■ President, AE-PCOS Society’sMessage &PCOS Society LaunchPage 04
■ Announcing FirstInternational Conferencefor more detailssee page 05
■ Scientific Article:Pathophysiology of PCOSPage 06
■ Scientific Article:Mechanisms of Anovulationin PCOSPages 07
■ PCOS Society Membership &PCOS Conference FormsPages 09-10
www.pcosindia.org | www.pcosindia.com
2
■ Founder President, The PCOS Society, India■ President Elect of the Indian Society for Assisted
Reproduction (ISAR)■ Chair of the Education Committee of the
International Menopause Society (IMS)■ President of the Federation of Obstetric &
Gynecological Societies of India (FOGSI) (2006)
Dr. Duru ShahMD, FRCOG, FCPS, FICS, FICOG,FICMCH, DGO, DFPGynaecologist
Founder Members
■ Vice President, The PCOS Society, India■ President, Endocrine Society of India■ President, Indian Academy of Diabetes■ President, Association of Physcians of India (2014)■ Indian Chapter Chair, Amercian Association of
Clinical Endocrinology
Dr. Shashank R. JoshiMD, DM, FACP, FRCP, FACEEndocrinologist
■ Vice President, The PCOS Society, India■ Founder President Cosmetology Society India (CSI),
now CDSI – Cosmetic Dermatology Society (India)■ Member, Board of Directors – International Society
of Dermatology (ISD)■ Received Maria Duran Lectureship Award by
Dr. Rekha ShethMD, DVDDermatologist
■ Honorary Secretary, The PCOS Society, India■ Diplomate of the American Board of
Endocrinology, Diabetes & Metabolism
■ Diplomate of the American Board ofInt. Medicine
Dr. Piya Ballani ThakkarMD, DNB, DGO, FCPS, FACEEndocrinologist
■ Hon Treasurer, The PCOS Society, India
■ Vice President FOGSI (2015)
■ Chairperson Medical Disorders In Pregnancy ofFOGSI (2006-2008)
Dr. Uday ThanawalaMD, DGO, FCPS, DNBGynaecologist
■ Chairman of the Indian College of Obstetrics &Gynecology (ICOG) (2008-2009)
■ The First Indian to receive the very prestigious"Distinguished Merit Award"from theInternational Federation of Gynecology &Obstetrics (FIGO), which is the International GlobalBody of Gynecologists, for the service she hasoffered towards women's health in India
■ Past President of RSSDI and AIRRO, Emeritus Editor,JAPI
■ Awarded the Padma Shri by the Government ofIndia in 2014 for his services to the field ofmedicine
■ Scientific Co-ordinator,The PCOS Society, India
■ Founder Member of The PCOS Society, India andFertility Preservation Society of India (FPSI)
■ Editor-in-Chief, Journal of Human ReproductiveSciences
Dr. Madhuri PatilMD, FCPS, DGO, DFP, FICOGGynaecologist
International Society of Dermatology (ISD)■ First Indian woman to be appointed as the Vice
President of the International Society ofDermatology (ISD) in 2009
■ Pioneer in conducting clinical research for cosmeticcompanies following GCP guidelines.
Special Awards and Recognition:
■ America’s Top Physicians by the ConsumersResearch Council of America
■ Physician Recognition Award withCommendation: American Medical Association
■ Joint Secretary FOGSI (2005)
■ Founder Secretary & Past President Navi MumbaiOBGY Society
■ Founder President of Karnataka Chapter of IndianSociety for Assisted Reproduction (KISAR)
■ Course Co-coordinator and examiner forFellowship & Certificate course in ReproductiveMedicine of Rajiv Gandhi University of healthSciences, Karnataka and Indian College ofObstetrics and Gynecology
Dr. Nalini Mahajan
Patrons, 2015
Dr. Abha Majumdar Dr. Kanthi Bansal
Dr. Sujata KarDr. P. C. Mahapatra Dr. Sujata Misra
■ Joint Hon Secretary, The PCOS Society, India
■ Joint Secretary, MOGS, 2002
■ Joint Secretary, FOGSI, 2006
Dr. Sangeeta AgrawalMD, DNB, DGO, FRCOGGynaecologist
Presidential Message
Dr. Duru ShahMD, FRCOG, FCPS, FICS, FICOG,FICMCH, DGO, DFPDirector, Gynaecworld, The Center forWomen’s Fertility & Health, MumbaiEditor
Editorial Team
Dr. Sabahat RasoolMD, DNB, MNAMS, FMAS, MRCOG (UK)Ian Donald Diplomate in OBGY Ultrasound, CroatiaFertility Consultant, Gynaecworld, MumbaiAssociate Editor
Ms. Rochelle LoboAdministrative Assistant
Dear Friends,
Managing PCOS in an adolescent or a young woman was dedicated to managing her symptoms.
Today, it is based on evidence accumulated from very diligent and precise research. As science
rapidly progresses, so does excellence in the art of this science progress. To highlight the various
aspects of this very much needed disorder, the PCOS Society, India has been initiated.
It is my pleasure to inform you that a new Society has been created termed "The PCOS
Society"(India), which will focus on the subject of PCOS. The Society is a multi-disciplinary
society and has a mix of Gynecologists, Endocrinologists, Dermatologists and all health specialties
which deal with PCOS patients.
The Launch of the Society was held on Thursday 6th August 2015, by our Chief Guest Prof. Anuja
Dokras, the current President of the Androgen Excess and PCOS Society (AEPCOS) and the Executive
team consists of Dr. Shashank Joshi, Dr. RekhaSheth, Dr. PiyaThakkar, Dr. SangeetaAgrawal, Dr.
UdayThanawala, Dr. Madhuri Patil and myself.
The Society plans to:
Conduct and organize lectures, seminars and meetings by inviting well known educationist and
experts in the field of PCOS, serve as a forum for the interchange of ideas between professionals
from different scientific and clinical backgrounds, strive to stimulate evidence-based studies that
will assist in developing our own Recommendations and Guidelines, provide a forum to collect
and disseminate recent findings in PCOS research which have been either published or presented
at meetings, which will be updated regularly and made available on the PCOS website and through
our Newsletter, Pandora. Through the ‘ PCOS Connect Program’ we aim to educate patients and
the lay public about PCOS.
I would like to take this opportunity to profusely thank my colleagues who joined me as founder
members to create this Society and others who have contributed by becoming Patrons and
Members. I would also like to thank my team members for the support I have received towards
developing the Newsletter, the forthcoming International Conference material and the PCOS
Website (www.pcosindia.org | www.pcosindia.com). I sincerely thank USV for supporting the
launch of our Society and for being our corporate partner for this year’s Newsletter
As President of this Society, I extend to you an opportunity to join this Society and help to grow it
into a very strong and creditable organization,seving the cause of the Polycystic Ovary Syndrome.
Disclaimer – Published by the The PCOS SOCIETY(INDIA). Contributions to the editor are assumedintended for this publication and are subject toeditorial review and acceptance. PANDORA is notresponsible for articles submitted by any contributor.These contributions are presented for review andcomment and not as a statement on the standard ofcare. All advertising material is expected to conformto ethical medical standards, acceptance does notimply endorsement by PANDORA. www.pcosindia.org | www.pcosindia.com
I had the privilege ofinaugurating the PCOSSociety of India in August2015. PCOS is thecommonest endocrinedisorder in reproductiveage women, yes even more
common than hypothyroidism. It can affect a woman through a greater part ofher life – adolescence, adulthood and peri-menopause. The diagnosis is complexdue to the heterogeneous phenotypes and a number of patients are dissatisfiedwith the difficulties with establishing an accurate diagnosis and the fragmentedcounselling they receive. The establishment of a Society dedicated to PCOS allowsclinicians and researchers to focus their efforts to optimize diagnosis and developnew treatments for this disorder. There is urgent need to establish normogramsfor the diagnostic criteria of PCOS in the Indian population. Increasing awareness
and ongoing education is critical to the mission of this Society. I am pleased tobe the guest speaker at the first meeting to be held in June 2016. As President ofthe AE-PCOS Society, the theme during my tenure has been to focus on ourpatients. I therefore hope the Indian Society will also seek opportunities to increaseawareness of PCOS amongst the general population allowing for early diagnosisand timely therapeutic interventions and more importantly, clarify misconceptionsassociated with PCOS. Dr. Duru Shah has brought together highly acclaimedspecialists from different medical fields to lead this Society. I applaud her effortsand strongly encourage you to join this multi-disciplinary Society and activelyparticipate in its mission with the goal of bringing PCOS awareness to all womenin India.Anuja DokrasMD.,PhD.President, AE-PCOS Society, Director, Penn PCOS CenterProfessor of OBGYN, University of Pennsylvania, Philadelphia, USA
Media
Dr. Anuja DokrasPresident of the AndrogenExcess & PCOS Society
Dr. Rama Vaidya (extreme right), a senior and well respected reproductive endocronologist who honoured thePCOS Society duing its launch, seen here with the Founder Members.
The PCOS Society Launch
5
11.00 am to 1.30 pm – Workshop IPCOS – the Impact of the Disease on PregnancyThis workshop will highlight various issues related topregnancy in women with PCOS, varying from early to latepregnancy, culminating into delivery followed by lactation.■ How does PCOS lead to early and recurrent pregnancy
losses? Can we prevent such losses and how can wemanage them better?
■ How do we diagnose gestational diabetes, when shouldwe start looking for it, how do we prevent it and howdo we manage it effectively to prevent complicationsfor the mother and baby?
■ How should we use Metformin safely?■ If we initiate Metformin to promote fertility, should we
continue it through pregnancy, during labour and
lactation? Does it cause fetal hypoglycemia? Can weprevent diabetes in future in such women?
■ Can we recommend bariatric surgery to a young girl,before she has had her children? Will it affect thenutrition of her fetus?
To discuss these practical questions we have experts ofgreat repute varying from obstetricians, IVF experts andendocrinologists, who will update you on all what you needto know and want to know.
2.30 pm to 5.00 pm – Workshop IIPCOS – Management of Cosmetic ConcernsWe see young women in our clinical practice with concernssuch as acne, facial hair, hair loss,obesity, stretch marks,pigmentation, etc. which affect them tremendously ! Theyare concerned by their distressing symptoms which affects
their self-confidence and body image, leading to a lot ofanxiety and mood changes. As clinicians attending to theseyoung adolescents, it should be our endeavor to lookbeyond their symptoms and manage them correctly in orderto prevent serious problems in future.
To discuss the latest advances in the management of theirmanifestations we have a team of renowned experts inthe field of dermatology and cosmetic surgery to interactwith you in this extremely useful workshop.
It is a "must workshop" for all to attend.
Inaugural Lectures■ Understanding the Science of Hyperandrogenaemia
and Insulin Resistance.■ Do Genes Matter?
7.30 – INAUGURATION
8.30 – pm onwards DINNER
Saturday 18th 20168.15 am – Free Papers
9.15 am – The History of PCOS
9.30 am – PCOS – The dilemma in diagnosis■ How should we work up a patient of PCOS?■ Are ultrasound criteria changing?■ Is AMH a new marker for PCOS?■ Are we over diagnosing the problem in the
adolescent?■ Interaction
11.30 am – PCOS – Associated Disorders■ Image, Mood and Anxiety disorders –
how stressful can they be?
■ Sleep Apnoea – how serious can it be?■ Hypothyroidism – is it associated with PCOS?■ Is the lean PCOS different from the lean PCOS?■ Interaction
2.00 pm – PCOS and Obesity –Managing Weight Loss■ Which is the best diet program?■ Which is the best exercise program?■ Medical Management: What's the
4.00 pm – Drugs in PCOS■ Metformin■ Newer Insulin Sensitizers■ OC pills■ Vitamin D■ Interaction5.30 pm – Panel Discussion onThe Trials and Tribulations of OvulationInduction in PCOS
7.00 pm – Posters
8.00 pm – Cultural Program
9.00 pm onwards COCKTAILS & DINNER
Sunday 19th, 20169.00 am – PCOS & Infertility –optimizing pregnancy rates■ An evidence based strategy for treating infertility in PCOS■ Assessing Ovarian Reserve in PCOS / Ovarian Drilling?■ Luteal support in PCOS – How do we customize it?■ Minimizing the risk of hyper stimulation and multiple
pregnancies with Gonadotropins■ Assisted Reproduction for PCOS – are the results
different?■ Interaction
11.30 pm – Concerns of tomorrow■ The Metabolic Syndrome■ Cardiovascular Disorders
Dr. Madhuri PatilMD, DGO, DFP, FCPS,FICOG (Mumbai)
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IntroductionPolycystic ovary syndrome (PCOS) is a heterogeneousand complex disorder with varied collection of signsand symptoms so as no single test is diagnostic. Ithas both adverse reproductive and metabolicimplications for affected women. It is a complexgenetic disorder and may be familial. PCOS is seento cluster in families and both female and malerelatives can show stigmata of the syndrome,including metabolic abnormalities. It is a multi-geneenvironmental interaction, resulting in the signs andsymptoms, most of them related to abnormalgonadotropin secretion, hyperandrogenemia andinsulin resistance with hyperinsulinism.
We know that diagnosing a woman with PCOSimplies an increased risk for infertility, dysfunctionalbleeding, endometrial carcinoma, obesity, type 2diabetes mellitus (DM), dyslipidemia, hypertension,and possibly cardiovascular disease (CVD), and mayrequire lifelong treatment.
PrevalenceThe overall incidence of PCOS varies from 8-10 %,but it has been observed that1 the incidence is higherin South Asian population and is about 50% PCOSas against the Caucasian population, where theincidence is 5-25% PCOS.
PathophysiologyExact pathophysiology and its initiating event haveyet to be elucidated. However, various biochemicalabnormalities are described, and associations andlinkages of one to another have been established.Many abnormalities reinforce each other in viciouscircles. It is a multifactorial disease with full clinicalexpression being the result of synergistic pathologicalinteraction of genetic, epigenetic and environmentalfactors. External factors like nutrients, physicalactivity, pollutants, psychological stress and androgenexcess can program and modify epigenome and leadto PCOS.
PathogenesisHyperandrogenism, abnormal feedback ofgonadotrophins (higher mean concentration of LH,low or low-normal FSH, increased circulating estronelevels), insulin resistance (IR) and dysregulation ofgenes encoding enzymes in androgen biosynthesispathway and insulin secretion and action (INS VNTR,CYP11a, CYP17- P450c17alpha) are responsible forthe for this metabolic disorder. (Figure 1)
Hypothalamic-pituitary abnormalitiesElevated LH and low-normal FSH: In PCOS, there isincreased frequency and amplitude of pulses ofluteinizing hormone (LH) (normal is 10% to 20%2),while that of follicle-stimulating hormone (FSH) isunchanged or muted. Thus, LH values may beelevated, and the LH:FSH ratio can be increased tomore than 2.5, even in ovulatory cycles.
Elevated GnRH. The inappropriate secretion ofgonadotropins is thought to be due to an
some androstenedione to testosterone, and in PCOSthis is amplified. Thus, the increased circulatingtestosterone comes from the ovaries and fromperipheral conversion of estrone to testosterone.
Androgen levels are elevated in both obese as well
abnormality of the gonadotropin- releasing hormone(GnRH) pulse generator in the hypothalamus. Itremains unclear whether this is a primary abnormalityor a secondary one.
Elevated prolactin. Elevated prolactin is seen in 25%of patients and this elevation of prolactin maystimulate adrenal production of dehydro-epiandrosterone sulfate (DHEA-S).
Ovarian AbnormalitiesHyperandrogenismAll patients with PCOS have an increased sensitivityto androgens and up to 70% have elevatedandrogen levels, and the other 30% are in the high-normal range. Excess androstenedione in thecirculation is converted to estrone, which exerts atonic effect on LH production while contributing toa relative suppression of FSH production. In the faceof a high LH: FSH ratio, more androstenedione issynthesized but is not aromatized, thus perpetuatinga vicious cycle driving LH production and someprolactin production. (Figure 2). The ovary converts
as non-obese PCOS, but the pathogenesis is differentin both the groups.This is clearly explained in thefigure 3 below. Amplification of signs and symptomsof PCOS is seen with increasing obesity and insulinresistance.
Abnormalities of estrogen secretionEstrogen secretion is usually abnormal in PCOS.Estradiol levels may be low to normal, and in theanovulatory cycle there is tonic production withoutincrease in levels before ovulation or in the midlutealphase, as in normal women.3,4 Estrone levels increasedue to extraglandular conversion of andro-stenedione in adipose tissue.
Adrenal abnormalitiesExcess adrenal androgen generated during stress oradolescence or due to congenital adrenal hyperplasiabecause of enzyme defects might initiate the cycleof abnormal LH/FSH stimulation and lead to PCOS.
Figure 2: Vicious cycle of hyperandrogenemia
Figure 3: Mechanism of androgen excessin obese and non-obese PCOS
Continued on page 08
Insler et al. Hum Reprod. 1993
Scientific Article – Pathophysiology of PCOS
7
Scientific Article – Mechanisms of Anovulation in PCOS
Enrico CarminaM.D. and Ettore Guastella, M.D.Reproductive Endocrinology UnitDepartment of Mother and Child HealthUniversity of Palermo, Palermo, Italy
For many years chronic anovulation and excessiveandrogen secretion have been considered the maincomponents of clinical pattern of PCOS, bothnecessary for diagnosing this disorder. However, it isnow well understood that PCOS may present withanovulatory but also with ovulatory phenotypes.1-3
The anovulatory phenotype, while being the mostcommon in patients who are referred to specializedclinics,4, 5 may not be the most common in generalpopulation.6-8 Understanding the cause ofanovulation in PCOS may represent a key step infinding the link between genetics and clinicalexpression of the disorder.
There is evidence that anovulation in PCOS is notthe consequence of increased androgen ovariansecretion. In fact, although patients with the classicNIH anovulatory phenotype tend to have higherandrogen levels than patients with thehyperandrogenic ovulatory phenotype,1, 9 elevatedandrogen levels may be found in non PCOS patientswithout determining anovulation.10, 11
Instead, most data suggest that in PCOS theanovulation is the consequence of the derangementof early follicle development that is characteristic ofthis disorder.12 Studies in cultures of follicles derivedfrom anovulatory women with PCOS have shownthat their granulosa cells are hyper-responsive to FSHin terms of estradiol production and tend to respondto LH also when the follicles are still small(3-4 mm).13, 14,15 When granulosa cells from ovulatoryPCOS patients were evaluated, these cells behavednormally in terms of estradiol response to FSH andresponded to LH only when taken from a largerdominant follicle.13
It has been hypothesized that the inappropriateresponse in small follicles to LH could result interminal differentiation of the granulosa cells andthence in premature arrest of follicle growth andanovulation.12 Because in the same studies, therewas a large heterogeneity in the behavior of studiedfollicles of anovulatory women, with granulosa cellsof some follicles responding normally to LH15,mathematical models have been developedsuggesting that in a heterogeneous population ofsmall follicles, if a group of follicles is relatively moremature, anovulatory arrest will develop.12
However, it is unlikely that the derangement of earlyfollicle development is the only cause of chronicanovulation in PCOS. While the cause of the earlyfollicle alteration in PCOS remains unclear, it isprobable that is linked in some way to the geneticalteration that has been found in these patients.However, genetic studies have been unable todifferentiate between ovulatory and anovulatoryPCOS patients.16 Mostly important, the majority of
anovulatory women with PCOS become ovulatorywhen they lose weight and at the contrary increaseof body weight may transform an ovulatory PCOSwoman in an anovulatory PCOS patient.1,9 It isunclear how it could be possible if the problem isjust depending on an inherited alteration affectingthe early follicle development.
Interestingly, anovulatory PCOS patients present anendocrine character that may be partially revertedwhen they lose weight: these patients have higherinsulin levels than ovulatory PCOS patients.10,17 Inanovulatory PCOS women, ovulation may also occurafter administration of most insulin-sensitizing drugs,including metformin and thiazilenediones. All itsuggests that increased insulin circulating levels playa major role in the anovulation of women with PCOS.
It is confirmed by in vitro studies showing thatincreased insulin levels, also in a condition of insulinresistance, may affect ovarian steroidogenesis anddetermine arrest of follicle growth.18,19
Other mechanisms of anovulation may be operativeand may be important in subgroups of PCOSpatients. About one third of classic hyperandrogenicanovulatory PCOS patients has normal body weightand 50% of them have normal fat distribution,normal insulin levels and no insulin resistance.22 AlsoPCOS patients with the normoandrogenic phenotype(chronic anovulation, polycystic ovaries and normalandrogen levels) generally present normal bodyweight, normal insulin and insulin sensitivity,too. 2, 10, and 23 Therefore, mechanisms independenton insulin have to exist and may determine arrest offollicle growth and anovulation. No evidence on whatmay be these mechanisms exist but it is possible thatin some patients the genetic alteration is particularlysevere and able to induce anovulation also in absenceof hyperinsulinemia.
In fact, it has been suggested that increased AMHvalues may play a role in the arrest of follicle growthby inhibiting the recruitment of primordial follicles
Figure 1. Anovulation in PCOS – A Possible Model
On the other hand, the majority of obese womenhave normal ovulatory cycles 20,21 and it suggests thathyperinsulinemia alone is not able to induceanovulation but affects follicle growth only inpresence of some previous derangement of follicledevelopment. In conclusion, in the majority ofwomen with PCOS the mechanism of anovulationrequires two concomitant alterations, one mainlygenetically induced, the early follicle development,and the second, mainly environmentally determined,a chronic hyperinsulinemia.
In figure 1, the possible pathophysiologicalmechanism of anovulation in PCOS is summarized.In this model, different gene variants may producetwo essential characters of PCOS: derangement ofearly follicle development and ovarian androgenexcessive production. The consequence is (generally)the ovulatory PCOS. Increased insulin levels (probablysecondary to obesity or altered fat functiondetermined by environmental factors) determine thearrest of follicle growth and transform the ovulatoryPCOS to an anovulatory (classic) PCOS.
and diminishing the response of recruited folliclesto FSH, thus impairing the selection of the dominantfollicle.24 It is possible that, in some patients, aparticularly severe alteration of folliculogenesis maydetermine very high levels of AMH sufficient to impairthe selection of the dominant follicle.
However, in the majority of PCOS patients, increasedAMH does not seem to play a main role in blockingthe selection and growth of the dominant follicleand the ovulation.25 Accordingly to it, patients withanovulatory normoandrogenic PCOS have relativelylow AMH values.26 More studies are needed tounderstand the mechanism of anovulation in thedifferent subgroups of PCOS but chronic anovulationin PCOS seems to be generally the consequence ofan interplay between genetic mechanisms affectingthe early follicle development and environmentalfactors inducing obesity or altered fat distributionand chronic hyperinsulinemia.
References on page 11
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Pituitary gonadotropin does not directly stimulateadrenal androgens, but prolactin can stimulateDHEA-S production. In adrenal glands, DHEA-S isco-secreted with cortisol. DHEA-S has littleandrogenic activity and small amounts can beconverted to androstenedione and subsequently totestosterone.
Peripheral abnormalitiesDecreased SHBG. Elevated levels of androgens in thecirculation, especially testos- terone, inhibitproduction of hepatic sex hormone-binding globulin(SHBG). With less SHBG in circulation, moreandrogens are left unbound and therefore producea greater clinical response in terms of hirsutism, acne,and other manifestations of androgen excess. Thus,hyperandrogenism begets more hyperandrogenism.
Insulin resistance and hyperinsulinemiaInsulin resistance (IR) probably plays a pathogeneticrole in PCOS5 and is a forerunner of several metabolicalterations.The incidence of IR is higher in obese,irrespective of ethnicity. Adipose tissue dysfunctionmay be a major factor contributing to IR.
Because hyperandrogenism and hyperinsulinemiacoexist in PCOS, the important question is whetherone causes the other. We know that that exogenousandrogens and androgen producing tumors resultin hyperandrogenism, which can result in glucoseintolerance and elevated insulin levels.5,6
There is abundant evidence that indicates thathyperinsulinemia begets hyperandrogenism.7-9 Insulinmay increase androgen synthesis by variousmechanisms. It may directly increase ovarianandrogen synthesis by interacting with its ownreceptor or with the receptor for insulin-like growthfactor-1, thereby increasing P450c17-alpha enzymeactivity. Insulin amplifies the LH response of granulosacells, thereby causing an abnormal differentiationof these cells with premature arrest of folliculargrowth and so anovulation. It may also change theovarian response to LH. It also suppresses hepaticproduction of SHBG, which increases freetestosterone levels. Thus, insulin alters normal
folliculogenesis by increasing intra-ovarianandrogens, altering gonadotropin release, or bydirect effects on the ovary. (Figure 4)
While PCOS is associated with insulin resistance andhyperinsulinemia, the ovary itself is not insulin-resistant and, in fact possibly responds excessivelyto the hyperinsulinemia. Cell surface insulin receptorsare at normal levels, but there is a postreceptor defectin signal transduction, causing a decrease in glucosetransport. The post-receptor binding defect is anincrease in insulin receptor-mediated serinephosphorylation with a concomitant decrease inprotein kinase activity and necessary tyrosine kinaseactivity, thereby interfering with transduction of theinsulin signal and causing it to be defective.10
Adipose tissue dysfunction and PCOSAdipose tissue dysfunction may be a central factorin the pathogenesis of PCOS.There exists a complexinteraction between the pituitary gland, pancreas
and ovary that results in a changedhormonal secretion pattern. PCOS isthought to be mediated by ghrelin, (agastric peptide) which is orexigenic andadipogenic. Obesity is known to increaseandrogen, insulin & leptin levels, insulinresistance and risk of early pregnancy loss.It also decreases SHBG, GH, IGFBP-I,response to COS thus requiring higherdoses of GT with longer duration ofstimulation and cycle cancellation rate. Italso increases the peak E2concentrations, number of oocytesretrieved and can affect the endometrialreceptivity and corpus luteum functionalong with early embryo development.
Subcutaneous and omental fat geneexpression studies have shown alteredexpression of genes related to obesity,insulin resistance, inflammation andsteroidogenesis. Epigenetic modificationis linked to metabolic disease and geneticand environmental factors affect humanmuscle and adipose tissue epigenetics inPCOS and Type 2 Diabetes.
Evidence of possible dysregulation in the secretionof several adipocytokines, including leptin,adiponectin, tumor necrosis factor alpha (TNF-a), IL-6, monocyte chemoattractant protein-1 (MCP-1),visfatin, and retinol-binding protein 4 (RBP4), werereviewed. Data suggested, however, that the mainfactor perturbing adipocyte function in PCOS wasthe degree of abdominal obesity.11 Importantly,ovulatory women with PCOS generally exhibit smallerquantities of abdominal fat than anovulatory PCOS,and because of this have less evidence of adipocytedysfunction.12 There was one study, which reportedsignificantly higher levels of circulating vaspin, a noveladipokine in women with PCOS.13 It was alsoobserved that atrial natriuretic peptide andcatecholamine-induced lipolysis is impaired in PCOSwomen.
How obesity in PCOS results in anovulation(Figure 5)
It has also been observed that abnormalities of leptinsecretion predispose to weight gain in women withPCOS. Leptin resistance was seen more commonlyin insulin resistant states and overweight womenrather than thin PCOS. Intake of leptin is associatedwith decrease in hypothalamic neuropeptide - Y andincrease in GnRh and sympathetic nervous system
activity. This inturn reduces food Intake, increasesthermogenesis and the reproductive potential
Genetic
Although PCOS can be familial, genetic studies havefailed to reveal any specific gene markers orchromosomal abnormalities associated with thedisorder. Gene expression studies from PCOS tissueshave identified novel pathways and genes importantin PCOS pathophysiology, which may be different inlean and obese PCOS women.14 Studies onsubcutaneous adipocytes from PCOS women haverevealed resistance to insulin stimulated glucosetransport and inhibition of lipolysis15,16 thus,adipocyte dysfunction may have a role in thepathogenesis of the syndrome. W634 alterations arealso seen in expression of genes involved in insulinsignalling including cAMP-GEF II and tribble whichregulate the activity of Akt/protein kinase B, a keyenzyme in one of the arms of insulin signalingpathway.
Several studies suggest that the activator protein-1(AP-1) transcription factor FBJ murine osteosarcomaviral oncogene homolog (FOS) may have a role inthe patho-genesis of PCOS. Microarray analysisperformed on whole ovary (containing both stromaland cortical fractions) found decreased FOSexpression in PCOS ovaries com- pared with normalovaries.14 In vitro studies have demonstrated thecacell CYP17 expression and androgen synthesis wereinhibited by FOS.17 Differential gene expression insubcutaneous fat and genetic association at the FOSlocus in PCOS subjects implicates a role for thistranscription factor in PCOS. FOS dysfunction maybe a common factor between hyperandrogenismand insulin resistance.18
Immune dysfunctionLeukocyte telomere length (LTL) plays an importantrole in the pathophysiology of PCOS and haspotentially important implications for ourunderstanding of the etiology of the disease. LTL isstrongly associated with PCOS and that there is asignificant negative correlation between LTL andserum DHEAS concentrations in healthy controls.19
In women with PCOS, the mean expression of GAB1is reduced as compared with normal fertile women.Endometrial GAB1 protein and mRNA expression arereduced in women with PCOS, suggesting that theendometrium of PCOS women has a defect in insulinsignaling due to GAB1 down-regulation.20
Three TGF-isoforms (TGF-1, TGF- 2, and TGF-3) havebeen identified in humans.21 The ovaries of womenwith PCOS show all the characteristics of TGF-hyperactivity including increased vascularity andincreased deposition of collagen in ovarian stromaand theca.22,23 There are some genetic studies
Figure 5: Anovulation due to obesityContinued from page 06
Pathophysiology of PCOS
Figure 4: Link between hyperinsulinemia andhyperandrogenemia
Continued on page 11
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11
supporting the role of TGF- dysregulation in PCOSand showing that allele 8 of D19S884 within intron55 of the fibrillin-3 gene is associated with PCOSand increased insulin resistance (IR) in women withPCOS.24,25 Fibrillins are matrix components ofextracellular microfibrils that are regulated by TGF.This may contribute to the metabolic disturbancesin women with PCOS.26
Vitamin D and PCOSDecreased vitamin D levels27, have been correlatedwith increased insulin resistance, body mass index(BMI), total testosterone, and DHEAS in PCOSwomen.28,29 Beneficial effects of vitamin D treatmentin women with PCOS may be mediated via VitaminD's effects on TGF- 1 and /or sENG.30
ConclusionPCOS is oligogenic disorder representing aquantitative trait in which small number of key genescontribute in conjunction with environmental factorsto produce the observed clinical & biochemicalheterogeneity. Cellular signaling abnormalities inPCOS are due to hyperinsulinemia. Insulin actssynergistically with LH to stimulate ovarian androgenproduction. Suppressive effect of insulin on SHBGproduction also contributes to higher levels of freeor bio-available testosterone and indirectly to theabnormalities in GT secretion.
Key Points■ PCOS is characterized by amenorrhea, hirsutism and infertility.
It is caused by a complex interaction of abnormalities ingonadotropins, androgens and estrogens. Insulin resistance andhyperinsulinemia contribute significantly to its underlyingpathophysiology.
■ Intrauterine environment together with genetic predispositionaffects the offspring.
■ Prenatal androgen excess may predispose to PCOS via alterationof the epigenome.
■ Obesity contributes to the development of PCOS.■ Lifelong monitoring for cancer, diabetes and coronary artery
disease is crucial.
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MJ. The prevalence of polycystic ovary syndrome in a communitysample assessed under contrasting diagnostic criteria. HumReprod. Nov 12.2009 Epub.
2. Taylor AE, McCourt B, Martin KA, et al. Determinants ofabnormal gonadotropin secretion in clinically defined womenwith polycystic ovary syndrome. J Clin Endocrinol Metab 1997;82:2248-2256. ?
3. Franks S. Polycystic ovary syndrome. N Engl J Med 1995;333:853-861. ?
4. Chang RJ, Katz SE. Diagnosis of polycystic ovary syndrome.Endocrinol Metab Clin North Am 1999; 28(2):397-408.
5. Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the poly-cystic ovary syndrome revisited: an update on mechanisms andimplications. Endocr Rev. 2012;33:981-1030.?
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8. Nestler JE, Barlascini CO, Matt DW, et al. Suppression of seruminsulin by diazoxide reduces serum testosterone levels in obesewomen with polycystic ovary syndrome. J Clin Endocrinol Metab1989; 68:1027-1032.
9. Pasquali R, Attenucci D, Casimirri F, et al. Clinical and hormonalcharacteristics of obese and amenorrheic hyperandrogenicwomen before and after weight loss. J Clin Endocrinol Metab1989; 68:173-179.
10. Dunaif A. Hyperandrogenic anovulation (PCOS): a unique?disorder of insulin action associated with an increased risk ofnon-insulin-dependent diabetes mellitus. Am J Med 1995;98(suppl 1A):33S-39S.
11. Carmina E, Bucchieri S, Esposito A, Del Puente A, Mansueto P,Orio F, et al. Abdominal fat quantity and distribution in womenwith polycystic ovary syndrome and extent of its relation toinsulin resistance. J ClinEndocrinolMetab2007;92:2500-5.
12. Carmina E, Bucchieri S, Mansueto P, Rini G, Ferin M, Lobo RA.Circulating levels of adipose products and differences in fatdistribution in the ovulatory and anovulatory phenotypes ofpolycystic ovary syndrome. Fertil Steril. Published online May 1,2008.
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