-energy ultrasound pulses

(sonications), each lasting approximately 20 to 40 seconds.

The interval between each sonication is approximately 90

seconds to allow the tissue temperature to normalize. Multi-

ple sonications are required over one to four hours to treat

each fibroid, depending on its size. The patient normally

returns home within 1 to 2 hours after the procedure. Post-

procedure pain is usually manageable with over the counter

oral analgesics. Patients typically return to normal activity

within three days. The ExAblate 2000 (InSightec, Inc. Haifa,

Israel) was the first MRgFUS system approved by the U.S.

Food and Drug Administration in 2004 for the treatment of

symptomatic fibroids in women who had completed child-

bearing.

Because MRgFUS has only recently come into use for

fibroid treatment, only short-term outcome data are available

in the literature. The treatment has been shown to improve

fibroid symptoms, with the degree of improvement varying

significantly according to the treatment volume. In an early

study, Hindley et al. report a case series including 109 pa-

tients who underwent MRgFUS for fibroid treatment [124].

The protocol used in the study resulted in a treatment volume

of approximately 25% and a mean fibroid volume reduction

of approximately 13.5% at 6 months. Interestingly, despite

the small degree of volume reduction, 79.3% of the patients

experienced significant improvement of their symptoms as

measured by the Uterine Fibroid Symptoms and Quality of

Life Questionnaire score. The follow-up report from the

same study showed that 51.2% of the patients who still re-

mained in the study at 12 months (42 of 82 patients) still had

significant improvement in their symptoms [125]. Nine seri-

ous adverse events were reported in the study, although only

one patient had nausea after the procedure that was thought

to be related to the surgery [124]. The rest of the adverse

events were related to patients’ underlying conditions

(fibroids) or treatment failure. Five percent of the patients

reported minor skin burns after treatment, which were due to

incomplete removal of the abdominal wall hair. Previous

studies have shown an increased risk of minor skin burn

from abdominal wall hair, likely from air becoming en-

trapped in the particular areas [126]. One patient reported leg

and buttock pain from sciatic nerve palsy (which was shown

in the MRI images to be in the far field of the sonication

path). The patient was noted to have recovered completely

from the symptoms, using only symptomatic management, at

a 12-month follow-up visit. Since the incident, the treatment

protocol has changed to ensure at least a 4 cm distance be-

tween the treatment area and any major nerve bundles that

are situated in close proximity to the bone surface of the sa-

crum.

Later studies modified the treatment protocol to include a

larger treatment volume. A case series by Fennessy et al. compared the outcomes of 96 patients who were treated with

the original protocol with that of 64 patients who were

treated with the modified protocol [127]. The modified pro-

tocol leads to a larger treatment area and longer treatment

time. Repeat treatment, if needed, was also allowed within 2

weeks in the modified protocol. In both protocol groups, the

greatest symptom improvement was noted at 3 months and


the effects were sustained up to the 12 month time point of

the study. At 3 months, patients in the modified protocol

group reported greater improvement in symptoms than the

original protocol group, and 91% and 72% of patients in the

modified and original protocol groups continued to report

symptom improvement at 12 months. Thus, the degree of

symptom improvement seems to be associated with treat-

ment volume. At the end of the procedure, 28% and 37% of

the patients in the original and modified protocol groups

required alternative therapy.

The longest outcome report was authored by Stewart

et al. [128]. In that study, 359 patients who were treated by

MRgFUS were followed for 24 months. Because 4 different

protocols were used to treat patients, the relationship be-

tween the outcomes and treatment protocols was standard-

ized by the degree of treatment volume. As expected, pa-

tients who had higher treatment volume (>20%) had signifi-

cantly more improvement in their fibroid symptoms than the

patients with lower treatment volume (<20%) both at 3

months and beyond 3 months. This study also found that

treatment volume has a significant effect on the number of

patients who need additional therapy and the increase in he-

matocrit in women with anemia.

The advantages of MRgFUS are that it is a non-invasive,

outpatient procedure, requiring no surgical incision, and re-

sults in a short recovery time after surgery compared with

hysterectomy or myomectomy. Unlike UAE, after which

most patients develop severe pain from post-embolization

syndrome immediately after the procedure, post-MRgFUS

pain can be managed with oral analgesics. MRgFUS has

many limitations as well, including limits on the size, type,

and location of fibroids that can be treated with this method

[129]. The cost of treatment and the very limited availability,

due to few treatment centers in the U.S., are also major limi-

tations. The procedure cannot be performed if the patient has

abdominal wall scar tissue or if the fibroids are too close to

the neurovascular bundle or other vital organs (such as the

bowel or bladder) or if there are structures (for example,

bowel loop) that could interfere with the ultrasound beam.

The procedure is also not suitable for patients with multiple

fibroids due to the duration of the treatment, which takes 2 to

4 hours per fibroid. Thus, only 1 or 2 fibroids can be treated

at a time. The procedure is currently limited to the treatment

of six or fewer fibroids that are less than 10 cm in diameter.

Smart et al. reported a protocol that involved pretreating

patients who have fibroids larger than 10 cm with a GnRH

agonist for 3 months prior to MRgFUS, with promising re-

sults (130). In this study, patients who were pretreated with a

GnRH agonist had a larger treatment area than the patients

who did not receive a GnRH agonist. The authors hypothe-

sized that GnRH agonists decrease the vascularity in the fi-

broids, which in turn contributes to the rate of temperature

increase in the fibroids during MRgFUS treatment and in-

creases the extent of the tissue necrosis [130].

The effect of MRgFUS in patients who desire future fer-

tility is still not well studied. Thus far, there are only 4 case

reports and one case series that have reported pregnancy

outcomes after MRgFUS [131-135]. All of the case reports

reveal patients who had vaginal delivery at term after

MRgFUS [131-134]. In the case series, there were 54 preg-

nancies in 51 women who were treated with MRgFUS [135].

Forty-one percent (22 patients) of the pregnancies resulted in

delivery and 20% were ongoing. Twenty-six percent of the

pregnancies resulted in miscarriage (13% of those were elec-

tive terminations). Two patients had placenta previa whereas

12 of 22 patients delivered without complications, with all

but one delivery at full term. One patient developed uterine

atony and severe postpartum hemorrhage after a cesarean

section due to breech presentation and intramural fibroids.

Although the sample size was small, the pregnancy out-

comes and complications are favorable in comparison to the

pregnancy outcomes after UAE. Currently, the trial using

MRgFUS for patients with fibroids who have infertility is

ongoing and likely will provide us with more information in

the future.

In conclusion, MRgFUS is a promising new technology

for the treatment of fibroids that appears to be safe and effec-

tive. However, the procedure also has limitations, and long-

term outcomes are not yet available.

EXPERT COMMENTARY

Currently, there are several treatment options available

for fibroid treatment. Hysterectomy is the only definitive

treatment for relief of fibroid symptoms and the only proce-

dure that prevents the recurrence of fibroids. For sympto-

matic women who wish to preserve their fertility or simply

do not want to undergo invasive surgical procedures, many

minimally invasive or radiological procedures are available.

Hormone and NSAID therapy are appropriate for first-line

symptoms, particularly those related to menorrhagia and

anemia, but they have no effect on the size of fibroids.

GnRH agonists are effective in improving hemoglobin and

hematocrit as well as in reducing uterine size. Due to the side

effect of bone loss with long term use, GnRH-agonist usage

is limited to short term use (between 3 to 6 months) for de-

creasing uterine and fibroid size prior to surgery. The

levonorgestrel-releasing intrauterine system has been shown

to increase hematocrit in women with menorrhagia due to

fibroids who have a normal uterine cavity, although the pres-

ence of fibroids theoretically could increase the chances of

expulsion of the device. Uterine artery embolization is a safe

and effective alternative to hysterectomy. It provides a

shorter recovery time and fewer major complications than

hysterectomy. Patients, however, should be aware that ap-

proximately 20% to 25% of patients will later require further

treatment due to treatment failure. MRgFUS has promising

short-term outcomes, but data on long-term outcomes are

currently not available. It is important that patients talk with

their physicians about their treatment options and the relative

risks and benefits of each procedure prior to undergoing any

procedures or treatments.

FIVE-YEAR VIEW

Current therapy options for women with symptomatic

uterine fibroids are primarily limited to mechanical methods

of excision, ablation, or devascularization. With increased

experience using conservative, non-surgical procedures to

treat uterine fibroids, non-invasive technologies will con-

tinue to improve to expand eligibility, and allow safe and

effective long-term resolution of fibroid-related symptoms.


The approach to fibroids will also benefit from a comprehen-

sive approach, including the incorporation of evolving medi-

cal management options in the fibroid treatment armamen-

tarium. Ultimately, the future of fibroid management may

involve multimodal therapy that will allow early intervention

to prevent growth of fibroids that are asymptomatic or re-

duce rate of fibroid recurrence after treatment.

As we continue to increase our understanding of the

pathophysiology of fibroids, we are learning about several

compounds involved in fibroid growth, which may provide

therapeutic targets in the future. The influences on growth of

leiomyoma cells are multifactorial. Although modulation of

hormonal effects, for both estrogen and progesterone, on

leiomyoma cells are an area of particular research interest,

many studies show that there are other important cytokines

and growth factors that play a critical role in the develop-

ment of fibroids. Many of these growth factors are still being

studied in cell culture systems or they are in early phases of

clinical trials. However, these limited studies show therapeu-

tic potential for inhibition of leiomyoma cell growth path-

ways or interference with collagen production as promising

adjuncts to the non-hormonal management for fibroids [136].

Interferon-alpha (IFN- ) has been shown to inhibit leio-

myoma cell growth in vitro [137]. One case report found

persistent shrinkage of a single fibroid in a patient who

received IFN- for hepatitis treatment [138]. Pirfenidone, an

antifibrotic agent being studied for treatment of pulmonary

fibrosis, has been shown to inhibit DNA synthesis and

inhibit mRNA production for collagen type I in leiomyoma

cells and normal myometrial cell cultures in a dose-dependent

manner [139]. A heparin-like compound, RG13577, has been

shown to inhibit DNA synthesis of normal myometrial

and leiomyoma cells, with the effect more pronounced in

leiomyoma cells [139]. Halofuginone significantly inhibits

cell proliferation, collagen production, and TGF mRNA

levels in both normal and leiomyoma cells [140]. This

medication is not currently used in humans and its toxicity is

unknown [136]. Pioglitazone, a peroxisome proliferation-

activated receptor-gamma (PPARgamma) ligand, has also

been shown to inhibit cell proliferation of both normal

and leiomyoma cells in a dose-dependent manner [141]. In

addition, various methods of gene therapy are currently

being studied in animal models as a potential non-surgical

treatment intervention for fibroids [142-144].

KEY ISSUES

• Several non-surgical treatment options for fibroids treat-

ment are available.

• NSAIDs, progestins, and combined oral contracep-

tion are often prescribed to alleviate symptoms related

to fibroids, although they do not decrease the size of

fibroids.

• GnRH agonists are effective in decreasing fibroid and

uterine size as well as increasing hemoglobin/ hematocrit

in patients with anemia. Due to their side effects with

long-term administration, they are used only short-term

prior to surgery.

• GnRH agonist pretreatment prior to surgery allows many

women to have a vaginal hysterectomy, which might not

have been possible prior to treatment due to uterine size.

The pretreatment might also allow surgeons to use trans-

verse incision instead of vertical incision.

• Mifepristone and asoprisnil have been shown in small

studies to be effective in reducing fibroid size and

improving fibroid-related symptoms. Large randomized

controlled trials are needed to confirm their efficacy.

• The levonorgestrel-releasing intrauterine system is

effective in decreasing the amount of bleeding in women

with fibroids who have a normal uterine cavity.

• Uterine artery embolization has been shown to be an ex-

cellent alternative to hysterectomy for the treatment of

fibroids; resulting in shorter hospital stay, shorter

recovery time, and fewer major complications.

• Approximately 20%-25% of patients who undergo UAE

will require further treatment.

• The short-term and long-term outcomes of UAE are

promising, with more than 80% of the patients still

satisfied with their treatment 3 to 5 years after treatment.

• Pregnancy outcomes after UAE are limited. Although

successful pregnancies have been reported, several re-

ports showed increased risks of pregnancy complications

in UAE patients when compared with the general popula-

tion.

• MRgFUS is the newest minimally invasive treatment for

fibroids. The short-term outcomes of this procedure are

promising.

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Surgical Management Options for Patients with Infertility and Endometriosis

Michelle Catenacci1,* and Tommaso Falcone

2

1Department of Obstetrics and Gynecology, Reproductive Endocrinology and Infertility, Cleveland Clinic, Department

of Obstetrics and Gynecology-A81, 9500 Euclid Avenue, Cleveland, Ohio 44159, USA; 2Cleveland Clinic Department of

Obstetrics and Gynecology-A81, 9500 Euclid Avenue, Cleveland, Ohio 44159, USA

Abstract: Aim: Endometriosis is an important cause of infertility. The disease is both diagnosed and treated surgically.

Its pathogenesis is not entirely known; however, retrograde menstrual flow and a pro-inflammatory state in the

peritoneum are thought to support its development. Many studies have been done to help better assess the effects of the

disease on fertility rates and how surgical removal of disease can improve these fertility rates. The aim of this study was

to review the current literature on the effects of endometriosis on infertility and the benefit of surgical treatment for these

patients.

Methods: Review of recent publications through Pubmed and the Cochrane data base.

Results: The effects of minimal and mild disease on infertility are debatable, and studies have shown inconsistent results.

Surgery through laparoscopic removal has been shown to be beneficial for women with moderate and severe

endometriosis; however, those with severe disease may not benefit as much. Removal of ovarian endometriomas by an

excisional process appears to be superior to fenestration and coagulation for spontaneous pregnancy outcomes.

Conclusion: Laparoscopic removal of endometriosis is an important treatment option for patients with endometriosis-

related infertility. Questions remain, however, and further research should be done on the effects of Stage I/II disease and

bowel endometriosis on infertility.

Keywords: Infertility, endometriosis, laparoscopy, ovarian endometrioma.

INTRODUCTION

Endometriosis is the presence of ectopic endometrial

glands and stroma outside the uterine cavity and it is

frequently associated with infertility. The disease and its

pathogenesis are not entirely understood, but continued

research is helping to better understand this disease. Women

can present with a spectrum of disease severity with the most

severe disease leading to deep adhesions and alteration of

normal anatomy. The main treatment options for infertile

patients with endometriosis include surgical removal of

disease and in vitro fertilization (IVF). The focus of this

article is to briefly review the pathogenesis of endometriosis

and review current literature on disease treatment for

infertility with a focus on laparoscopy.

PATHOGENESIS

The most widely accepted theory to explain the develop-

ment of endometriosis was described by Sampson in 1927.

His theory of retrograde menstruation describes menstrual

debris escaping through the fallopian tubes into the pelvis

[1]. It has been found that patent fallopian tubes during the


Gynecology, Reproductive Endocrinology and Infertility, Cleveland Clinic,

Department of Obstetrics and Gynecology-A81, 9500 Euclid Avenue,

Cleveland, Ohio 44159, USA; Tel: +1 216 444 1758; Fax: +1 216 445 6325;


time of menstruation significantly increase the likelihood of

finding blood in the peritoneal cavity [2, 3]. This increase in

peritoneal blood is thought to be from refluxed menstrual

blood; however, actual endometrial cells in the peritoneal

cavity have yet to be identified [3].

The anatomic distribution of endometriosis seen in the

abdomen and pelvis give additional support to the theory by

Sampson [4]. Gravity appears to have an influence on

location of endometriosis lesions with a greater proportion of

endometriosis adhesions/deep implants being located in the

pelvis, particularity the posterior (most dependent) pelvic

compartment [5, 6]. Additional support is that locations of

peritoneal fluid stasis show increased endometriosis implants

when compared with other compartments in the peritoneal

cavity. Specifically, the Pouch of Douglas, the region of the

appendix, the region of the sigmoid colon, and the right

paracolic gutter are areas in which peritoneal fluid can

get trapped, and these regions correspond to areas where

endometriosis lesions are commonly seen [4, 6, 7]. If

retrograde menstruation is indeed an important step in the

disease process, then it would seem understandable that

regions exposed to increased menstrual blood would be more

likely to develop the disease. Gravity would cause the

majority of the blood to be deep in the pelvis, leading to

more disease in the more dependent regions of the pelvis,

and upper abdominal lesions could be formed with menstrual

blood trapped in regions of peritoneal fluid stasis.

162 Current Women’s Health Reviews, 2010, Vol. 6, No. 2 Catenacci and Falcone

The mere presence of blood, however, is not the only

causal factor leading to the development of endometriosis.

Considering that women with and without the disease have

been found to have increased blood in the peritoneal cavity

during menstruation, other factors need to be present for

endometriosis lesions to develop. Endometrial cells would

need to attach to the peritoneal cavity. This attachment is

thought to be due to abnormalities of both the endometrium

as well as the patient’s immune system. Endometrial lesions

need a vascular supply for support after attachment to

the peritoneal layer. Increased vascularization has been

documented in the red endometriotic lesions [8]. Angiogenic

factors are thought to play a critical role in the increased

vascularization and endometriosis disease process. In parti-

cular, vascular endothelial growth factor (VEGF) has been

found in increased amounts in the peritoneal fluid of patients

with endometriosis when compared with controls [9, 10].

Other endometrial abnormalities thought to lead to

development of endometriosis include disorders of

apoptosis. Apoptosis is thought to remove endometrial cells

during the late secretory and menstrual phases of the

menstrual cycle. In patients with endometriosis, apoptosis is

decreased, leading to increased survival of endometriotic

cells [11]. Matrix metalloproteinase (MMP) also has been

implicated in the pathogenesis of endometriosis. This family

of enzymes participates in normal tissue remodeling, and

altered expression of MMPs has been noted in women with

endometriosis [12]. Further research is needed to help clarify

the roles of these endometrial abnormalities as they pertain

to the development of endometriosis.

Immune response abnormalities also seem to play a role

in the development of endometriosis. The immune system

should provide a defense to the formation of endometriosis,

and its alteration has been found in patients with the disease.

Cytokines are associated with a pro-inflammatory state that

is hypothesized to promote endometriosis implantation.

Several studies have demonstrated increased levels of

various cytokines in the peritoneal fluid of women with

endometriosis [13-15]. However, other studies have failed to

confirm these findings and further investigations are

warranted [16].

Other areas of the immune system that have been studied

in regards to their association with endometriosis include

natural killer cells and macrophages. Macrophages speci-

fically are thought to exacerbate inflammation, and studies

have found increased number of macrophages in endometrial

tissue in patients with endometriosis [17]. Studies continue

to support the idea that women with an altered immune

response leading to a pro-inflammatory state are more

susceptible to developing endometriosis (Table 1).

Endometriosis and Infertility

Endometriosis is a known cause if subfertility and

infertility. Stage III/IV disease leads to infertility with

adhesions and distortion of normal anatomy. There is more

debate, however, on the extent of infertility caused by Stage

I/II disease. Several studies have looked at the peritoneal

fluid in these patients in the hopes of discovering a potential

cause of decreased fertility. The increase in cytokines and

inflammatory cells found in the peritoneum of these patients

is thought to contribute to decreased fertility. The elevated

cytokines seen are thought to disrupt the normal cell cycle,

leading to increased infertility [18]. Other observations that

have been noted include reduced sperm motility on exposure

to interleukin-6 [19]. Increases in inflammation seen in the

peritoneum of these patients can lead to an increase in

oxidative stress and reactive oxygen species thought to

further hinder fertility.

Table 1. Factors Hypothesized to Contribute to The Patho-

genesis of Endometriosis

- Retrograde menstruation

- Gravity and peritoneal stasis

- Increased vasularization

- Disorders of apoptosis

- Matrix Metalloproteinases

- Abnormalities of the immune response

- Pro-inflammatory state

An increase in oxidative stress is seen in patients with

endometriosis and is thought to contribute to decreased

fertility [20]. Endometriosis patients may have damage to

their oocytes from the increase in oxidative stress. One

mechanism studied showed that hydrogen peroxide and

tumor necrosis factor- alter oocyte microtubule and spindle

cell structure. The amount of damage was increased with

higher concentration of hydrogen peroxide and tumor

necrosis factor- and longer exposure to these substances

[21]. This is just one example of how oxidative stress can be

detrimental to fertility in endometriosis patients.

Treatment of Stage I/II Endometriosis

As stated previously, some controversy exists regarding

the association between minimal or mild endometriosis and

infertility. Several studies give conflicting results when

looking at fecundability of patients with minimal and mild

disease. Some studies have shown no significant difference

in fertility rates when comparing these patients to those with

unexplained infertility [22, 23]. A more recent retrospective

study looked at natural conception rates between women

with Stage I/II disease and women with unexplained

infertility. Patients were diagnosed by visualization of

disease and no treatment was given. The study reports that

these patients were followed for three years and found that

patients without endometriosis had a significantly greater

chance of pregnancy [24]. To add to the discrepancies, the

removal of minimal and mild endometriosis has been shown

to have mixed results in regards to fertility outcomes.

Several studies have suggested a benefit for treating minimal

and mild disease for both natural cycles and cycles using

controlled ovarian hyperstimulation and intrauterine

insemination [25, 26]. Others, however, have failed to

replicate these results [27, 28]. Several of these studies are

flawed, however, due to their retrospective nature and small

study numbers.

Two groups have studied the effect and treatment of

minimal and mild endometriosis in larger prospective studies

Surgical Management Options for Patients with Infertility and Endometriosis Current Women’s Health Reviews, 2010, Vol. 6, No. 2 163

in an attempt to settle this debate. A Canadian group first

published its result on infertility associated with minimal and

mild disease. The group’s first objective was to look at the

effects of mild and minimal endometriosis on fertility.

Women enrolled in the study underwent diagnostic laparo-

scopy for infertility. The first part of the study looked at

women with Stage I/II endometriosis that had only diag-

nostic laparoscopy without any treatment or disease removal.

These women were compared with women with unexplained

infertility (no endometriosis found on laparoscopy). The

women were followed for 36 weeks after laparoscopy to

compare pregnancy rates between the two groups. In total

168 women with minimal and mild endometriosis were

compared with 263 women with unexplained infertility. The

probability of becoming pregnant and carrying the

pregnancy to 20 weeks gestation did not differ statistically

between the two groups [29].

The same researchers then looked at the effects of

treating minimal and mild endometriosis on fertility

outcomes. This portion of the study compared women

randomized to laparoscopic treatment of disease with

laparoscopic diagnosis only. This study compared 172

women with excision or ablation of disease to 169 women in

the diagnosis only group and again followed them for 36

weeks. Removal of disease was associated with a clear

advantage to patients. Treatment increased the cumulative

probability of pregnancy by 73% with 30.7% of the

treatment group achieving pregnancy and 17.7% of the

diagnosis group achieving pregnancy in the 36 week follow

up period [30].

The second prospective randomized trial to examine the

effects of treatment on Stage I/II endometriosis came from a

group in Italy. Women were randomized at time of

laparoscopy to treatment or diagnosis alone and followed for

one year postoperatively. Unlike the Canadian study, the

study in Italy failed to show that surgery was beneficial to

women with minimal and mild disease. In the treatment

group, 12/51 (24%) women achieved pregnancy compared

with 13/45 (29%) of the no-treatment group. This was not

statistically significant. After spontaneous abortions, only

10/51 (20%) of the treatment group and 10/45 (22%)

delivered. This again was not significant [31]. Due to the

discrepancies found in these two studies, additional, larger

studies are needed to help clarify the impact minimal and

mild endometriosis have on fertility.

Treatment of Stage III/IV Endometriosis

There is less debate surrounding the effect of moderate to

severe endometriosis on infertility. Dense adhesions/fibrosis

can lead to a loss of normal anatomy and obvious hurdles in

achieving pregnancy. The best treatment for these patients to

give them the highest chance for success, however, is still

being investigated.

Laparoscopic removal of disease can be utilized to treat

infertile patients. Early studies reported a benefit to laparo-

scopic removal of severe disease in regards to fertility

outcomes [32, 33]. Although technically challenging, laparo-

scopic removal is minimally invasive and cost-effective and

is the preferred treatment method for moderate and severe

disease [34]. However, pregnancy rates still may remain low

after laparoscopic removal, especially for patients with the

most severe disease. One prospective study found the pre-

gnancy rate for infertile women after laparoscopic removal

of Stage III disease to be 44%. Women in the same laparo-

scopic study with Stage IV had a pregnancy rate of only

16.7% after disease removal [35].

Some women with severe endometriosis will have bowel

involvement. Bowel resections have been done for these

patients to relieve pain symptoms associated with the deeply

infiltrating disease, but the utility of bowel resection in

regards to improving fertility outcomes in these patients is

unclear. Few studies have started to look at fertility

outcomes in this subgroup of patients with severe disease.

One retrospective study looked at pregnancy rate and live

birth rates after bowel resection. In this study, 22 women

desired pregnancy after bowel resection, and 10 of these

women achieved pregnancy after surgery with a median time

to conceive after surgery of 8 months. Although this small

study showed promising results for fertility outcomes in

patients after bowel resection, it also discussed potential

complications. Two patients in this study had complications.

One developed a rectovaginal fistula and the other developed

a pelvic abscess. Both of these women required further

surgery, reminding us that bowel resection is not a benign

surgery [36].

Another prospective non-randomized study compared

pregnancy rates in infertile patients after bowel resection by

either laparotomy or laparoscopy. This study found

improved outcomes in the group that underwent laparoscopic

surgery with 57.6% of the women in the laparoscopic group

becoming pregnant compared with only 23.1% of the women

in the laparotomy group [37]. Another interesting study

looking at the influence of bowel endometriosis on fertility

compared three groups of patients: Group A had surgery for

endometriosis with colorectal resection, Group B had

surgery for endometriosis and evidence of endometriosis in

bowel but did not have a colorectal resection, and Group C

had surgery for moderate or severe endometriosis with no

evidence of disease in the bowel. These women were then

followed for four years with pregnancy rate being a primary

outcome. Pregnancy rate was found to be significantly lower

in the group that had bowel endometriosis present (Group

B). The monthly fecundity rate in Group A was 2.3%, Group

B 0.84% and Group C 3.95% [38]. These studies appear to

indicate that removal of bowel endometriosis may not only

benefit a patient’s pain symptoms, but may also improve

their chances for successful pregnancy.

Although surgery for infertility related to moderate-

severe endometriosis has been shown to improve fertility

outcomes, many patients will not achieve success after

surgical resection. Pregnancy rates are the highest in the

months immediately following surgery [39]. Many

physicians will use one year as the time point for additional

intervention if pregnancy has not occurred. Six months also

can be used, especially in older patients. Options for the

patient at that point include re-operation or IVF. Two studies

have compared these choices. One looked at women who

had laparotomies for endometriosis and compared those who

underwent repeat laparotomy verses those who underwent


IVF. Pregnancy rates in this study were low and only one

cycle of IVF was compared, but this study found a 22%

chance of achieving pregnancy within one year of re-

operation and a 12% chance of pregnancy after one cycle of

IVF [40]. Another study looking at laparoscopic reoperation

versus IVF found cumulative pregnancy rates to be 5.9%,

18.1%, and 24.4% at 3, 7, and 9 months out from reopera-

tion. This was significantly lower then the pregnancy rate

after two cycles of IVF (69.9%) [41]. In the absence of other

symptoms, moving to IVF may be more beneficial for

patients than repeat surgery.

Treatment of Ovarian Endometriomas

One area that has been studied extensively is the effect of

ovarian endometriomas on fertility and infertility treatments.

Ovarian endometriomas can usually be easily detected with

transvaginal ultrasound. Several studies have looked at the

risks and benefits of removing these masses for both

spontaneous pregnancies and prior to IVF. A potential risk of

removing endometriomas would be incidental removal of

normal ovarian tissue. Ovarian endometriomas can be more

challenging to remove than other ovarian cysts. That being

said, the removal of normal ovarian tissue along with the

cyst has been shown to be more likely when removing

endometriomas compared with other ovarian cysts [42]. In

addition to loss of normal ovarian tissue, removal of ovarian

endometriomas also potentially can lead to decreased blood

flow to the ovary if damage to its vascular supply occurs

during the removal. Loss of normal ovarian tissue or

decreased vascular supply to tissue can lead to a decreased

ovarian response during controlled ovarian hyperstimulation.

Alternatively, one could leave the endometrioma and

proceed to IVF. Somigliana et al. looked at women with one

ovary affected by at least one endometrioma during IVF

stimulation and found that larger endometriomas or multiple

endometriomas resulted in a decreased response in the ovary

with disease [43].

Several other retrospective studies have looked at the

effects of ovarian endometriomas on IVF cycles with mixed

results. Some studies suggested that removal of

endometriomas did not affect the number of follicles

obtained during IVF cycle [44, 45]. This is in contrast to

other studies that have found a significant reduction in the

number of follicles generated after laparoscopic cystectomy

for endometriomas [46]. A prospective randomized trial

compared women with endometriomas of 3 - 6 cm during

IVF cycles. They were randomized into two groups: Group I

underwent cystectomy prior to IVF; Group II had no surgical

intervention prior to IVF. They found that Group I needed

more stimulation and had less oocytes retrieved then the

group that did not have surgery. However, there was no

difference in fertilization, implantation, or clinical pregnancy

rates between these two groups [47]. Larger prospective

studies should be done to help clarify the mixed results seen

regarding the effects of endometriomas and their removal

prior to IVF.

After deciding to operate on an ovarian endometrioma

for fertility treatment, a choice should be made on the

treatment method to be used. A Cochrane review was

published comparing excisional versus ablative treatment of

endometriomas that looked at both spontaneous pregnancy

outcomes and controlled ovarian hyperstimulation [48]. The

review included three randomized, controlled trials that

evaluated the two laparoscopic surgical techniques on

patients with ovarian endometriomas of at least 3 cm [49-

51].

Two prospective studies in the Cochrane review

considered the effect of these two surgical techniques on

spontaneous pregnancy outcomes [49, 50]. In one study of

62 infertile patients with endometriomas, 32 were treated

with cystectomy, and 30 were treated with fenestration and

coagulation. Patients were followed for one year during

which no infertility medications or procedures were

administered or performed. The group that had cystectomies

had a significantly higher pregnancy rate (59.4%) compared

with the group that underwent fenestration and coagulation

(23.3%) [49]. The other study included in the Cochrane

review also compared spontaneous pregnancy outcomes after

laparoscopic cystectomy versus drainage and coagulation of

endometriomas. This was a smaller study that compared 9

infertile patients in the cystectomy group to 17 patients in the

coagulation group. Pregnancy rates were monitored for 24

months, and the cystectomy group exhibited a statistically

higher pregnancy rate (66.7%) than the coagulation group

(23.5%) [50]. The Cochrane review used these two studies to

conclude that overall spontaneous pregnancy rates favor

excision with an odds ratio of 5.21 [48].

The same Cochrane review also compared follicular

response to ovaries during controlled hyperstimulation after

cystectomy versus fenestration and coagulation. A single

prospective study compared fenestration and coagulation

versus cystectomies prior to controlled ovarian

hyperstimulation. In one arm of the study, patients had

bilateral endometriomas with one removed by cystectomy

and one by fenestration and coagulation. Patients in the other

two arms had one enodmetrioma and were randomized to be

treatment by cystectomy or by fenestration and coagulation.

This study failed to find a significant difference in the

number of follicles obtained regardless of treatment method.

Neither was there a difference in the number of follicles

obtained between treated ovaries and normal ovaries that did

not require surgery [51]. The Cochrane review stated that

evidence is insufficient at this time to state which surgical

technique should be employed prior to controlled ovarian

hyperstimulation [48].

CONCLUSION

Endometriosis is believed to arise from a combination of

menstrual blood refluxed through the fallopian tubes and a

peritoneal environment that is supportive of its implantation.

An alteration of immune response leading to a pro-

inflammatory state is thought to promote its development.

Endometriosis is classified based on the extent of disease

found during surgery. Stage I and II are also termed minimal

and mild disease, and their effects on infertility remain

controversial. Further prospective studies should be done to

help clarify the role of minimal and mild disease in sub- and

infertility and what effects removal of disease has on fertility

outcomes.

Surgical Management Options for Patients with Infertility and Endometriosis Current Women’s Health Reviews, 2010, Vol. 6, No. 2 165

Unlike Stage I/II disease, clear evidence supports the

negative impact that Stage III/IV disease has on fertility.

Moderate and severe endometriosis can lead to extensive

adhesions and deep infiltrating disease. Surgical removal of

Stage III/IV disease will improve fertility rates; however,

those with the most severe disease may not benefit as much

with surgery alone. Recent studies have suggested the

removal of bowel endometriosis may also improve fertility

outcomes in this subset of patients, although studies remain

limited on this subject. Finally, large or multiple endome-

triomas can lead to a decreased ovarian response in con-

trolled ovarian hyperstimulation. Further studies need to be

done to determine what surgical technique for endometrioma

removal will give the best results during controlled ovarian

hyperstimulation. On the other hand, it has been shown that

removal of endometriomas by excisional procedures appears

to be superior to ablation of endometriomas in improving

spontaneous pregnancy outcomes. It is clear from the studies

reviewed here that laparoscopy has a significant role for

the treatment of endometriosis-related infertility. Many ques-

tions remain, however, and continued research is needed to

help specify these roles so that the best recommendations

can be offered to this patient population.

EXPERT COMMENTARY

This article’s intention was to briefly highlight the

pathogenesis of endometriosis and then review current

clinical evidence for treatment of this disease in regards to

improving fertility outcomes. We still have much to be

learned about the disease mechanism, and continued research

will not only help understand this disease but also will help

formulate improved treatment options. Additional investi-

gations are needed on the molecular level to help clarify the

roles of various cytokines and inflammatory cells. This will

give us a better understanding of why endometriosis occurs

in some women and may lead to prevention and treatment

options for these patients.

In addition to improving our understanding of disease on

the molecular level, further clinical studies will help us

provide optimal management for our patients with endo-

metriosis. Additional studies are needed to clarify the role of

minimal and mild endometriosis on infertility. Another area

of interest for future research involves assessing the effects

of bowel endometriosis on infertility. Larger studies should

be done to validate whether removal of bowel endometriosis

can improve fertility rates. As additional knowledge is

gained through continued clinical and in vitro studies,

improved outcomes for these patients should be achieved.

FIVE YEAR VIEW

As stated previously, continued research is being done on

the molecular level to help better understand this disease.

Potential benefits of this work could include possible serum

markers to help identify patients with endometriosis. This

would be significantly less invasive than the surgical

diagnosis that is needed to diagnose the disease today.

Improved prediction models can not only help identify

patients with endometriosis but also could potentially be

used to follow patients after treatment. Elevated markers

potentially could alert the physician to disease recurrence.

Current trends are moving towards less invasive procedures,

and serum markers have the potential to play an important

role in the diagnosis and management in endometriosis

patients.

As treatment evolves in this direction, the role of

diagnostic laparoscopy for infertile patients is becoming

uncertain. Specifically, the value of diagnostic laparoscopy

for patients that do not suffer from pain and have normal

imaging studies is in question. Limited data currently

support the removal of minimal and mild endometriosis for

infertility. Due to the controversial role that Stage I/II

endometriosis have on infertility, recommendations are

moving away from performing diagnostic laparoscopies on

infertile patients. Ultimately, this will lead to less surgery for

these patients and increased medical management for

patients with infertility-related endometriosis.

KEY ISSUES

• Mixed data on the effects of treating Stage I/II endo-

metriosis.

• Pregnancy rates are highest in the months immediately

following surgery.

• Removal of bowel endometriosis may improve fertility

rates.

• If surgery fails to restore fertility, IVF may yield a higher

success rate.

• Cystectomy for endometriomas gives superior natural

pregnancy results.

• Mixed data on the effects of ednometriomas or their

removal prior to IVF.

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Surgical Strategies for Fertility Preservation in Women with Cancer

Mohamed A. Bedaiwya,b

, Kristine Zanottia, Ahmed Y. Shahin

b, Mohamed Yahya Abdel Rahman

a,c,

and William W. Hurda,*

aDepartment of Obstetrics and Gynecology, University Hospitals Case Medical Center, Case Western Reserve

University, Cleveland, OH 44106, USA; bDepartment of Obstetrics and Gynecology, University of Assiut, Asyut, Egypt;

cDepartment

of Obstetrics and Gynecology, University of Sohag, Sohag, Egypt

Abstract: Survival has significantly improved for women diagnosed with cancer during the reproductive years. The

majority of these women will desire children after completion of their cancer therapy. Future fertility often is eliminated

or impaired by surgical removal of reproductive organs for the treatment of gynecologic cancers or by radiation or chemo-

therapy for the treatment of other cancers. As a result, several strategies have been developed in an attempt to preserve

fertility in these women, including alternate surgical approaches, protecting reproductive organs during treatment, and

removing and storing oocytes prior to cancer treatment for future use. Surgical approaches used in women with early

gynecologic cancers include unilateral oophorectomy for ovarian cancer, radical trachelectomy for cervical cancer, and

progestin therapy to avoid surgery for endometrial cancer. Ovarian function and fertility can be preserved in women

requiring pelvic irradiation by ovarian transposition away from the treatment field. In women requiring systemic chemo-

therapy, surgical removal of ovarian tissue followed by cryopreservation and subsequent transplantation after the patient

is determined to be in remission has been shown to restore ovarian function and result in pregnancy. To provide the

best chance of future fertility, these surgical approaches to fertility preservation must be implemented as part of the initial

cancer therapy, prior to definitive radiation or chemotherapy.

Keywords: Fertility preservation, gynecological cancers, ovarian transplatation.

INTRODUCTION

Survival has significantly improved for women diag-

nosed with cancer during the reproductive years primarily as

a result of significant advances in the field of cancer treat-

ment [1]. The overall cancer death rates for women de-

creased by 11.4% from 1991 to 2005, particularly because of

advances made in the diagnosis and treatment of breast and

colorectal cancers. Between 1991 and 2005, more than

160,000 cancer deaths were averted in women in the United

States [1].

Approximately 70% of reproductive-aged women diag-

nosed with cancer will desire children after completion of

their cancer therapy [2,3]. Although modern cancer therapy

dramatically improves survival, it often adversely impacts

fertility as a result of the effects of chemotherapy and radio-

therapy on reproductive organs. In the case of gynecologic

cancers, surgical removal of reproductive organs can also

impair or completely eliminate future fertility.

The increasing need to consider fertility preservation

in these women is well appreciated. The American Society

of Clinical Oncology recommends that cancer patients in

the reproductive years be counseled about fertility preserva-

tion [4]. The President’s Cancer Panel released a strong


Gynecology, University Hospitals Case Medical Center, Case Western

Reserve University School of Medicine, 11100 Euclid Ave, MCA 7007,

Cleveland, OH 44106, USA; Tel: 216-844-5345; Fax: 216-844-3796;

E-mails: [email protected], [email protected]

recommendation addressing the need for more research on

fertility preservation [5].

Several strategies for fertility preservation have been

developed for reproductive-age women diagnosed with can-

cer. These strategies include 1) altering surgical treatment of

gynecologic cancer to preserve fertility, 2) protecting repro-

ductive organs during radiation or chemotherapy, and 3)

removal and cryopreservation of ovarian tissue prior to can-

cer treatment for later transplantation back into the patient

when she is in remission. This review will address the surgi-

cal approaches for these strategies that are currently being

used in reproductive-age women with cancer.

GYNECOLOGIC CANCERS: SURGICAL TREAT- MENTS THAT PRESERVE FERTILITY

Treatment for most gynecologic cancers includes re-

moval of the uterus, ovaries, and tubes, often rendering the

patient sterile. However, for reproductive-age women with

early disease, fertility-sparing surgery sometimes is possible.

This section will address fertility-preserving surgical ap-

proaches to cancer of the cervix, ovary and endometrium

(Table 1).

Cervical Cancer

Cervical cancer is the most common gynecologic cancer

diagnosed in the reproductive years. Although cervical can-

cer accounts for only 16% of all cancers in women, 40% are

diagnosed before the age of 45 [6]. In the United States, the

age-adjusted incidence rate is approximately 8 per 100,000

168 Current Women’s Health Reviews, 2010, Vol. 6, No. 2 Bedaiwy et al.

women per year, and almost 1/3 of these women will die

from their disease [6]. The five-year survival rate is currently

70%.

Standard Therapy

Therapy for cervical cancer depends on the extent of the

disease (i.e. stage) at diagnosis. Approximately 50% of

women with cervical cancer will be Stage II-IV, where the

cancer is found to have spread beyond the cervix, either

to adjacent structures, to regional lymph nodes, or to more

distance sites [6]. Standard therapy for most of these women

is a combination of chemotherapy and radiotherapy.

The remaining women will be found to have Stage I cer-

vical cancer, where the disease is confined to the cervix [6].

Surgical therapy for women with this condition who no

longer desire fertility is radical hysterectomy with pelvic

lymphadenectomy [3]. Cases have been reported in which

women who have undergone this procedure have had chil-

dren utilizing in vitro fertilization (IVF) and the assistance of

a surrogate mother to carry the pregnancy [7, 8]. Depending

on recurrence risk factors, adjuvant pelvic radiotherapy may

be administered after radical hysterectomy. However, the

ovary has poor tolerance to radiation, and standard pelvic

radiotherapy doses of 45 to 50 Gy will reliably induce pre-

mature ovarian failure. Successful surrogate pregnancies

have been reported when either oocytes were removed from

the ovaries or the ovaries were surgically transposed out of

the pelvic radiation field at the time of radical hysterectomy

[7,8].

Fertility-Sparing Surgery

Cone Biopsy

Observational data suggest that lesions meeting criteria

for microinvaasive cervical carcinoma, designated as “Stage

Ia1,” have a negligible risk for lymphatic metastasis and can

be excised using less radical procedures, such as cold knife

conization [9]. Controversy exists regarding the impact of

cone biopsy on obstetric outcomes. While some studies re-

port no increase in adverse outcome [10, 11], other studies,

including a recent large meta-analysis, have suggested that

this approach increases the risk of both pre-term delivery and

low birth weight infants [12, 13].

Radical Trachelectomy

Another fertility-sparing approach for patients with very

early invasive cervical cancer is radical trachelectomy,

where the cervix is removed along with the surrounding

vaginal and parametrial tissue while preserving the uterine

fundus [14-17]. This approach might be used for smaller,

cervix-confined lesions, such as lesions otherwise meeting

criteria for microinvasion but are accompanied by lympho-

vascular invasion, Stage IA2 lesions; and Stage IB1, visible

lesions < 4 cm confined to the cervix with superficial inva-

sion and no vascular space invasion [9].

Radical trachelectomy can be performed using an ab-

dominal approach combined with pelvic lymphadenectomy

to exclude lymphatic spread [18]. Alternatively, this proce-

dure can be performed vaginally with the addition of laparo-

scopic lymphadenectomy [19]. After excision of the cervix

and parametria, a permanent cerclage is typically placed

and the vaginal mucosa is re-approximated to the uterine

stump.

The recurrence and survival rates for this approach ap-

pear to be similar to traditional radical hysterectomy in ap-

propriate early-stage patients. Three studies with a total of

151 patients followed for 23-60 months reported acceptable

recurrence rates of 2.8% to 5% [15, 20, 21]. Data focusing

on oncologic outcomes in women with larger cervical lesions

is more limited.

Radical trachelectomy is often effective in preserving

fertility, although obstetric complications are increased.

While first trimester miscarriage rates are similar to that seen

in the general population, rates of both second trimester

losses and pre-term delivery are significantly increased in

patients who have undergone trachelectomy. In a review of

520 patients treated with radical vaginal trachelectomy, 43%

attempted to conceive after surgery and 70% of these women

achieved pregnancy [22]. Of these 227 pregnancies, 21%

ended in first trimester miscarriage and 8% in second trimes-

ter miscarriage, 21% were born prematurely, and 50% were

born at < 36 weeks. As many will have a permanent cerclage

placed at the time of their trachelectomy, delivery by elective

cesarean section is typically warranted.

Ovarian Cancer

Ovarian cancer was ranked as the fifth leading cause of

cancer deaths in the United States in 2009 [1]. Although the

peak age of occurrence of ovarian cancers is after meno-

pause, up to 17% of all ovarian cancers occur in women <40

years of age [23]. Many women in this age group wish to

preserve their reproductive potential and ovarian endocrine

function.

Table 1. Fertility-Sparing Surgery for Reproductive-Age Women with Gynecologic Cancers

Cancer Type Standard Therapy Fertility-Sparing Approach Requirements

Cervical Total abdominal hysterectomy, bilateral

salpingoophorectomy

1. Cone biopsy

2. Radical trachelectomy

1. Stage IA1

2. Stage IA2- IB1

Ovarian Total abdominal hysterectomy, bilateral

salpingoophorectomy

Unilateral oophorectomy 1. Borderline tumors

2. Stage IA-C Grade I or II

Endometrial Total abdominal hysterectomy, bilateral

salpingoophorectomy

Surgical staging without hysterectomy

or oophorectomy;

Progestin therapy

Stage I, Grade I

endometriod cancer

Surgical Strategies for Fertility Preservation in Women with Cancer Current Women’s Health Reviews, 2010, Vol. 6, No. 2 169

Survival rates can be predicted by the stage and his-

tological grade of ovarian cancer at the time of diagnosis. In

general, women with ovarian cancer confined to the ovary

(Stage I) have >90% five-year survival rate, whereas those

with Stage III-IV tumors have < 40% five-year survival rate.

Because >75% of ovarian cancers are Stage III-IV at diagno-

sis, the overall five-year survival rate for women diagnosed

with ovarian cancer is <45% [6, 24].

Ovarian Cancer Subtypes

Ovarian cancer can be divided into three major catego-

ries: epithelial ovarian tumors, germ cell tumors, and stromal

tumors. Each histologic subtype is associated with clinical

features that are relevant to determining the advisability of a

fertility-sparing procedure, such as age at presentation, typi-

cal stage at presentation, and incidence of bilateral ovarian

involvement. Fortunately, many of the histologic subtypes

seen more commonly during the reproductive years are ame-

nable to less radical surgical approaches.

Epithelial ovarian malignancies usually arise from the

ovarian surface epithelium or within epithelial inclusion

cysts. They account for at least 80% of ovarian malignancies

[25]. Approximately 75% of invasive epithelial cancers pre-

sent in stages III or IV; however, most are diagnosed in post-

reproductive age women [24]. An important group to distin-

guish are tumors of low malignant potential, or borderline

epithelial tumor. These relatively indolent lesions are found

most frequently in the reproductive age group. Moreover,

they tend to remain ovary-confined for long periods of time

and can often reach an impressive size prior to diagnosis.

Approximately 90% present with Stage I disease (confined

to one or both ovaries) but will be bilateral in 25% of cases

[26, 27].

Germ cell tumors account for approximately 10-15% of

ovarian tumors, but malignant germ cell tumors are rare.

While germ cell malignancies account for fewer than 5% of

all ovarian cancers, they account for 2/3 of the ovarian ma-

lignancies seen in the first two decades of life [28]. Ovarian

dysgerminoma is the most common malignant germ cell tu-

mor, accounting for 40% of germ cell cancers. Approxi-

mately 75% are Stage I at diagnosis;, however, 15% present

with bilateral ovarian involvement. Other germ cell malig-

nancies, such as immature teratoma, endodermal sinus tu-

mor, and choriocarcinoma are rarely bilateral.

Ovarian stromal tumors, such as granulosa-theca and

Sertoli-Leydig cell tumors are quite rare and usually low-

grade; approximately 70% are Stage I at presentation. They

are rarely bilateral [24, 29].

Standard Therapy

Surgical therapy for women with ovarian cancer who no

longer desire fertility is hysterectomy and bilateral salpingo-

oophorectomy. For staging purposes, many patients also

undergo lymphadenectomy and partial omentectomy. For

those with sufficient risk for recurrence, adjuvant combina-

tion chemotherapy may be advised postoperatively [25].

Fertility-Sparing Surgery

Fertility-sparing surgery for ovarian malignancies refers

to unilateral oophorectomy, usually with removal of the ad-

jacent fallopian tube. Often staging lymphadenectomy and

relevant biopsies are performed as well. However, the con-

tralateral ovary and uterus are not removed. There are many

situations in which removal of the contralateral ovary and

uterus does not impact overall oncologic outcomes or prog-

nosis. In these cases, fertility-sparing surgery is quite reason-

able practice.

Most unilateral germ cell and sex cord stromal malignan-

cies will be amenable to fertility-sparing surgery. Fortu-

nately, aggressive histologic subtypes and/or advanced sur-

gical stage are uncommon in the reproductive age groups. In

these cases, adjuvant multi-agent chemotherapy often is rec-

ommended to reduce the risk of recurrence [30]. One series

reported a 90% 10-year overall survival following fertility-

sparing surgery for germ cell malignancies; moreover, suc-

cessful subsequent pregnancies are reported, even among

women who received chemotherapy [31].

Unilateral borderline tumors usually are amenable to fer-

tility-sparing surgery, and there is little evidence that on-

cologic outcomes are compromised, even in the setting of

metastatic disease [32]. In one series, the recurrence rate was

approximately 5%, regardless of whether patients were

treated with radical or fertility-sparing surgery. That being

said, bilateral ovarian involvement is common in borderline

malignancies, and the remaining ovarian tissue was the most

common site of tumor recurrence in those opting for fertility-

sparing procedures, thus indicating a need for close surveil-

lance of the remaining ovary [32]. In this series, 18% of 184

women subsequently had successful pregnancies after fertil-

ity-sparing surgery.

Invasive epithelial ovarian cancers can be treated with

conservative fertility-sparing surgery in selected unilateral

Stage I cases [33]. When fertility-sparing surgery is planned

for these women, complete staging is silll recommended.

Pelvis washings, lymph node sampling, and omentectomy

will reveal occult metastases in 15% of women presenting

with apparent ovary-confined disease [25, 34]. Some experts

suggest performing a wedge biopsy on the contralateral nor-

mal-appearing ovary with intraoperative frozen section to

exclude occult malignancy [35]. Except in cases of low-

grade histology, most women diagnosed with invasive

epithelial ovarian carcinoma of any stage will be treated with

adjuvant chemotherapy after surgery.

Even after unilateral oophorectomy and chemotherapy,

many women with malignant epithelial ovarian tumors will

be able to conceive. The majority will experience resumption

of menstrual function, and in one series more than 70% sub-

sequently had a successful pregnancy [25, 36].

Endometrial Cancer

Endometrial cancer is the most common gynecologic

cancer, accounting for approximately 6% of all cancers in

women [37, 38]. However, the majority of women diagnosed

with endometrial cancer are post menopausal. Less than 5%

of endometrial cancers are diagnosed in women <40 years of

age, and in this cohort these neoplasms tend to be well dif-

ferentiated with an indolent biology and confined to the

uterus at diagnosis [6]. Excess estrogen, such as that seen in

obesity and anovulation, is the main risk factor for the de-


velopment of low-grade endometrial neoplasms. Indeed,

approximately 25% of young women who develop endo-

metrial cancer will have polycystic ovary syndrome (PCOS)

[38]. The overall five-year survival rate for this so-called

“low risk” endometrial cancer is in excess of 90%.

Standard Therapy

The standard therapy for endometrial cancer is hysterec-

tomy and bilateral salpingo-oophorectomy [39]. Adjuvant

postoperative radiation therapy or chemotherapy may be

recommended for high-risk histology or advanced disease.

Since the majority of women with endometrial cancer are

beyond the reproductive years, fertility-sparing surgery is

rarely considered.

Fertility-Sparing Therapy

In select younger women with low-grade endometrial

carcinoma who are motivated to preserve their fertility, fer-

tility-sparing approaches may be considered. These ap-

proaches typically involve medical treatment with progestin

therapy. This approach is appropriate only in young women

with non-invasive (Stage Ia), hormone-sensitive lesions

(typically Grade I histology) who desire fertility preservation

and have an otherwise reasonable chance for conception af-

ter therapy [40-42].

Pre-Treatment Studies

Thorough endometrial sampling though D&C and accu-

rate pathology review are essential prior to embarking on a

strategy of medical management for endometrial carcinoma

[40]. Immunohistochemistry studies evaluating progesterone

receptor content are to be helpful in predicting response to

progestin therapy. However, in a study of metastatic endo-

metrial carcinoma, 37% of women with tumors demonstrat-

ing progesterone content responded to progestin therapy,

whereas only 8% of those responded whose tumors did not

[43]. Most FIGO Grade I endometrial neoplasms will ex-

press progesterone receptors to varying degrees. The value of

further quantifying progesterone content in women consider-

ing for medical management has not yet been evaluated.

As non-invasive or minimally invasive lesions are con-

sidered the only candidates potentially amenable to medical

management for endometrial carcinoma, an important part of

pre-treatment evaluation is determining depth of myometrial

invasion. The most accurate imaging technique available for

this purpose is the contrast-enhanced MRI [44,45]. Pelvic

MRI is also highly sensitive for detection of neoplastic

lymph node involvement, albeit lymphatic metastasis is oth-

erwise a very uncommon occurrence for non-invasive and

early-invasive FIGO Grade I endometrial lesions [46].

Progestin Therapy

To avoid the need for hysterectomy, progestin therapy is

used in an attempt to eradicate early-stage, well-differentiated

endometrial cancer [6, 47, 48]. Although there is no standard

treatment regimen, two commonly use progestin regimens

are megestrol acetate, 80 mg/day or medroxyprogesterone,

200 mg/day. Medroxyprogesterone doses as high as 1000

mg/day have been advocated by some; however, this higher

dose has not been found to be more effective than 200 mg/

day for women with advanced disease, and thromboembolic

complications were markedly increased [43].

Follow-up

Definitive assessment of treatment response requires en-

dometrial sampling, either biopsy or D&C, which has been

recommended every 1 to 3 months [41]. Once D&C verifies

that the endometrium has reverted to normal histology, preg-

nancy can be attempted [40]. Monthly transvaginal ultra-

sonography and serum CA-125 might be useful as early in-

dicators of disease progression [41, 49].

Outcomes

Approximately 50% of well-differentiated tumors show a

complete response to hormonal treatment. As a result of on-

going risk factors, approximately 25% of responders will

suffer a relapse after initial successful therapy [50]. Thus,

patients should be counseled regarding the potential for fail-

ure with this approach.

Subsequent Fertility

Several authors have reported successful pregnancies

after progestin therapy for endometrial carcinoma [40]. Al-

though the reports are somewhat limited, it appears that as

many as 1/3 of women will conceive after such therapy. Un-

fortunately, as stated before, recurrence is common, and so

continued close follow-up is required as long as the patient

retains her uterus [40]. Unfortunately reported conception

rates are low, reflecting both inadequate regression of endo-

metrial pathology as well as inherent fertility issues in this

typically subfertile patient population. As PCOS and anovu-

lation are common in this population, ovulation induction is

often necessary.

PROTECTING OVARIES AND OOCYTES DURING

CANCER TREATMENT

Cancer therapy often has devastating effects on ovarian

function and future fertility. Pelvic irradiation can be cura-

tive for a number of cancers common in young women, in-

cluding gynecologic cancers and lymphomas. However, if

the ovaries are within the treatment field, premature ovarian

failure is common. Likewise, systemic chemotherapy is an

effective treatment for these types of cancers in addition to

cancers outside the pelvis such as breast cancer and leuke-

mia. Multi-agent chemotherapy results in ovarian failure in

approximately 40% of women < 40 years and more than75%

in women > 40 years and is likely to impair fertility in an

even greater number [51].

The key to fertility preservation in women requiring pel-

vic irradiation or systemic chemotherapy is protection of

oocytes from damage. Both non-surgical and surgical meth-

ods for fertility preservation have been developed for women

undergoing these cancer therapies.

Non-Surgical Approaches

Although the focus of this manuscript is surgical ap-

proaches to fertility preservation, existing non-surgical ap-

proaches should be mentioned. These approaches fall into


two categories: oocyte retrieval for in vitro manipulation

and cryopreservation, and pituitary down-regulation during

chemotherapy.

Oocyte Retrieval for In Vitro Manipulation

Oocyte removal for in vitro manipulation is the most ef-

fective non-surgical approach to fertility preservation [52].

The highest pregnancy rates have been achieved with a com-

bination of hormonal stimulation followed by timed

transvaginal retrieval of mature oocytes, in vitro fertilization

and embryo cryopreservation (IVF-ET). The cumulative

pregnancy rate with this approach after thawing and intrau-

terine transfer is currently > 60% per embryo [53]. Oocyte

cryopreservation can be used if the woman does not desire

fertilization of her oocytes; the current pregnancy rate after

thawing, fertilization, and intrauterine transfer is 57% per

embryo [54]. The disadvantages of these techniques is that

they delay planned cancer therapy for two or more weeks

from the beginning of the next menstrual period and expose

the women to higher than normal estrogen levels during

ovarian stimulation.

To decrease the time until retrieval and avoid high estro-

gen levels in women with estrogen dependent cancers (e.g.

breast, endometrial), methods have been developed to re-

trieve immature oocytes [55, 56]. The oocytes can be hor-

monally treated using a process called in vitro maturation

(IVM). The resulting mature oocytes can be fertilized and

the embryos frozen, or the oocytes can be frozen without

being fertilized. Although there have been reports of preg-

nancy rates comparable to those attained with standard IVF-

ET, these approaches have yet to become widely applied

[57].

Pituitary Down-Regulation During Chemotherapy

A pharmacologic approach to decreasing ovarian damage

from chemotherapy is down-regulation of the pituitary with

gonadotropin-releasing hormone agonist (GnRHa) [58]. Sev-

eral hypotheses exist to explain why this approach might

limit the gonadotoxic effects of chemotherapy. First, inhibi-

tion of FSH secretion might hinder recruitment of preantral

follicles. Second, decreased FSH and LH stimulation might

diminish ovarian perfusion. Finally, decreased FSH stimula-

tion of the ovary up-regulates sphingosine-1-phosphate

which might serve as an ovarian cytoprotectant [52, 58, 59].

The ability of pituitary down-regulation to inhibit re-

cruitment of preantral follicles has been called into question.

It has been observed that primordial follicles continued to

grown in a patient with Hodgkin disease treated with GnRH-

a [60]. In vitro studies of human ovarian tissue have

suggested that preantral follicles exhibit FSH independent

growth, and this might explain why pituitary down-

regulation does not completely inhibit antral follicle devel-

opment [52]. Other researchers have observed that primor-

dial follicles continue to initiate growth during GnRH-a

therapy and during the hypogonadal state before puberty

[61].

A recent review of clinical studies of GnRH-a use during

chemotherapy concluded that, although there is some evi-

dence that GnRH-a therapy reduces chemotherapy-related

gonadotoxicity, it has yet to be proven statistically [62]. In

the nine studies they analyzed the incidence of ovarian fail-

ure after chemotherapy was 11% in patients who received

GnRH-a compared with 56% in those who had not. How-

ever, because most of these studies were small, retrospective,

and non-randomized, the benefit of GnRH-a remains uncer-

tain.

SURGICAL APPROACHES FOR PRESERVING

OVARIAN FUNCTION

Radiation therapy and chemotherapy are commonly used

treatments for gynecologic cancers and other cancers in the

reproductive years, most notably breast cancer and lympho-

mas. Since both pelvic irradiation and systemic chemother-

apy can damage the ovaries, surgical methods have been

developed that attempt to preserver ovarian function. Two

surgical approaches have been reported for this purpose: 1)

ovarian transposition and 2) ovarian tissue cryopreservation

and reimplantation (Table 2).

Ovarian Transposition

Ovarian transposition (or oophoropexy) is the surgical

mobilization of the ovary with its vascular pedicle, followed

by relocation of the ovary out of the planned field of radia-

tion therapy. The goal is to minimize ovarian radiation expo-

sure to preserve ovarian function and possibly fertility [63].

Techniques and results for ovarian transposition have been

reported for women undergoing local pelvic or abdominal

radiotherapy for a number of cancers, including cervical,

vaginal, dysgerminona and Hodgkin disease [64-67].

Standard external beam radiation and brachytherapy are

designed to deliver a radiation dose to the pelvis of >4000

cGy [68]. Doses to the ovary of > 1200 cGy will result in

premature ovarian failure in >50% of women. After transpo-

sition from the pelvis, ovaries receive approximately 5–10%

of the total pelvic dose as a result of scatter [69]. As a result

Table 2. Surgical Methods for Preserving Ovarian Function for Reproductive-Age Women with Cancer Undergoing Pelvic

Irradiation or Systemic Chemotherapy

Method Indication Approaches Effectiveness

Ovarian

transposition

Cancer requiring pelvic radiation

therapy

• Lateral transposition

• Medial transposition

• Often preserves ovarian function

• Might require IVF to restore fertility

Ovarian

transplantation

Cancer requiring pelvic

irradiation or systemic

chemotherapy

1. Laparoscopic removal of ovarian tissue

2. Cryopreservation

3. Transplantation of ovarian tissue

• Remains experimental

• Preservation of ovarian function and

fertility is possible


of both radiation scatter and changes in circulation resulting

from surgery, ovarian function is not uniformly spared by

surgical transposition.

Technique

Ovarian transposition was originally performed via lapa-

rotomy [70, 71]. More recent reports utilize a laparoscopic

approach [67]. A standard technique begins with occlusion

and division of the utero-ovarian ligament followed by sepa-

ration of the fallopian tube from the ovary [71]. The ovaries

are mobilized by incising the peritoneum along the in-

fundibulo-pelvic ligament. Finally, the ovaries are laterally

displaced and fixed to the peritoneum high in paracolic

gutters.

Alternatively, the ovaries can be repositioned behind the

uterus when lateral pelvic radiation therapy is required, as is

often the case with lymphomas [67]. The theoretical disad-

vantage of the midline oophoropexy is higher radiation ex-

posure of the ovaries as a result of internal scatter.

Ovarian Function Preservation

Ovarian transposition prior to pelvic irradiation has been

reported to preserve ovarian function in 50 to 79% of women

[66, 70]. These relatively short-term studies have not deter-

mined how many patients will subsequently experience pre-

mature ovarian failure.

Fertility Preservation

Ovarian transposition is less effective for preserving

fertility than ovarian hormonal function. Separation of the

ovaries from the fallopian tubes and lateral displacement is

likely to significantly decrease fertility. In one series of 37

patients, 16 pregnancies occurred spontaneously, although

in12 of these women the ovaries were not separated from the

fallopian tubes [66].

In some cases where the ovaries have been separated

from the fallopian tubes and spontaneous pregnancy does not

occur, oocyte retrieval followed by IVF-ET has been suc-

cessful. However, transvaginal oocyte retrieval is likely to be

difficult following lateral transposition and might require a

transabdominal or laparoscopic approach for retrieval.

OVARIAN TISSUE TRANSPLANTATION

For many patients with cancer, especially adolescent girls

and children, ovarian tissue transplantation is an experimen-

tal approach with significant potential. Ovarian tissue is s

removed surgically prior to radiation or chemotherapy and

cryopreserved. After the patient has completed cancer ther-

apy and is in remission, the ovarian tissue is transplanted

back into the patient (e.g. autologous transplantation). This

experimental approach has been used to preserve both ovar-

ian function and fertility.

Two approaches have been used for surgical removal of

ovarian tissue for later transplantation: 1) removal of the

entire ovary or large sections of the ovary with a vascular

pedicle, and 2) removal of ovarian cortex tissue. Ovarian

cortex tissue can be transplanted back on to the ovary

(termed “orthotopic”) or to subcutaneous sites distant from

the pelvis (termed “heterotopic”) Fig. (1) shows different

sites and approaches for ovarian transplantation.

Fig. (1). Various sites of ovarian transplantation with and without vascular anastomoses. A- Those with vascular anastomosis could be at

orthotopic or heterotopic locations. Microvascular anastomosis could be performed using end-to-end, end-to side or fish mouth modification

approaches. The heterotopic sites are the upper limb to the humeral vessels and the abdominal wall to the inferior epigastric vessels. B-Those

without vascular anatomosis entail transplantation of part or most of the cortical tissue orthotopically or heterotopically. From: Bedaiwy MA,

Shahin AY, Falcone T. Reproductive organ transplantation:advances and controversies. Fertil Steril 2008; 90(6): 2031-55.


Ovarian Tissue Transplant with Vascular Pedicles

Surgical removal of ovarian tissue with a vascular pedi-

cle with subsequent orthotopic transplantation back into the

adnexal region has been used to re-establish ovarian function

in women with premature ovarian failure by transplanting

the ovary of her identical twin into her adnexa [72]. Cur-

rently, microvascular anastomoses are performed via lapa-

rotomy, although laparoscopic methods are being investi-

gated [73].

This approach remains experimental. It has been shown

to be feasible in the animal model where the ovaries were

harvested with their vascular pedicles and then autotrans-

planted. The ovarian vessels were anastomosed to the deep

inferior epigastric vessels using either end-to-end, end-to-

side, or fish mouth modification. The end-to- end anastomo-

sis yielded the highest patency rate of the vascularized grafts

[73].

Ovarian Cortex Transplant

Surgical removal of ovarian cortex followed by cryopre-

served subsequent orthotopic transplantation back to the

donor’s adnexal region has had some success in humans

[74]. Heterotropic transplantation to a subcutaneous site

distant from the adnexal has also been reported in humans

[75-77].

Orthotopic Transplantation

Reimplantation of human ovarian cortex back to the

ovarian surface has been reported by several investigators

[78-81]. Reestablishment of ovarian functions after trans-

plantation usually takes more than 4 months [82]. The length

of time that grafts remain viable after transplantation is vari-

able and has been reported to range from a few months to

more than 5 years [82]. Although this approach can restore

menstrual function in women with previous ovarian failure,

basal FSH levels remain elevated; indicating decreased ovar-

ian reserve [83].

Fertility Preservation

Live births have been reported after autologus transplan-

tation of frozen-thawed cortical tissue to orthotopic sites [78,

79, 81]. The majority of these pregnancies occur spontane-

ously after establishment of menstrual function and normali-

zation of the FSH and most often occurred during the first

year after transplantation. WhenIVF is attempted in the

transplanted ovaries, oocytes harvested from transplanted

ovarian cortex might tend to be immature and of poor quality

[84].

Heterotropic Transplantation

Reimplantation of human ovarian cortex to subcutaneous

sites distant to the pelvis has also been reported [53, 85]. It

avoids the risk of a second surgery required to transplant

tissue back onto the ovary. However, the ischemia experi-

enced by the tissue prior spontaneous neovascularization is

likely to be detrimental to subsequent functionality of an

ovarian tissue transplant. In addition, subsequent fertility

will require oocyte retrieval and IVF. To date, no pregnan-

cies have been reported with this technique.

Expert Commentary

The purpose of this article is to review the surgical ap-

proaches to preserving fertility in reproductive-age women

with cancer. A subset of reproductive-age women and gyne-

cologic cancers can be treated with fertility-sparing surgery.

Appropriate patient selection can result in survival rates

comparable to traditional radical surgery, while sparing fer-

tility. Select women with ovarian cancer that is borderline or

Grade I, Stage I can be treated with unilateral oophorectomy.

Women with Stage I cervical cancer can be treated with

radical trachelectomy. Young women with Stage I endo-

metrial cancer can be treated with progestins so that hyster-

ectomy can be avoided.

Surgical approaches for fertility preservation can also be

used for reproductive-age women diagnosed with cancer

who require pelvic irradiation or systemic chemotherapy.

Ovarian translocation prior to pelvic irradiation has been

demonstrated to preserve subsequent ovarian function. When

systemic chemotherapy is planned, experimental methods

are being developed to surgically remove and cryopreserve

ovarian tissue. After the patient is determined to be in remis-

sion, transplantation of ovarian tissue back into the patient

has been demonstrated to restore both ovarian function and

pregnancies.

Methods continue to be developed to preserve ovarian

function and fertility in reproductive-age women undergoing

cancer treatment. These methods must be implemented as

part of the initial approach to cancer therapy and prior to

definitive radiation or chemotherapy if the patient is to have

the best chance of continued ovarian function and fertility.

Five-Year View

The future of fertility preservation for reproductive-aged

women with cancer is likely to involve removal of ovarian

tissue, followed by in vitro follicle culture of the tissue and

removal of oocytes [86]. Immature eggs thus obtained will

be subjected to in vitro maturation. More effective tech-

niques are being developed for cryopreservation of both oo-

cytes and embryos.

KEY ISSUES

• Survival has significantly improved for women diag-

nosed with cancer during the reproductive years.

• The majority of these women desire children after com-

pletion of their cancer therapy.

• For women with early gynecologic cancers, fertility-

sparing surgery is often possible.

For women requiring pelvic irradiation or systemic che-

motherapy for a variety of cancers, surgical methods for pre-

serving ovarian function include ovarian transposition, and

removal of ovarian tissue prior to therapy for cryopreserva-

tion and later transplantation.


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Innovative Roles for Surgical Robotics in Reproductive Surgery

Ehab Barakat1,*, Mohamed Bedaiwy

2 and Tommaso Falcone

1

1Department of Obstetrics and Gynecology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA;

2University

Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH 44106, USA

Abstract: In the area of reproductive surgery and infertility, minimally invasive techniques appear to have outcomes

similar to those of laparotomy for tubal reanastomosis and myomectomy. Studies have shown that robotic use in these

surgeries is feasible and that it may be used as an alternative for conventional laparoscopic surgery. The robot can

overcome many of the limitations seen with conventional laparoscopy through improved dexterity and ergonomics. In this

review, we will evaluate the current applications of robotics in reproductive surgery.

Keywords: Robotic surgery, reproductive medicine, tubal reanastomosis, myomectomy, Da Vinci.

HISTORY OF ROBOTIC SURGERY

The first appearance of the robot in surgery was in 1985

when the PUMA 560 robot was used to perform CT-guided

brain tumor biopsies [1]. The next step in the surgical use of

the robots occurred at the Imperial college, London in 1988

where a device named PROBOT was involved in performing

transurethral resection of the prostate guided by a preopera-

tive construction of a three-dimensional image [2]. In 1992,

the ROBODOC machine was used in orthopedic surgery to

perform total hip replacement in humans [3]. These early

robots were designed to function autonomously after preop-

erative mapping [4].

The biggest step in the development of the surgical robot

was the evolution of robotic telepresence technology, which

gives the surgeon the ability to operate remotely. This was

created in a collaboration between the Stanford Research

Institute, United States Department of Defense and the

United States National Aeronautics and Space Administra-

tion (NASA) [5].The main goal for developing this system

was to provide immediate surgical care to soldiers in a bat-

tlefield area. Robotic arms were designed to be mounted on

an armored vehicle that would travel to the wounded soldiers

guided by a surgeon from a remote location [6]. This tech-

nology was subsequently commercialized, and the surgical

robot was no longer autonomous but functioned only with

help from surgeon’s movements [4].

In this review, we will evaluate the current applications

of robotics in reproductive surgery.

SURGICAL ROBOTS USED IN GYNECOLOGY

Three surgical robot systems have been described in the

area of gynecologic surgery. The first was the AEOSP

(Automated Endoscopic System for Optimal Positioning

*Address correspondence to this author at the Cleveland Clinical Founda-

tion, Department of Obstetrics and Gynecology, Cleveland Clinic Founda-

tion, Cleveland, OH, 44195, USA; Tel: 216-444-4402; Fax: 216-636-3100;

E-mails: [email protected], [email protected]

Computer Motion Inc., Goleta, CA) device, which was the

first commercially available surgical robotic technology. It

was used to hold a laparoscopic camera guided by a voice

command system [7].

The second system was the ZEUS robot (Computer

Motion Inc., Goleta, CA, USA). It was developed in the

early 1990’s. This system was composed of three robotic

arms attached to an operating table and a robotic console

where the surgeon was sitting. One of the robotic arms

was used to hold a laparoscope camera, and it was voice

activated. The surgeon controlled the other two arms using

handles on the console. The tip of ZEUS instrument had an

articulation that allowed some wrist movement but was

never intuitive [8].

The third robotic system used in gynecologic surgeries is

the da Vinci. In 2000, the FDA approved the da Vinci robot

system for use in abdominal surgeries. This system (Intuitive

surgical, Mountain View, California) consists of a surgical

console where the surgeon sits and a surgical tower at the

bedside. The insight vision system provides binocular vision

with a three-dimensional view. The console has two handles

that control the robot arms [9].

The patient tower has three to four robotic arms one

holds the camera and the others hold surgical instruments

such as graspers or scissors. The use of the da Vinci robot

provides a three-dimensional view of the operative field as

well as increased dexterity and precision in both dissection

and suturing procedures. The use of the endowrist instru-

ments that imitate the human wrist gives seven degrees of

freedom in movement, facilitating a wide range of motion.

There are some limitations with the use of the surgical robot,

however, that include the initial system cost, maintenance

costs and the expense of disposable instruments. The system

is very bulky, limiting patient access. Lack of tactile feed-

back during the procedure requires use of visual cues to

properly perform surgical tasks. There are no randomized

clinical trials comparing robotic to conventional laparoscopy

or laparotomy [10]. Also, it is unclear how many surgeries

are needed before a surgeon obtains technical proficiency.

178 Current Women’s Health Reviews, 2010, Vol. 6, No. 2 Barakat et al.

The first application of the surgical robot in reproductive

surgery was tubal renastomosis. After an initial success, it

was implemented in myomectomies, complex hysterecto-

mies and more intensively in gynecologic oncology–parti-

cularly for endometrial cancer staging.

ROBOTICALLY ASSISTED TUBAL REANASTO-

MOSIS

Tubal reanastomosis surgery was traditionally performed

through a small Pfannenstiel incision; microsurgical tech-

nique was used for the reconstruction. The disadvantages of

this procedure were postoperative pain and prolonged conva-

lescence. A minilaparotomy approach can be performed as

an outpatient procedure with good results [11]. However this

approach has not been generally adapted. With the develop-

ment of minimally invasive surgery, tubal reanastomosis was

performed laparoscopically with shorter hospital stays and

recovery times, smaller incisions and decreased postopera-

tive pain levels [12].

The use of laparoscopy in such a procedure requires pre-

cise dissection, delicate handling, and suturing of the fallo-

pian tubes. In addition, the learning curve of conventional

laparoscopy is high and requires a multitude of laparoscopic

surgical skills [13]. The skill set needed to perform such pro-

cedures has made this approach less popular. Consequently,

use of the minimally invasive approach, which could obviate

all these limitations, is desirable. Robotically assisted tubal

reanastomosis appears to be a good alternative to conven-

tional approaches [14].

Use of the surgical robot managed to overcome many of

the limitations seen with conventional laparoscopy. The first

reported case of robotic tubal reanastomosis was with the

Zeus robot in 1999 [15]. The most commonly used system

for robotic surgery is the da Vinci system, which provides a

three-dimensional view of the tubal architecture. The endow-

rist instruments provide seven degrees of freedom in dissec-

tion and knot tying. In addition, it eliminates the tremors

resulting from user fatigue and the use of fine sutures [16-

18].

We reviewed the literature for previous evaluations

on the use of the robot in tubal reanastomosis surgery.

Eight publications were identified and are summarized in

Table 1.

The first attempt at implementing robotics in reproduc-

tive surgery was in 1998 at Cleveland Clinic when an animal

study using a pig model was performed. Three approaches to

tubal reversal-type surgery were compared: open and laparo-

scopic with or without robotic assistance. This animal

experiment concluded that the use of Zeus robot is helpful in

performing tubal microsurgical reanastmsois and results in

shorter operative times compared with those of conventional

laparoscopy [19].

A case report of full robotic assistance in tubal steriliza-

tion reversal was published in 1999 by the same group. Sur-

gery with the Zeus Robot was accomplished successfully

without conversion to laparotomy. Tubal patency was docu-

mented at the end of the operation [15]. In further work by

Falcone et al., a human pilot study with the Zeus robot was

conducted with 10 patients undergoing tubal reanastomosis.

The procedure was completed successfully except in one

patient with dense intraperitoneal adhesions, which allowed

only unilateral access of the tube. There was 100% patency

Table 1. Summary of Literature on Robotic Tubal Reanastmosis Surgery

Author Year Robot Used Number of Robotic Cases Tubal Patency Rate Pregnancy Rate

1 Margossian, 1998 [19] 1998 Zeus System 1 Pig animal 100% -

2 Falcone, 1999 [15] 1999 Zeus System A case Report 100 % Not followed up

3 Degueldre, 2000 [14] 2000 Da Vinci 8 patients 100% 2 of 8

(25%)

4 Falcone, 2000 [18] 2000 Zeus System 10 patients 97.5% 5 of 10

(50%)

5 Goldberg, 2003 [20] 2003 Zeus System 10 patients 89.5% 5 of 10

(50%)

6 Rodgers, 2007 [21] 2007 Da Vinci 26 patients NA 19 pregnancies of 14

patients

(61%) (11%) ectopic

16% spontaneous abortion

7 Vlahos, 2007 [22] 2007 Da Vinci 5 patients 100% 4 of 5

(80%)

8 Dharia Patel, 2008 [16] 2008 Da Vinci 18 patients NA (62.5%)

(28%) intrauterine

(22%) ectopic

(11%) sp pregnancy loss

Innovative Roles for Surgical Robotics in Reproductive Surgery Current Women’s Health Reviews, 2010, Vol. 6, No. 2 179

in all reanastomosed tubes with a 70 ml mean blood loss.

By 12 months, 5 patients (50 %) had achieved pregnancy

[18].

In 2003, Goldberg and Falcone compared 10 patients

who underwent robotically assisted tubal reanastomosis

surgery with a control group of 15 patients who underwent

the same procedure by conventional laparoscopy. Five preg-

nancies (50 %) were reported in the robotic group and all

carried their pregnancies to term. The recorded operative

time was significantly longer in the robotic group. A statisti-

cally but not clinically significant higher blood loss was

detected in the robotic group [20]. The Zeus robot is no

longer available.

In 2000, a feasibility study described 8 women who

desired fertility restoration after tubal ligation surgery. Using

the da Vinci surgical system, bilateral tubal reanastomosis

was performed in all the patients. There was no recorded

perioperative or postoperative complications. Short and

long-term follow up data showed patent tubes on HSG

(hysterosalpingogram) in four patients and pregnancy in 2

patients within 4 months after surgery [14].

Rodgers et al., in 2007, compared minilaparotomy as an

outpatient procedure with the use of robotics in performing

tubal reanastomosis surgery. In 26 patients, the da Vinci

robot was used whereas the minilaparotomy was the pre-

ferred approach in 40 other patients. The operative time was

longer and costs were higher with the use of robotics. In ad-

dition, there was no significant difference between the 2

groups in hospitalization times, but there was a significantly

decreased convalescence time seen in the robotic patients.

There was no significant difference in pregnancy rates: 61%

of the patients in the robotic group and 79% of patients in the

minilaparotomy group became pregnant. The ectopic preg-

nancy rate was 11% in the robotic group versus 13% in the

minilaparotomy group. The rate of spontaneous abortion was

16% in the robotic group and 38 % in the minilaparotomy

group [21].

In 2007, Vlahos et al. published a study that reviewed 5

patients who underwent robotic tubal reanastomosis surgery.

All procedures were completed successfully without major

complications. They also noticed a trend in the time needed

to prepare for surgery by robot positioning and set up and

perform the robotic surgery both declined as the surgeons

became more familiar with using the technology. Four of the

five patients conceived resulting in two viable pregnancies

(there was one ectopic pregnancy and a chemical pregnancy

that resolved spontaneously) [22].

Finally, Daharia et al., in 2008, reported on a prospective

study comparing tubal renanastmosis surgery performed via

an open technique versus robotic assistance. There were 18

patients in the robotic group and 10 patients in the lapa-

rotomy group. Although the operative time was significantly

longer in the Robotic assistance, these patients needed

less postoperative analgesia and less time to recover. Both

approaches had similar overall costs. In the robotic group,

there were x (28%) intrauterine pregnancies, x (22%) ectopic

pregnancies and x (11%) spontaneous pregnancy losses

versus x (30%), x (10%) and x (10%), respectively, in the

laparotomy group [16].

ROBOTICALLY ASSISTED MYOMECTOMY

The evolution of robotics in gynecologic surgery offered

the chance for a minimally invasive approach to be used for

complicated surgical procedures that were challenging by

conventional laparoscopy. Hysterectomy and colposacro-

pexy are widely performed with robotic assistance [17, 23]

as are procedures in gynecologic oncology [24].

Myomectomy remains the best choice of treatment for

symptomatic fibroids in patients desiring to preserve their

fertility, even with newer modalities such as uterine artery

embolization [25, 26]. Open myomectomy was the preferred

approach until the emergence of the minimally invasive

surgical technique. Laparoscopy was used to perform

myomectomy with better cosmesis and shorter postoperative

pain and hospital stay but the procedure was highly challeng-

ing for the surgeon. With conventional laparoscopy, precise

dissection of the fibroid without unnecessary breaching

of the endometrial cavity is key. Moreover, it is necessary

to suture the fibroid bed in layers with precise approxima-

tion of edges to prevent rupture of the uterus during

labor [27]. Laparoscopic suturing is a difficult skill to

master. These challenges limited the acceptance of this

technique, and open myomectomy remained the approach

of choice.

We reviewed the literature for previous experiences in

robotic myomectomy 7 studies were identified (Table 2).

The first work was reported by Advincula P, et al. in

2004. This was a preliminary study that included 35 patients

who underwent robotically assisted myomectomy between

2001 and 2004. The number; weight and diameter of the

removed myomas were recorded. All cases were performed

with the da Vinci Robot the conversion rate to laparotomy

was 8.6%. The average estimated blood loss was 169 ±198.7

ml and the median length of stay was 1 day [27].

A case report was published by Mao SP, et al. in 2007

that featured a 38-year-old gravida 2 para 2 female patient

with an anterior wall subserosal myoma measuring 7x 8 x 9

cm. The myoma was successfully removed with the use of

the da Vinci Robot in 3 hours with an estimated blood loss of

150 ml. There were no recorded adverse events [28].

Bocca S, et al. in 2007 documented for the first time

an uncomplicated full-term pregnancy in a patient who had

undergone robotically assisted myomectomy. The surgery

was successfully completed with the use of da Vinci robot,

which removed a 3-cm single fundal intramural uterine

myoma. Approximately four months later, the patient

became pregnant after clomiphen citrate and HCG (human

chorionic gonadotropin) treatment. Delivery of a full-term

healthy baby was done by Caesarian section at 38 weeks

[29].

In 2007, Advincula et al. compared robotically assisted

myomectomy with open myomectomy. This study included

58 patients; 29 in the robotic group and 29 in the open group.


No statistically significant differences were seen between the

two groups in regards to age, BMI and weight of the re-

moved myomas. The patients in the robotic group had sig-

nificantly less blood loss and a shorter length of stay but the

Hospital costs were higher in this group. The operative time

was longer in the robotic group, but the rate of complications

was higher in the laparotomy group [30].

More recently, in 2009, Nezhat C, et al. compared 15

cases of robotically assisted myomectomy with 35 cases of

standard laparoscopic myomectomy. No differences were

seen between the 2 groups in regards to patient age, BMI,

parity, and previous abdominopelvic surgery. No significant

difference was seen between both groups in the size, number

and location of the removed myomas. However, the mean

surgical time was longer in the robotic group. There were no

differences between the 2 groups in regards to estimated

blood loss, length of hospital stay or rate of postoperative

complications [31].

A retrospective data analysis was conducted by George

A, et al. that included 77 cases of robotically assisted myo-

mectomy. The aim of this work was to analyze the effect of

the patients’ BMI on the surgical outcomes of the procedure.

This study recorded no association between patient BMI and

short-term surgical outcomes such as length of stay, esti-

mated blood loss and length of procedure [32].

Bedient CE, et al., compared robotic and laparoscopic

myomectomy in a retrospective chart review of 81 patients--

40 patients were in the robotic group and 41 patients were in

the laparoscopic group. No differences were recorded be-

tween the 2 groups regarding the operative time, mean blood

loss or length of stay. There was a significant difference,

however, noted in the laparoscopic group they had a larger

preoperative uterine size, a larger mean size and a larger

number of removed fibroids [33].When adjusted for uterine

size, there was no difference in regards to intra-operative or

postoperative complications.

CONCLUSION

Robotic surgery has been successfully implemented in

reproductive surgery. The surgical robot offers 3-D vision,

improved dexterity, and easier precise suturing, which ap-

pears to be critical in fertility preserving surgeries. The sur-

gical robot can provide the surgeon with the dexterity of an

open approach while keeping the minimally invasive advan-

tages. The disadvantages of using this technology remain the

cost and the bulky size of the robot. Further studies are war-

ranted to evaluate the potential role of the robot in random-

ized clinical trials. The cost effectiveness and long-term post

surgical reproductive outcomes of these surgeries need to be

critically evaluated.

EXPERT COMMENTARY

The main objective of this article is to review the current

experience of robotic surgery in the field of reproductive

medicine. The robotic approach has been used successfully

Table 2. Summary of Literature on Robotic Myomectomy Surgery

Author Year Number of

Robotic Cases

Type of Study Removed Myomas

Weight

Results

1 Advincula

AP, et al. [27]

2004 35 Preliminary experience Mean=223.2±244.1

g

Robotic Myomectomy is

new promising approach

2 Mao SP,

et al. [28]

2007 1 Case report Not Available Successful Robotically assisted

excision of large uterine myoma

measuring 9x8x7 cm

3 Bocca S,

et al. [29]

2007 1 Case Report Not Available Achievement of uncomplicated

full term pregnancy after

robotic myomectomy

4 Advincula

AP, et al. [30]

2007 29 Retrospective case matched

study between robotic and

open myomectomy

Mean

= 227.86±247.54 g

Robotic myomectomy approach

is comparable to open approach

regarding short term surgical

outcome and costs

5 Nezhat C,

et al. [31]

2009 15 Retrospective case matched

between robotic and Laparo-

scopic myomectomy

Mean= 116 g

(min25-max350) g

Robotic Myomectomy had significant

longer surgical time without offering

any major advantages.

6 George A,

et al. [32]

2009 77 Effect of the BMI on the

surgical outcome

Median =235g

(range 21.2-980) g

Obesity is not a risk factor for

poor surgical outcome in

Robotic Myomectomy

7 Bedient CE,

et al. [33]

2009 40 Comparing Robotic to

laparoscopic Myomectomy

Mean 210 g

(range 7-1076) g

No difference in relation to

short term surgical

outcome measures.

Innovative Roles for Surgical Robotics in Reproductive Surgery Current Women’s Health Reviews, 2010, Vol. 6, No. 2 181

to perform tubal reanastomosis and myomectomy. The use

of the robot has overcome many of the challenges seen pre-

viously with conventional laparoscopy such as precise

laparoscopic suturing. The surgical robot provides the three-

dimensional vision required for depth perception and im-

proved dexterity, which helps the surgeon in precise dissec-

tion and suturing. There seems to be improved immediate

postsurgical outcomes by reducing the blood loss and length

of the hospital stay with subsequent rapid return of the pa-

tient to normal activities. The loss of haptic feedback and the

high cost are limitations in its widespread use and applica-

tion. Randomized clinical trials will be required to study the

value of the surgical robot in these procedures with respect

to short and long term outcomes. Cost effectiveness studies

will be important to determine the role of this technology.

FIVE YEAR VIEW

The use of surgical robotics in reproductive medicine is

expected to continue to expand. In the United States, it is

expected that more surgical procedures will be performed

using the robotic approach. Expansion of robotics outside the

States will be slower mostly because of the high costs. In the

States, public health policy may require clear evidence that

added technology makes a difference in outcomes. Random-

ized controlled trials are warranted to compare open, laparo-

scopic and robotic use for different indications. Short and

long term outcomes need to be assessed. The development of

robotic technology with smaller size prototypes and lower

cost are expected to appear in the future.

KEY ISSUES

• The surgical robot was developed to perform complex

surgical tasks with minimally invasive techniques.

• For certain procedures, the robot can help surgeons over-

come the reported limitations of conventional laparo-

scopy.

• The surgical robot can provide the surgeon improved

ergonomics.

• In gynecology, robotic surgery has been used for many

surgical procedures with reported success in benign

gynecology, gynecologic oncology and reconstructive

pelvic surgery.

• Reduced hospital stay and blood loss with the use of the

robot were recorded in many retrospective studies.

• The bulky size, high cost and loss of the tactile feedback

are still considered disadvantages with the use of the

surgical robot.

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Surgical Management of Müllerian Duct Anomalies

Ali M. El Samana,*, Jennifer A. Velotta

b and Mohamed A. Bedaiwy

a,b

aDepartment of Obstetrics & Gynecology, Assiut University, Assiut, Asyut, Egypt;

bDepartment of Obstetrics and

Gynecology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH 44106, USA

Abstract: Developmental anomalies of the müllerian duct system represent an interesting field of disorders in obstetrics

and gynecology as they can affect any of the reproductive organs from the Fallopian tubes to the hymen. The purpose of

this article is to review the available treatment options for müllerian duct anomalies with special emphasis on simple and

advanced surgical approaches. Surgical options are presented based on a novel treatment plan classification system

adapted from the American Fertility Society classification of müllerian duct anomalies. Care was taken to include all pre-

viously termed unclassified anomalies as well as the important category of longitudinal fusion defects. Important diagnos-

tic approaches are discussed with special emphasis on detection of associated anomalies of the urinary system and other

relevant systems. Early establishment of an accurate diagnosis is important for planning management options and prevent-

ing complications in the genital organs and surrounding systems. Classifying müllerian anomalies based on the available

treatment options seems logical and the inclusion of previously unclassified entities is important for a comprehensive un-

derstanding and management of this group of disorders. The surgical approach for the correction of müllerian duct anoma-

lies is individualized to the type of malformation. The value of a given surgical procedure should be assessed on terms of

its capability to improve a patient's postoperative ability to have healthy sexual relations and achieve successful reproduc-

tive outcomes.

Keywords: Müllerian duct anomalies, vaginoplasty, vaginal agenesis, bicornuate uterus, septate uterus, transverse vaginal

septum.

INTRODUCTION

Developmental anomalies of the müllerian duct system

represent an interesting spectrum of disorders in obstetrics

and gynecology [1]. The exact prevalence is unknown, and

the present classifications have inherent limitations. The

main objective of current treatment modalities is to conserve

or restore all or some of a patient’s reproductive goals. These

goals include restoring menstrual functions through treat-

ment of crypto menorrhea, which eliminates pain, prevents

endometriosis and other consequences, and gives the patient

a true chance for natural conception. In other cases where

functioning uterine or vaginal tissue are not present, treat-

ment goals are directed towards achieving a normal sexual

life via the creation of a neovagina and appropriate psycho-

sexual support. The later field has undergone continuous

improvement, especially in the past five years—for example,

patients who have undergone partial or total construction or

reconstruction of the vulvovaginal complex can initiate sex-

ual activity as early as one week after surgery. In the future

restoration, of full reproductive potentials for those women

without functioning endometrial tissues through stem cell

therapy and/or uterine transplant may become possible.

Embryological Backgrounds

The genital systems of male and female embryos are

morphologically identical at 6 weeks. Both embryos have

*Address correspondence to this author at the Department of Obstetrics &

Gynecology, Assiut University, PO Box 30, Assiut, Asyut, Egypt;

Tel: 01120-88-2354488; Fax: 01120-88-2337333;


two sets of paired genital ducts: the müllerian ducts and the

wolffian ducts. In females, the wolffian ducts regress, and

the vestiges provide a template for the developing müllerian

ducts. This explains the frequent associations observed later

between müllerian defects and renal-urinary system malfor-

mations [2-4]. The traditional hypothesis maintains that the

müllerian ducts are fused in a caudal-cranial direction. How-

ever, the müllerian anomalies characterized by a septate

uterus, cervical duplication, and longitudinal vaginal septum

supports the alternative hypothesis in which fusion of the

müllerian ducts is segmental and bidirectional [4].

Recent data, both experimental and observational, [2, 5,

6] support early 20th century studies that identified the sino-

vaginal bulbs as being derived from the caudal aspects of the

wolffian ducts and the müllerian ducts. These bulbs were

designated as wolffian bulbs. The hymen is a vestige of the

endodermal membrane that separates the vaginal lumen from

the UGS cavity; it usually ruptures perinatally and remains

as a thin mucous membrane [7, 8].

Etiological Backgrounds

The diversity of structural anomalies seen in müllerian

duct defects results from interruption or inappropriate regu-

lation in müllerian-duct development at various stages of

morphogenesis. Well-known factors, such as intrauterine and

extrauterine elements, genetics, and teratogens (eg, diethyl-

stilbestrol [DES], thalidomide), have been associated with

müllerian duct anomalies [7]. The genetics of müllerian duct

anomalies are complex. In general, they occur sporadically,

and most familial cases are multifactorial. Other modes of

inheritance, including autosomal dominant, autosomal reces-

184 Current Women’s Health Reviews, 2010, Vol. 6, No. 2 El Saman et al.

sive, and X-linked disorders, also exist. Müllerian anomalies

may also represent a component of a multiple malformation

syndrome [9, 10].

Classifications

The form of classification that includes agenesis or hy-

poplasia, lateral fusion defects, vertical fusion defects, and

DES-related abnormalities, is not mutually exclusive be-

cause many müllerian duct anomalies often coexist. Classify-

ing müllerian duct anomalies using the method described by

Buttram and Gibbons and others [8, 12-18] bears merit be-

cause it correlates anatomic anomalies with arrests in

morphogenesis. However, this method is awkward and con-

fusing.

The most widely accepted method of categorizing mülle-

rian duct anomalies is the American Fertility Society (AFS)

classification [11]. There are some limitations of the AFS

classification, however. We suggest the treatment plan clas-

sification, which will be discussed in this article (Table 1).

SURGICAL MANAGEMENT OF MÜLLERIAN DUCT ANOMALIES

According to the treatment plan classification, the surgi-

cal management of müllerian duct anomalies is organized

Table 1. AFS and Treatment Plan Classification of Müllerian Duct Anomalies

Classification AFS Classification Treatment Plan Classification

Class I

Segmental or

complete agenesis

or hypoplasia.

Agenesis and hypoplasia may involve the vagina, cervix,

fundus, tubes, or any combination of these structures.

Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is the

most common example in this category.

Class Ia – Affecting Fallopian tubes.

Class Ib - Affecting the uterine fundus.

Class Ic- müllerian aplasia (MRKH) syndrome.

Class Id- cervical aplasia (isolated or associated

with vaginal aplasia).

Class Ie- isolated vaginal aplasia.

Class II

Unicornuate uterus

with or without a

rudimentary horn.

When an associated horn is present, this class is subdivided

into communicating (continuity with the main uterine cavity

is evident) and noncommunicating (no continuity with the

main uterine cavity). The noncommunicating type is further

subdivided on the basis of whether an endometrial cavity is

present in the rudimentary horn. These malformations have

previously been classified under asymmetric lateral fusion

defects. The clinical significance of this classification is

that they are invariably accompanied by ipsilateral renal

and ureter agenesis.

Class IIa-Unicornuate uterus without a rudimentary horn.

Class IIb- Communicating horn with or without

functioning endometrium.

Class IIc-Non-communicating without functioning endometrium.

Class IId-Non-communicating with functioning endometrium

Class III

Didelphys uterus.

Class IV

Complete or partial

bicornuate uterus.

Complete or partial duplication of the vagina, cervix,

and uterus characterizes this anomaly.

Complete bicornuate uterus is characterized by a uterine

septum that extends from the fundus to the cervical os. The

partial bicornuate uterus.

Class IIIa – Partial bicornuate uterus

Class IIIb - Complete bicornuate 2 separate horns and single cervix.

Class IIIc- Partial duplication with two cervices.

Class IIId- Complete duplication of the uterus, cervix, and vagina.

Class IIIe- any of the above with unilateral or bilateral

obstruction of menstrual outflow

Class IV

Complete or

partial septate

uterus.

A complete or partial midline septum is present

within a single uterus.

In both variants, the vagina and cervix

each have a single chamber.

Class IVa - A complete or partial midline septum is

present within a single uterus without fundal depression,

Class IVb- A complete or partial midline septum is present

within a single uterus with fundal depression,

Class IVc – Any combination of the above in addition to

septate cervix and vagina.

Class IVd – Any combination of the above with

unilateral or bilateral obstruction.

Class V

Longitudinal

fusion defects

Not mentioned in the AFS classification. Class Va- partial transverse vaginal septum

Class Vb-complete transverse vaginal septum.

Class Vc- lower segmental vaginal atresia with upper heamtocolpos.

Class Vd- imperforate hymen.

Class VI Arcuate

uterus

Class VII DES-

related

abnormalities

A small septate indentation is present at the fundus.

A T -shaped uterine cavity with or without

dilated horns is evident.

Class VI (insignificant & historical anomalies).

Class VIa – Arcuate uterus.

Class VIb - DES-related abnormalities

Surgical Management of Müllerian Duct Anomalies Current Women’s Health Reviews, 2010, Vol. 6, No. 2 185

based on the anatomical hierarchy of each class. Also in-

cluded in the organization is the clinical significance of the

available interventions as well as the presence or absence of

current surgical options.

For example, the first category includes segmental or

complete agenesis or hypoplasia of the tubes, uterus, or va-

gina. According to the anatomical hierarchy presentation,

tubal anomalies will be addressed first followed by uterine

anomalies then cervical and vaginal anomalies.

Treatment of Class I (Segmental or complete agenesis or

hypoplasia) (Table 2- Fig. 1)

Class Ia – Segmental or Complete Agenesis or Hypoplasia

Affecting the Fallopian Tubes

Congenital fallopian tube disorders are either asympto-

matic or presenting with infertility, ectopic pregnancy or

acute abdominal pain due to torsion of an accessory tube

[12-14]. Types of tubal anomalies range from aplasia, hy-

Table 2. Description of AFS and Treatment Plan Classification of Class I Müllerian Duct Anomalies


Class I

Segmental or complete

agenesis or hypoplasia

Agenesis and hypoplasia may

involve the vagina, cervix,

fundus, tubes, or any combination of

these structures. Mayer-Rokitansky-

Kuster-Hauser (MRKH) syndrome

is the most common example

in this category.

Class Ia – Segmental or complete agenesis or hypoplasia affecting the Fallopian tubes.

Class Ib - Segmental or complete agenesis or hypoplasia affecting the uterine fundus.

Class Ic - müllerian aplasia (Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome

Class Id - cervical aplasia (isolated or associated with vaginal aplasia)

Class Ie - isolated vaginal aplasia

Segmental or complete agenesis or hypoplasia affecting the vagina

Subclass Available Treatment Options

Class Ia

Class Ib

Class Ic

Class Id

Class Ie

Microsurgery, open, laparoscopic, robotic reconstruction/excision or ART

No surgical treatment if the vagina is adequate+ psychosocial support

Neovagina + appropriate psychosocial

Cervical canalization + utero vaginal anastomosis

Neovagina + uteroneovaginal anastomosis

Fig. (1). Shows segmental or complete agenesis or hypoplasia affecting the fallopian tubes, uterine fundus, (Class Ib) müllerian aplasia

(Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, (Class Ic) cervical aplasia (isolated or associated with vaginal aplasia Class Id) and

isolated vaginal aplasia (Class Ie).


poplasia, non-canalization, segmental atresia, accessory

ostia, congenital diverticula, and elongation to accessory

tubes and duplication. Few anomalies are amenable to surgi-

cal correction through open microsurgery, laparoscopic mi-

crosurgery or robotic surgery. Others may require corrective

surgery and or excisions in the event of torsion or ectopic

pregnancy. Assisted reproductive technology (ART) repre-

sents an important effective backup for uncorrectable iso-

lated tubal anomalies such as aplasia, hypoplasia and non

canalization.

Class Ib - Segmental or Complete Agenesis or Hypoplasia

Affecting the Uterine Fundus

In cases of isolated uterine aplasia and/or hypoplasia

with a functioning vagina, there are no treatment options if

the present vaginal pouch permits adequate marital relations

[1].

Class Ic - Müllerian Aplasia (Mayer-Rokitansky-Kuster-

Hauser Syndrome)

Vaginal agenesis occurs in 1 out of 4,000-10,000 fe-

males. The most common cause of vaginal agenesis is mülle-

rian aplasia or agenesis (Mayer-Rokitansky-Kuster-Hauser

[MRKH] syndrome). The hormonal profile helps distinguish

the MRKH syndrome from androgen insensitivity syndromes

[15-17].

Trans-abdominal and trans-rectal ultrasonographic and

MRI findings can add support to the clinical findings and

detect the presence of normal ovaries [18-20]. Fusion of the

cervical vertebrae, a component of Klippel-Feil syndrome,

can result in cervical rigidity that may substantially interfere

with the intubation procedure [21]. Discovery of a pelvic

kidney is important in planning corrective surgery because

its presence may limit the potential space available for graft

placement [22, 23]. Laparoscopy is confirmatory for diagno-

sis and is one of the indispensable methods for treatment [24,

25]. There are three main well known treatment strategies for

MRKH syndrome—a fourth one was recently introduced

[26]. The first strategy, and the least invasive one, is the non-

surgical use of successive dilators, which requires high com-

pliance and patience, and good results are achievable over

months of dilatation only if the patient is sufficiently moti-

vated. The second strategy is the surgical correction via the

creation of a surgical space at the site of the absent vagina. It

is covered with a graft, and then a form is used to maintain

the graft. The third strategy is creation of neovagina from

native tissue through traction that is applied from above us-

ing an acrylic olive placed on the vaginal dimple

The fourth and newest treatment option is balloon vagin-

oplasty where traction is applied from above on a silicon

coated balloon catheter, creating a natural neovagina over a

shorter period of time [24]. Interestingly, with balloon

vaginoplasty, there is a possibility of manipulating both the

depth as well as the width of the neovagina using different

schedules of catheter traction and balloon distention [25].

Any surgical treatment should be well thought-out only

when the patient can participate in the decision making

wishes to become sexually active [27]. In certain countries,

the operation is only performed after planning for marriage

or after actual marriage [24-26].

Whereas a number of vaginoplasty methods have been

developed, refined, and modified, no state-of-the-art surgical

approach has been established. This is due to a number of

factors including regional differences, surgeon experience

and preference for a method, and patient choice [26, 28, 29].

The goal of vaginoplasty is to develop a space between

the bladder and the rectum. This is followed by grafting–

either by a full or split-thickness skin graft. The later has had

high rates of success and patient satisfaction. Scar formation

at the graft site has been a concern [30]. Human amnion has

also been used as a graft for vaginoplasties.

Transposition flaps have been used successfully in some

cases. One method is to use a de-epithelialized vulvar trans-

position flap as the graft. Another method is a pudendal

thigh fasciocutaneous flap, which has been described as

having good cosmetic and functional outcomes [31]. Most

recently, a triple flap relying on the use of labia minora

and suburetheral tissue has been reported with high success

rates.

Autologous buccal mucosa has also been used as a graft

source. These approaches used harvested bilateral full-

thickness buccal mucosa grafts that are expanded with

several stabs incisions and sutured over a condom-covered

soft stent. They are then placed in the newly created space.

Artificial dermis and absorbable adhesion barriers have

been used as exogenous graft sources in vaginal reconstruc-

tion with promising results. An acrylic resin form was cov-

ered with artificial dermis, inserted, and fixed to the newly

created vaginal space. The form was usually removed after 7

days; good results were reported with continued use of the

form at nighttime [32].

Absorbable adhesion barrier (Interceed; Ethicon,

Somerville, NJ) was used in a similar technique where

neovaginal epithelialization was reported in 1-4 months [33-

34].

A laparotomy procedure for peritoneal mobilization was

reported in 1969 by Davydov. The peritoneum from the

uterorectal space (pouch of Douglas) is advanced in such a

manner that a vaginal canal is created. Recently, a laparo-

scopic modification was developed where the peritoneum is

pulled through the newly created vesicorectal space using

high tension and by approximating it at the introitus. A stent

is then used for vaginal dilation. There are several benefits of

this procedure, including minimal scarring and functional

vaginas associated with comfortable intercourse [35].

Bowel vaginoplasty involving the distal sigmoid colon to

line the neovaginal space has gained popularity with some

pediatric surgeons. Classically, this approach requires con-

comitant laparotomy and bowel anastomosis. However, re-

cent reports describe a laparoscopic approach [34, 36, 37].

Bowel vaginoplasty does not require persistent dilation, and

the neovagina is self-lubricating [38].

The goal of split-thickness grafting is to generate a suffi-

cient space between the urethra and/or bladder. The graft is

placed over a sterilized stent with the epidermis facing the

surface of the stent and the dermis facing out. The labia mi-


nora are sutured around the stent, and, to avoid applying un-

desirable pressure to the stented graft, the transurethral

catheter is replaced with a suprapubic bladder catheter [22,

39, 40].

Continuous, prolonged dilatation and stent care during

the healing phase is important [23]. The patient is educated

to use the form continuously for 6 weeks, removing it only

for urination and defecation. Six weeks later, a silicone form

is used nightly for one year. In most cases, the vagina is

functional 6-10 weeks after surgery [22, 39, 40].

Serious complications include postoperative fistula (4%

risk) and enterocele [22, 41]. Other complications including

hemorrhage, infection, graft failure, graft contracture and

excess granulation tissue have been reported [22]. Rarely,

primary malignancy of the neovagina has been reported and

for this reason, yearly Pap smears are recommended as part

of long-term follow-up care [42, 43].

The Williams vulvovaginoplasty procedure is useful for

patients with a previously failed vaginoplasty or for patients

who have undergone radical pelvic surgery in areas where

other better alternatives are not affordable. The vagina cre-

ated by this approach is not anatomically similar to a normal

vagina as its axis is directly posterior and horizontal to the

perineum. However, the vagina is functional and well re-

ceived by patients, and dilation is required for only 3-4

weeks [44].

Native epithelium covered neovaginas are developed

from by expanding the natural epithelium at the dimple. Tis-

sue expansion is classically achieved either by pushing from

below with graduated dilators or by traction from above as in

the Vecchietti operation and its laparoscopic version. Re-

cently, a bidirectional (axial and circumferential) tissue ex-

pansion technique was developed through introduction of

balloon vaginoplasty where axial expansion which increases

vaginal length is effected through traction on the catheter

stem and circumferential expansion that increases the

neovaginal width is achieved through increasing balloon

distension. A native epithelium covered neovagia is more

favorable to one made from foreign tissue.

The original Vecchietti operation was developed in 1965.

Through laparotomy, sutures are attached to the traction de-

vice, which are connected to an oval plastic olive placed at

the vaginal dimple. By gradually increasing suture tension,

upward traction and continuous pressure lengthens the

neovaginal space over a period of one week.

The laparoscopic Vecchietti vaginoplasty (LVV) was

developed in 1992 with outcomes similar to those of the

original technique. The long-term clinical and sexual func-

tion outcomes were evaluated after LVV in 106 patients with

müllerian aplasia. Sexual function was successfully achieved

in 97% of cases and was comparable with that reported in

the control group [45, 46].

Another procedure is termed transretropubic traction

(TRT) vaginoplasty. In this procedure, a plastic olive is

placed on the vaginal dimple and is lifted by a mesh tape

inserted through the space of Retzius and anchored to the

anterior abdominal wall. Traction is placed on the mesh tape

and maintained by applying a plastic clamp over a special

supporting plate [47, 48].

Balloon vaginoplasty was recently introduced by El

Saman et al. using a laparoscopic approach. A silicon coated

balloon catheter is manipulated by a specially designed in-

serter, which is passed transperitoneally and through the pel-

vic floor where the balloon is positioned at the vaginal dim-

ple. An upward, gradual (1-2cm/day) traction is applied on

the catheter stem from the abdominal side for one week. A

concomitant increase in balloon capacity (5ml every other

day) to increase the width of the neovagina is also done [26].

Sexual relations were reported as early as one week after

surgery [24].

The concept of manipulating the neovaginal depth and

width is a novel characteristic of balloon vaginoplasty.

The manipulation is done using different distensions and

tractions schedules. This only served to worsen existing

dyspareunia. This resulted in more initial dyspareunia com-

pared to cases predominant distension. On the other hand,

patients who underwent a predominant increase in the bal-

loon distention developed a neovagina that was wide but a

bite shallower, and this resulted in minimal or no initial

dyspareunia. With time, both groups showed improvement in

dyspareunia

The idea of retropubic balloon vaginoplasty was born

when a patient with vaginal aplasia was referred to the As-

siut University Women Health Center for laparoscopic bal-

loon vaginoplasty. However, because of her past medical and

surgical history, laparoscopy was considered risky due to

extensive pelvic adhesion. Thus, the retropubic space was

thought to be a safe pass for catheter insertion. Through a

small supra pubic puncture, the catheter inserter was passed

into the retropubic space just behind the pubic bone and

guided to the center of the vaginal dimple. Then, a

cystoscopic examination was performed to ensure bladder

and uretheral integrity. This was followed by gradual con-

trolled distention of the balloon and traction on the catheter

stem as described in laparoscopic balloon vaginoplasty [49].

One inherent limitation of balloon vaginoplasty is the need

for a customized set of instruments such as the catheter in-

serter, supporting plate, and vaginometer for assessment of

outcomes. The authors of original balloon vaginoplasty

modified ed their the technique to allow its performance with

conventional laparoscopic instruments and other commer-

cially available accessories. The procedure was successfully

preformed with comparable outcomes [24].

Class Id - Cervical Aplasia (Isolated or Associated with

Vaginal Aplasia)

Cervical aplasia and / or hypoplasia are rare but challeng-

ing Müllerian anomalies. Hysterectomy was recommended

by some authors when canalization procedures fail or are not

viable for successful relief of the related symptoms [50].

Others adopted a conservative policy [50, 51]. Recently, two

endoscopic procedures were described. The principal advan-

tage is that dissection in atretic areas is not necessary as the

uterovaginal anastomosis can be established endoscopically.

The first technique is endoscopically monitored canalization

of isolated cervical atresia. In this procedure, a special in-

serter with a silicon drain attached to its caudal end is passed


across the uterine fundus to the vaginal pouch. The silicon

tubal drain is passed across the aplastic/hypoplastic cervix

and fixed securely for one month. The results were promis-

ing but more studies are required [52]. The second procedure

is a novel blend of retropubic balloon vaginoplasty and

laparoscopically monitored canalization, which is applied in

patients with combined cervical and vaginal aplasia. The

retropubic balloon vaginoplasty is the fastest way to create a

neovagina. This was done using upward traction on a silicon

coated catheter that was placed across the retropubic space to

the vaginal dimple. Another balloon catheter was manipu-

lated from below to the distended uterine cavity to drain.

Hematometra; down traction is exerted on the lower uterine

segment. Both up and down tractions are applied for few

days to one week, and the balloons are monitored by trans-

rectal US when they are suspected of being too close (kissing

balloons). The final step is utero-neovaginal anastomosis

[53].

Class Ie - Isolated Vaginal Aplasia: Segmental or Complete

Agenesis or Hypoplasia Affecting the Vagina

Patients with this class of anomalies present with hema-

tometra with or without upper hematocolops. This condition

is treated by uterovestibular anastomosis or vaginoplasty and

uteroneovaginal anastomosis. Uterovestibular anastomosis is

performed via combined abdominal and perineal approaches

that mobilize the uterus from above and create the anastomo-

sis from below. However, the logical management plan

should involve creation of a neovagina by any of the afore-

mentioned techniques followed by utero-neovagina anasto-

mosis. Because balloon vaginoplasty is the fastest way to

create a functional neovagina, it is the first choice of treat-

ment in cases of isolated vaginal aplasia [53].

Management of Class II (Unicornuate Uterus) Table 3

Fig. (2)

A unicornuate uterus may be not be diagnosed until the

end of the reproductive years, especially if there is no func-

tioning rudimentary horn. MRI reliably helps make this

diagnosis and represents the gold standard diagnostic tool for

all subclasses of unicornuate uterus [18-20, 54-56]. High-

resolution ultrasonography, intravenous urography and/or

renal ultrasonography assist in the evaluation of ipsilateral

renal agenesis, horseshoe kidney, and ipsilateral pelvic

kidney [57].

Women with unicornuate uterus subclasses IIa, IIb and

IIc (Fig. 2) are not normally considered for reconstruction

metroplasty [7, 58]. The main indication for surgery is the

presence of functioning endometrium in the accessory horn.

Laparoscopic hemihysterectomy of the rudimentary horn is

the treatment of choice [59-61]. The pedicle of the rudimen-

tary horn is coagulated using bipolar coagulation, and it is

excised (scissor excision) along with the ipsilateral Fallopian

tube; the functional ovary is not removed. Morcellation may

be required when the rudimentary horn is bulky. Successful

pregnancy in the major horn has been reported after laparo-

scopic removal of the accessory horn. .

Hysteroscopic endometrial ablation of the accessory horn

endometrium as well as hysteroscopic drainage of a hema-

tometra in a noncommunicating accessory horn using elec-

trocautery to create a communication between the horns has

been reported [62, 63]. No specific major complications apart

of those associated with laparoscopy and postsurgical obstet-

ric outcomes have been reported [59, 60].

Class III - Uterus Didelphys and Bicornuate Uterus Table 4

Both a bicornuate and a didelphys uterus arise when mid-

line fusion of the müllerian ducts is arrested [64]. An ex-

traordinary capacity of the didelphys uterus is that, in many

cases, intercourse is often possible in both vaginas. Moreo-

ver, simultaneous pregnancies in each uterus can occur, al-

though this is rare. Each pregnancy may be considered a

separate entity. In fact, a twin may be delivered after a long

Table 3. Description of AFS and Treatment Plan Classification of Class II Müllerian Duct Anomalies


Class II

Unicornuate uterus

with or without a

rudimentary horn

When an associated horn is present, this class is

subdivided into communicating and noncommuni-

cating. The noncommunicating type is further

subdivided on the basis of whether an endometrial

cavity is present in the rudimentary horn. The

clinical significance of this classification is that

they are invariably accompanied by ipsilateral

renal and ureter agenesis.

Class IIa-Unicornuate uterus without a rudimentary horn.

When a rudimentary horn is present, (asymmetric lateral

fusion defects) it is classified as follow:

Class IIb – Communicating horn with or without functioning

endometrium.

Class IIc –Non-communicating without functioning endometrium.

Class IId –Non-communicating with functioning endometrium.


Class IIa

Class IIb

Class IIc

Class IId

No surgical treatment

No surgical treatment vs. excision

Usually no surgical treatment is required

Laparoscopic hemihysterectomy is required as early as possible.


interval, ranging from 3 hours to 5 days to 8 weeks, after

delivery of its sibling [65-67].

Without obstruction, all subclasses are usually asympto-

matic until menarche. These patients are not candidates for

surgical unification. The condition is associated with favor-

able obstetrical outcomes and usually remains undiagnosed

until cesarean delivery or other procedures reveal its exis-

tence [39, 68, 69]. Undeniably, some authorities contend that

the results of unification surgery, especially for the uterine

didelphys, may be disappointing. Furthermore, cervical uni-

fication is technically difficult and can result in cervical

stenosis or incompetence [70].

Management of Class IIIa – Partial Bicornuate Uterus

The partial bicornuate uterus is characterized by two

separate horns with unified lower uterus and cervix originat-

Fig. (2). Shows Unicornuate uterus without a rudimentary horn, (Class IIa) unicornuate uterus with communicating horn,( Class IIb)

unicornuate uterus with non-communicating without functioning endometrium.( Class IIc) and unicornuate uterus with non-communicating

horn with functioning endometrium (Class IId).

Table 4. Description of AFS (Class III&IV) and Treatment Plan Classification of Müllerian Duct Anomalies


Class III

Didelphys

uterus

&

Class IV

Complete or

partial

bicornuate

uterus

Complete or partial duplication of the vagina,

cervix, and uterus characterizes this anomaly

Complete bicornuate uterus is characterized

by a uterine septum that extends from the

fundus to the cervical os. The partial bicornuate

uterus demonstrates a septum, which is located

at the fundus. In both variants, the vagina and

cervix each have a single chamber.

Class IIIa – Partial bicornuate uterus (characterized by 2 externally incompletely

separate horns with unified lower uterus and cervix).

Class IIIb - Complete bicornuate uterus is characterized by 2 externally

completely separate horns and single cervix.

Class IIIc- Partial duplication with two cervices.

Class IIId- Complete duplication of the uterus, cervix, and vagina.

Class IIIe- any of the above with unilateral or bilateral obstruction

of menstrual outflow.


Class IIIa

Class IIIb

Class IIIc

Class IIId

Class IIIe

No surgical treatment, strassman`s metroplasty is rarely if ever required

No surgical treatment vs. strassman`s metroplasty in selected cases

No surgical treatment vs. strassman`s metroplasty in selected cases

Excision of vaginal septum +/- strassman`s metroplasty in selected cases

Excision of vaginal septum, unification of obstructed hemi uterus is required as early as possible.


ing from failure of fusion. Its reproductive performance is

good, and Strassmann metroplasty of the partial bicornuate

uterus is very rarely, if ever, required [71].

Management of Class IIIb – Complete Bicornuate Uterus

Complete bicornuate uterus rarely requires surgical re-

construction. The condition is associated with favorable ob-

stetrical outcomes and usually remains undiagnosed until

cesarean delivery or other procedures reveal its existence

[39, 68, 69]. Metroplasty should be reserved for women who

have a history of recurrent spontaneous abortions, midtri-

mester loss, and premature birth and in whom no other etio-

logic factor has been identified [58]. The Strassmann proce-

dure removes the septum by wedge resection with subse-

quent unification of the two cavities. Transabdominal metro-

plasty can considerably improve the reproductive perform-

ance of women with a bicornuate uterus who have had recur-

rent spontaneous abortions or premature deliveries before

surgery [72].

Management of Class IIIc- Partial Duplication with Two

Cervices = Didelphys Uterus

The decision to perform metroplasty should be individu-

alized, and only selected patients with a long history of

recurrent spontaneous abortions or preterm deliveries may

benefit from Strassmann metroplasty [70].

Management of Class IIId- Complete Duplication of the

Uterus, Cervix, and Vagina

The management of a nonobstructing longitudinal sep-

tum is simple and appears to be associated with improve-

ment of fecundablity. Excision of the septum allows simul-

taneous insemination of both hemiuteri during a single act of

coitus. Cold knife/ scissor excision and diathermy excision

are reported to have similar outcomes. The management of a

nonobstructing longitudinal septum in pregnancy is not clear.

Some authors advocate excision whereas others recommend

leaving it undisturbed unless it becomes obstructing during

labor [39].

Class IIIe- any of the above with Unilateral or Bilateral

Obstruction of Menstrual Outflow

In hemivaginal obstruction, the clinical presentations are

variable and depend on the degree of obstruction and

whether the obstruction is complete or incomplete [73]. The

obstructed unilateral vagina is a clear indication for resection

of the vaginal septum. Uterine didelphys with obstructed

unilateral vagina requires full excision and marsupialization

of the vaginal septum. After the septum has been excised,

laparoscopic evaluation and treatment of associated endome-

triosis, adhesions, or both is recommended [74]. Excision of

an obstructing vaginal septum during pregnancy requires

leaving an adequate pedicle to help minimize possible bleed-

ing should the vaginal mucosa retract. In addition, leaving a

generous pedicle behind allows the surgeon to place hemo-

static sutures in basal parts of the septum rather than in the

walls of the vagina [39].

Hemihysterectomy with or without salpingo-oophorec-

tomy is rarely indicated and should be avoided to provide the

best opportunity for a successful reproductive outcome.

Favorable obstetrical outcomes were reported in ten intrau-

terine pregnancies. Five resulted in term delivery, four re-

sulted in preterm delivery, and one resulted in early sponta-

neous abortion [74].

Class IV: Complete or Partial Septate Uterus with or

without Fundal Depression or Obstruction Table 5

Management of Class IVa - A Complete or Partial Midline

Septum is Present within A Single Uterus without Fundal

Depression

A uterine septum can be diagnosed by HSG, hystero-

scopy, and laparoscopy. HSG reveals a 2-chambered uterus.

Laparoscopy can help the surgeon determine whether the

fundal contour is normal, which is the best approach for dis-

tinguishing between these entities. The partial septum does

not extend to the os. In the case of partial septa that is less

than 1 cm in length, there are usually no adverse effects on

Table 5. Description of AFS (Class IV) and Treatment Plan Classification of Class IV Müllerian Duct Anomalies


Class V

Complete

or partial

septate uterus

A complete or partial

midline septum is

present within a

single uterus..

Class IVa - A complete or partial midline septum is present within a single uterus without fundal depression,

Class IVb- A complete or partial midline septum is present within a single uterus with fundal depression,

Class IVc – Any combination of the above in addition to septate cervix and vagina.

Class IVd – Any combination of the above with unilateral or bilateral obstruction.

Subclass of TP

Classification

Available Treatment Options

Class IVa

Class IVb

Class IVc

Class IVd

Hysteroscopic metroplasty is usually required with or without laparoscopy

Hysteroscopic metroplasty is usually required with concomitant laparoscopy

Excision of vaginal septum & hysteroscopic metroplasty with concomitant laparoscopy

Excision of vaginal septum, unification of obstructed hemi uterus is required as early as possible followed by hysteroscopic metroplasty.


reproductive outcomes, and operative intervention is not

indicated based on data obtained from residual septa after

hysteroscopic metroplasty [75]. Not all women with a partial

septate uterus require surgery. However, those with recurrent

spontaneous abortions, a single second-trimester loss, or

histories of preterm delivery are considered candidates for

correction [76-78].

Hysteroscopic metroplasty with concurrent laparoscopy

is the state-of-the-art treatment plan [75, 79]. Laparoscopy

helps reduce the risk of uterine perforation and diagnose

associated pelvic pathology [80]. As an alternative, ultra-

sonographic guidance has been used as a monitoring tool for

hysteroscopic metroplasty [81]. Hysteroscopic metroplasty

can be performed by using microscissors, electrosurgery, or

a laser. Thick septa with broad base are best excised with a

resectoscope using monopolar or bipolar diathermy. In the

septate uterus with cervical extension, the cervical portion is

incised at the proximal aspect using Metzenbaum scissors,

laser, or needle electrode followed by hysteroscopic metro-

plasty [82]. Division of the septum is considered complete

when the hysteroscope can be moved freely from one cor-

nual end to the other without obstruction [80, 82].

Class IVb - A Complete or Partial Midline Septum is

Present within A Single Uterus with Fundal Depression

The fundal depression in this subclass results from in-

complete fusion of the paramesonephric ducts at the fundus.

Failure of resorption in the remaining part makes the down

prolongation of the dividing septum. Its presentation and

diagnosis is the same as that of the septate uterus. On laparo-

scopy, there is a shallow fundal depression. However, confu-

sion may result by relying on the anatomic appearance of the

external uterine fundus without correlating the depth of fun-

dal depression with the depth of the internal division. Thus,

it is important to incorporate the results of other investiga-

tions (MRI, US & HSG) with the laparoscopic appearance.

The depth of the groove and length of the uterine septum

depend in the adult uterus on the length of the incompletely

fused müllerian ducts in the fetus. Symptomatic cases with

this disorder are candidates of hysteroscopic metroplasty but

are at a greater risk of perforation. The use of laparoscopy

for monitoring is important for avoiding uterine perforation.

Reproductive performance appears to be considerably

improved after surgery [82-87]. javascript:showcontent

('active','references');. Cervical laceration during instrumen-

tation, blood loss, postoperative hemorrhage and uterine rup-

ture during a subsequent pregnancy are infrequently reported

complications [85, 88].

Class IVc – Any Combination of the above in Addition to

Septate Cervix and Vagina

Excision of the vaginal septum is done either by cold

knife/scissor division or diathermy resection. The decision to

perform metroplasty should be individualized; only selected

patients with a long history of recurrent spontaneous abor-

tions or preterm deliveries may benefit from hysteroscopic

metroplasty [70]. Hysteroscopic metroplasty is less morbid

than abdominal metroplasty which is cost-effective and as-

sociated with limited risk of pelvic adhesions. Recovery is

rapid with no prolonged postoperative delay in conception,

and it can be performed in an outpatient setting. In addition,

it allows for subsequent vaginal delivery [89].

Management of Class IVd – Any Combination of the

Septate Uterus, Cervix and Vagina with Unilateral or Bilateral Obstruction of Menstrual Outflow

An obstructed unilateral vagina is a clear indication for

resection of the vaginal septum. A septate uterus with an

obstructed unilateral vagina requires full excision and mar-

supialization of the vaginal septum. After the septum has

been excised, laparoscopic evaluation and treatment of asso-

ciated endometriosis, adhesions, or both is recommended

[74]. javascript:showcontent('active','references'); Excision

of an obstructing vaginal septum during pregnancy requires

the same precautions as mentioned for obstruction of

hemivagina uterine didelphys [39]. However, definitive re-

section of a cervicouterine extension of the septum.

Class V Longitudinal Fusion Defects Table 6

This important class represents a group of defects that

are not classified by the AFS system. Appropriate timely

diagnosis and management will alleviate many unfavorable

consequences on the reproductive organs. Fortunately, this

group of defects is amenable to complete surgical correction.

Class Va- Partial Transverse Vaginal Septum

Incomplete transverse vaginal septum (TVS) allows

menstrual flow to escape periodically, but hematocolpos and

hematometra often develop over time. Complaints include

foul-smelling vaginal discharge, dyspareunia secondary to

a short vagina, and infertility. The existence and severity

of the above mentioned symptoms varies according to

the caliber of the opening. In addition, TVS can cause soft

tissue dystocia in patients who eventually become pregnant

[90].

Definitive resection of an incomplete transverse vaginal

septum is not required often. However, this anatomic con-

genital defect may contribute to primary infertility [91]. Di-

lation under anesthesia followed by regular dilation is suffi-

cient for patients who experience difficult or painful coitus.

In other cases where symptoms are inadequately addressed

with dilation alone, definitive resection is required. Asymp-

tomatic cases may manifest themselves for the first time dur-

ing delivery where a generous episiotomy may be needed for

a low-seated vaginal septa. High seated and thick septa,

especially those involving a long segment of the upper third

of the vagina, are best managed by cesarean section with

definitive management accomplished at a later time [92, 93].

Class Vb-Complete Transverse Vaginal Septum

TVS can occur at nearly all levels in the vagina, but most

of these septa are located in the superior vagina [94]. Be-

cause management of a transverse vaginal septum is more

technically difficult, treatment should occur at a tertiary-care

center with a qualified surgical team. Cases presenting with

acute pain can be treated with laparoscopic drainage, which

provides a novel approach to the acute management of a

transverse vaginal septum, providing pain relief without

compromising the success of definitive surgery that can be

performed at a later date [95]. Cases with concurrent imper-


forate hymen and transverse complete vaginal septum have

been reported [95, 97].

Excision of the septum should be performed under tran-

sabdominal or transrectal ultrasound guidance. The widest

possible excision should be made by making two crossing X-

shaped incisions followed by excision of the four margins.

Careful approximation of the upper (proximal) and lower

(distal) edges at the base of the cut septum with fine delayed

absorbable sutures is important in preventing recurrence

[98].

Cyclical hematuria is a rare presentation of transverse

vaginal septum and occurs by menstrual blood flow out of

the lower urinary tract because of a vesical-vaginal commu-

nication. One treatment that has been reported for this condi-

tion is reconstruction using a transvaginal and transabdomi-

nal approach to create a direct anastomosis between the

proximal vaginal segment and the distal vaginal pouch [99].

Class Vc- Lower Segmental Vaginal Atresia with Hemato-

colpos

Vaginal atresia occurs when the urogenital sinus (UGS)

fails to contribute to the inferior portion of the vagina. The

müllerian structures are usually normal, but fibrous tissue

completely replaces the inferior segment of the vagina. Non-

surgical methods may be recommended as the first approach

in managing vaginal atresia. When nonsurgical methods fail,

surgical approaches are recommended. Children with this

anomaly may develop pyometrocolpos and present with ob-

structive uropathy, septicemia, or renal failure [100-102].

Transperineal ultrasonography reveals the presence of ova-

ries, a uterus, a cervix, and an obstructed blind-ending supe-

rior vagina. All of these features distinguish vaginal atresia

from vaginal agenesis [102, 103]. MRI can aid in detecting

the presence of a cervix, which should distinguish this

anomaly from cervical agenesis, which is quite rare [104].

Segmental atresias usually require some form of push

through or pull through vaginoplasty or reconstructive sur-

gery to cover the raw area created from excision of long

atretic segments [105, 106]. In extreme cases of segmental

vaginal atresia, retropubic balloon vaginoplasty may be re-

quired. Other techniques used for the creation of neovaginas

could be used for treatment of this rare condition. Some

surgeons have difficulty connecting the neovagina to the

superior functioning vagina. After surgical correction, most

patients can expect normal reproductive outcomes.

Class Vd- Imperforate Hymen

Imperforate hymen is a simple but often overlooked di-

agnosis. It was found in 9.8% of 81 cases with vaginal

anomalies [107-109]. Early diagnosis of the imperforate hy-

men and timely optimized interventions are of fundamental

importance in prevention of the largest part of its related

complications [110-115].

Premenarchal girls with asymptomatic cases diagnosed

on routine inspection of the external genitalia [116] are best

treated conservatively and followed up till puberty where

definitive treatment can be implemented. However, cases

presenting with mucolops or hydrocolops are treated at the

time of presentation to avoid two important complications;

infection and conversion into pyocoplos and urinary tract

obstruction [117, 118]. Traditionally, imperforate hymen is

treated with two perpendicular or X-shaped hymenotomy

incisions followed by complete excision. However, the im-

portance of the integrity of hymen varies in different cultures

and hymen sparing procedures are willingly preferred by

many patients and families in many countries [108, 119, 120,

121].

Class VI - Insignificant and Historical Anomalies Table 7

This class is further subdivided into 2 subclasses: VIa-

Arcuate uterus, a small septate indentation is present at the

fundus, and VIb- DES-related abnormalities.

The arcuate uterus represents an insignificant anomaly

that results from near-complete resorption of the uterovagi-

nal septum. It is characterized by a small intrauterine inden-

tation shorter than 1 cm and located in the fundal region. It is

the most commonly observed uterine anomaly detected by

HSG [122, 123]. It is a clinically benign anomaly--adverse

obstetric outcomes are rare-- and it may not affect reproduc-

tive outcomes [69, 122]. HSG reveals a single uterine cavity

Table 6. Description Treatment Plan Classification of Class V Müllerian Duct Anomalies (longitudinal fusion defects) which is not

Classified by the AFS


Class V

Longitudinal fusion defects

Not mentioned Class Va- partial transverse vaginal septum

Class Vb-complete transverse vaginal septum.

Class Vc- lower segmental vaginal atresia with upper heamtocolpos.

Class Vd- imperforate hymen


Class Va

Class Vb

Class Vc

Class Vd

No surgical treatment, vs. dilatation v. excision.

Adequate surgical excision.

Adequate surgical excision & end to end anastomosis +/- vaginoplasty.

Hymenectomy, hymenotomy, or circular excision to preserve hymeneal structural integrity in certain societies


with a saddle-shaped fundal indentation. MRI findings show

convex or flat external uterine contour. The indentation is

broad and smooth. Aberrant vascularity within the fundal

myometrium has been suggested [122, 124]. Arcuate uterus

rarely, if ever, requires surgical correction. It may be man-

aged similarly to septate uterus, but only in selected patients

who fulfill poor reproductive performance criteria after

exclusion of all other factors.

CONCLUSION

Early establishment of an accurate diagnosis is indispen-

sable for planning treatment and preventing complications in

the genital organs and surrounding systems. Classifying

müllerian anomalies based on the available treatment options

seems logical, and the inclusion of previously unclassified

entities is important for comprehensive understanding and

management of this group of disorders. The surgical ap-

proach for correction of müllerian duct anomalies is indi-

vidualized to the type of malformation. The value of a given

surgical procedure should be assessed on terms of its ability

to improve a patient's postoperative ability to have healthy

sexual relations and achieve successful reproductive out-

comes.

Key Points

Mullerian duct anomalies (MDA) represent an open

ended spectrum of disorders that present either in isolation

(affecting one organ e.g. tubes, uterus, cervix or vagina), in

combination (affecting more than one organ) or in associa-

tions with other body systems anomalies (renal, skeletal,

etc).

Appropriate and early diagnosis of MDA is of special

importance in the prevention of complications. The diagnos-

tic workup should include a search for associated anomalies

and complications.

Treatment should be individualized, and only sympto-

matic cases with poor reproductive outcomes should be con-

sidered for surgical correction. Obstructive cases are given a

unique priority for earliest corrective interventions. Simpli-

fied approaches for treatment of vaginal aplasia (e.g.balloon

vaginoplasty) and cervical atresia (e.g endoscopic canaliza-

tion) should be adopted as they are technically simple to per-

form and safety and have a high efficacy.

Fertility preserving procedures should be adopted, re-

fined and offered to cases with MDAs as a first choice

treatment options.

Expert Commentary: The past five years have seen the

introduction of balloon vaginoplasty where postoperative

dilatation was not needed and sexual activity could be initi-

ated as early as on the day of discharge from hospital (one

week after surgery). Compared to other procedures, this is

considered a great advance in management of vaginal aplasia

where vaginal functions were initially achieved only after

months of postoperative care. Also, the vagina created by

balloon vaginoplasty mimics the natural vagina and repre-

sents an excellent choice for cases with cervical aplasia asso-

ciated with vaginal apalsia where in these cases a utero-

neovaginal anastomosis represents an attractive, effective

and logical management option. . We hope the future carries

more benefits for cases with MDAs through blends of trac-

tion/ distension vaginoplasty, refined corrective surgeries,

uterine transplants and stem cell therapy.

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Table 7. Description of AFS and Treatment Plan Classification of Class VI Müllerian Duct Anomalies


Class VI

Arcuate uterus

&

Class VII

DES-related abnormalities

A small septate indentation is present at the fundus.

A T -shaped uterine cavity with or without dilated

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Both are put in one class (insignificant and historical anomalies)

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Received: January 10, 2010 Revised: March 08, 2010 Accepted: April 15, 2010

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