Polycystic Ovary Syndrome (PCOS)

DR. SOWMYA.D SMS Medical College, Jaipur

INTRODUCTION

Heterogenous syndrome of unknown etiology. This multifactorial syndrome emerges at

puberty and has cardiovascular and metabolic sequelae .

PCOS is a most common endocrine disorder in women related to fertility.

Leading cause of anovulation, hirsutism and infertility.

Definition of PCOS The original description given by Stein and Leventhal included obesity, amenorrhoea, infertility and hirsutism in association with bilateral enlarged cystic ovaries showing a typical histological appearance of thickened capsule, multiple cysts and dense hypertrophied interstitial tissue.

PCOS is the most important among the causes of anovulation and Speroff quotes that a cross section of ovaries in anovulatory women at any point will reveal polycystic ovaries (approximately 75%).

The concerns in adolescent with PCOS are twofold-

1. The first involves cyclic control of irregular menstruation cycles.

2. The second issue involves the avoidance of the long-term sequelae that are associated with-

a) obesity,

b) insulin resistance,

c) glucose intolerance, and

d) type 2 diabetes.

American Family Physician, 2003, 68(4), 697.

Largely unknown

Complex multigenic disorder so far, no

single gene defect has been identified.

Evidence suggest the role of heredity in

PCOS.

Intrauterine androgen excess may be the

earliest gestational factor linked with the

pathogenesis of PCOS.

Primary theca cell defects.

Neuroendocrine dysfunction of

hypothalamic - pitutary - ovarian axis →

Hyperandogenemia.

• Neuroendocrine Pathology• Ovarian Pathology• Adrenal Gland Pathology• Periphery(fat)

Endocrinol. Metab. Clin. N. Am. 2005;34:643–658.

• Congenital origin of syndrome. Some PCOS may begin in utero.

• Initial presentation as low birth weight. • In childhood - rapid catch-up of growth →

Obesity and premature pubarche. • In Adolescence: -

- Anovulatory symptoms

- Hyperandrogenism• In adulthood - infertility, cardio-vascular

dysfunction / Type-2 diabetes.

Studies of particular interest shown prevention of this natural progression after early pre-pubertal treatment with metformin.

Premature pubarche (PP presence of pubic hair before the age of 8) is considered a forerunner of PCOS.

As SGA and prematurity were associated with PP - various authors proposed that PP could be a marker of hyperinsulinism.

This evolutionary pathway of PCOS from fetal life to adulthood remains speculative and this should be further explored.

• Variable presenting signs and symptoms.• PCOS should be consider in adolescent with: -

* Hirsutism * Precious puberty* Persistent acne* Menstrual irregularity* Acanthosis nigricans* Obesity

• Some with PCOS may appear clinically normal (no signs of hyperandrogenism or hyperinsulinism).

• The diagnostic approach in should be based on history and physical exam• Avoid numerous laboratory tests that do

not contribute to clinical management

Guzick DA. Clinical Updates in Women’s Health Care. ACOG 2009

• Focus on several aspects regarding menstruation such as – age at menarche, – length of time between periods, –quantity of menstrual flow, and –presence of dysmenorrhea

.

Obtaining information regarding- • Development of secondary sexual

characteristics • Obesity• Manifestations of hyperandrogenism • Family history as it relates to PCOS and

diabetes • Diet and exercise patterns• Alcohol consumption and tobacco use

A. Menstrual Irregularities• Persistent irregular cycles two years after menarche.• Amenorrhoea (Primary or Secondary).• Oligomenorrhoea (≤ 6 cycles / year).• Dysfunctional uterine bleeding secondary to

endometrial hyperplasia in anovulatory cycles. B.Resistant - ACNE - may present to primary physician

or dermatologist. C. Hirsutism - increase in the number of terminal hair

on the face, chest, arms and legs.. D. Precocious puberty or premature adrenarche.

Look for clinical manifestation of hyperandrogenism and signs of hyperinsulinism.

• Note blood pressure and BMI• Acne (severe)• Virilization - Clitoromegaly. Male pattern

baldness. • Thyroid examination for enlargement or

nodule.

Hirsutism• Presence of terminal

(coarse) hairs in females in a male-like pattern.

• Prevalence 5 – 15% of women.

Hatch et al, 1981 Am J Obstet Gynecol 140: 815-30

• Hirsutism - Ask H/o removal of hair - show pictorial representation of Ferrimman-Galway Scoring System. of ≥ 8 is consider hirsule.

• Signs of Hyperinsulinism - Acanthosis nigricans - in the neck, axilla, chest, back, perineal area, hand and feet.

Stein and Leventhal (1935) PCOS in adult women as a syndrome consisting

of amenorrhoea, hirsutism and polycystic ovaries.

NIH Criteria (1990) Chronic oligomenorrhoea / anovulation. Clinical and/or biochemical signs of

hyperandrogenism. and exclusion of other etiologies : congenital

adrenal hyperplasia, androgen-secreting tumors, cushing's syndrome.

Rotterdam Criteria (2003) Redefined PCOS as a syndrome with two of

three prerequisites: - Oligo/anovulation and/or clinical and/or biochemical signs of

hyperandrogenism. Polycystic ovaries by ultrasound and exclusion of other etiologies.

Rotterdam consensus - PCOS is a functional disorder.

In 2006 Androgen excess society provided a

contemporary version of definition of PCOS.

Hyperandrogenism, clinical or biochemical, in combination with ovarian dysfunction, including both functional and ultrasonographic abnormalities, as the core characteristics of PCOS.

Since there are no established criteria for the diagnosis of PCOS in adolescents, the adult criteria are applied to adolescent as well.

No consensus regarding specific lab test for PCOS

• To document hyperandrogenism.• To rule out other endocrinopathies.• Look for metabolic abnormalities (commonly

seen with PCOS).• The underlying defects in PCOS are still unclear,

however insulin resistance and metabolic syndrome are common in both obese and non-obese PCOS patients, so that evaluation of glucose tolerance is recommended.

A. Total and/or Free Testosterone which may be elevated.B. Serum sex hormone binding globulin (SHBG) may be

decreased.C. An increased ratio of LH to FSH of >2 is found in 60% to 70%

of women with PCOS and is more commonly seen in non-obese women.

D. Lipid panel to rule out dyslipidemias.E. 2-hour OGTT to rule out diabetes or impaired glucose

tolerance.F. Prolactin should be checked to rule out prolactinomas.G. Thyroid function tests, because both hyper and

hypothyroidism are associated with menstrual irregularities.H. Dehydroepiandrosterone sulfate (DHEA-S) to assess adrenal

androgensI. Fasting 17 OH-Progesterone to assess 21- Hydroxylase

function in the adrenal gland.

• Ultrasound, especially transvaginal ultrasound, is a sensitive and specific tool for detecting polycystic ovaries (PCO).

• Limitations: Transvaginal ultrasound is not widely used in the adolescent population . Transabdominal ultrasound is limited by the inability to visualize at least one ovary in 16% of women.

Ultrasound

• Twelve or more subcapsular follicular cysts 2 − 9 mm in diameter and / or• Increase in ovarian volume up to

10ml3 (determined by transvaginal ultrasound).

Ultrasound Criteria for Diagnosis of PCO

Ann N Y Acad Sci. 2008; 1135: 85–94.

Fertility Sterility (2004) 81:19

Risk Factor Cut Off

1. Abdominal obesity (waist circumference)

> 88 cm (> 35 inch)

2. Triglycerides ≥ 150 mg/dL

3. HDL-C < 50 mg/dL

4. Blood Pressure ≥ 130 / ≥ 85

5. Fasting and 2-h glucose from oral GTT

110-126 mg/dL and/or 2-h glucose 140-199 mg/dL

No established therapeutic rules

• Treat - Anovulation- Hyperandogenemia- Insulin resistance

Pathophysiologically Interconnected

Maintenance of Normal WeightFirst therapeutic priority -

Weight Loss and Lifestyle Modification

10% loss over 6m to 1yr → improves menstrual functions, insulin resistance and metabolic aberrations.

Not only the quantity (calorie excess leading to obesity), but also the quality of food may contribute to the pathogenesis of PCOS.

• Westernized diet and certain types of Indian foods contain abundant amount of Advanced glycated end products (AGEs) is ovoided. • AGEs are oxidative molecules, induces

proinflammatory and proatherogenic cascade. • High levels of AGEs in lean, non-diabetic

women with PCOS may bear significant cardiometabolic implications.

Second step in therapeutic approach - Drug administration -

Insulin Sensitizers - Mainly Metformin - offer holistic therapeutic approach to

PCOS.

Insulin sensitisation

Androgen Decrease

Improvement of menstrual regularity

• Metformin is an oral biguanide, well established for the treatment of diabetes.

• Insulin concentrations are therefore decreased with a resulting – decrease in androgen – decrease in LH – increase in sex hormone‐binding globulin

• It may also have a direct action on theca cells, reducing androgen production.

• There are now many reports of clinical improvement with metformin in, mostly obese, adult women with PCOS.

Cochrane Database Syst Rev, 2003, 3,CD003053. Cont….

Insulin Sensitizing Agents contd..

Traditional treatment for symptom management. Flutamide - • Blocks at the level of the nuclear receptor. • Nonsteroidal antiandrogen,inhibitor of testosterone

bio synthesis, Beneficial effects on ovulatory function and metabolic

aberrations (in H/o Premature Pubarche). • Doses ‐ 250 mg twice/thrice day• Flutamide + Metformin → Maximises therapeutic

benefits

Anti-Androgens and OCPs

Cyproterone Acetate (CPA)- • Synthetic progestin,competative inhibition at

androgen receptor,Most commonly used anti‐androgen combined with ethnyl estradiol.

• Reverse sequential regimen(CPA 100mg/day 5‐15)and EE 30 to 50mg/day on cycle of 5 to 26),allows regular menstrual bleeding, excellent contraception and treatment of acne and hirsuitism .

Combined Oral Contraceptive• Suppressing LH Secretion• Increasing SHBG• Circulating androgen levels are reduced.• Estrogen decrease conversion of testosterone to DHT

Decreasing free testosterone

Beneficial Effect on: - • Hirsutism• Acne• Regular shedding of endometrium via withdrawal

bleeds.

OC with newer Progestin

EE + Desogestrel

EE + Cypterone Acetate

EE + Drospirenone

MEDROXYPROGESTERONE ACETATE

•It directly affects hypothalopituitary axis by decreasing GnRH production and release of gonadotropins.•20 – 40 mg daily in divided doses oraly•150mg,IM every 6 weeks to 3months in the depot form.

SPIRONOLACTONEAntagonist of aldosterone,effective in hirsuitism.50-100mg twice daily.KETOCONAZOLE Inhibits steroidogenic cytochromes,200mg/day.reduces testosterone,androstenedione

• DEXAMETHASONE: PCOS who have either adrenal or mixed adrenal and ovarian hyperandrogenism,0.25mg nightly.

• FINASTERIDE: Inhibitor of type 2, 5alphareductase enzyme activity.7.5mgdaily,decreases hirsuitism.

Reproductive

Hyperandrogenic

Metabolic Insulin Resistance

Proinflammatory

Cytokines and Adipokines

Irregular periods

Acne

Hirsutism

Alopecia

Hyperinsulinism

Dyslipidemia

IGT

T2DM

?HS-CRP*

?IL-6

?TNF-α*

?Adiponectin

?PAI-1*

TREATMENT : LIFESTYLE INTERVENTION

+ + +Metformin

OCPAnti-androgens

MetforminTZD*

??

44

Laproscopic Ovarian Drilling• Treatment option in

– Clomiphene resistant women– Hyperandrogenic women

• Decreases serum testosterone and increases FSH level

• 4‐10 punctures in both ovaries.(8mm needle,100 w cutting current for entry,40w coagulating current over 2 seconds,(8mm depth,4mm diameter)

• Side effects‐ Post operative adhesions are seen

OVARIAN WEDGE BIOPSY

MECHANICAL METHODS OF HAIR REMOVAL

Chronic Anvoulation Hyperandrogenism IR / HI

NIDDM

Cholestrol

HDL

PAI-I

BP

HirsuitismAcne

Alopecia

CardiovascularDiscase

Unopposed Estrogen

BREASTUTERUS

OligomenorrhoeAmenorrhoeaa

Abnormal uterinebleeding

Interfility

EndomitrialHyperplasiaEndometrailCarcinoma

Breast Carcmoma

PCOS

Long Term Consequences of PCOS