DR NISHMA BAJRACHARYAFCPS 1ST YR RESIDENTOBS/ GYNE

• PCOS is not merely a reproductive disorder but an endocrinological disorder affecting women in their reproductive years.

•Although hyperandrogenism and infertility that PCOS causes are distressing to young women, its metabolic sequelae eventually plague the individual in terms of morbidity and mortality

PCOS AKAs• Polycystic Ovarian Syndrome, • Functional Ovarian Hyperandrogenism, • Chronic Hyperandrogenic Anovulation, • Ovarian Hyperandrogenic Dysfunction, • Hirsutism-Anovulation Syndrome, • Stein Leventhal Syndrome, • PCO, • PCOD, • Polycystic Ovaries, • Sclerocystic ovary, • Stein’s Syndrome.

Historical Aspects of PCOS

• Vallisneri gave the first histological description of the polycystic ovary, 1721

• Sclerocystic changes in the ovary described by Chereau, 1844

• Class description of a bearded women with DM, Achard/Thiers 1921

• In 1935, Stein and Leventhal described 7 women with bilateral enlarged PCO, amenorrhea or irregular menses, infertility and masculinizing features.

• This seminal paper introduced clinicians to the concept of reproductive endocrinopathies.

Definition of PCOS

1990 US NIH Consensus Conference: 2 minimal criteria

1. Menstrual Irregularity due to oligo- or anovulation

2. Clinical or biochemical hyperandrogenism

a.Hirsutism,Acne,Male Pattern Baldnessb.Elevated Serum Androgen Levels

3. Above not attributable to other causes

2003 ESHRE/ASRM (Rotterdam,Netherlands) Consensus on the Dx of PCOS

• Requires the presence of two out of the following three criteria:

1. Oligo- and/or Anovulation2. Hyperandrogenism (clinical and/or biochemical)3. Polycystic Ovaries, with the exclusion of other

etiologies

Task Force Appointed by the Androgen Excess Society (AES) 2006

• Reviewed all available data and recommended a new evidence-based definition.

The Task Force identified 4 key clinical features of PCOS:

1.Ovulatory and Menstrual Dysfunction2.Hyperandrogenism3.Hirsutism, Acne and Androgenic Alopecia4.Polycystic OvariesPlus the exclusion of other disorders of androgen

(J Clin Endocrinol Metab.2006 Aug 29)

►2012Institutes of Health Evidence-based Methodology Workshop on PCOSConcluded 2003 Rotterdam criteria should be adopted because most inclusive

PCOS-Epidemiology

• PCOS affects 6.5 to 8% (NIH 1990) of the female population of reproductive age.• It’s prevalence among infertile women is 15% to 20%.• PCOS accounts for 95% of cases of hyperandrogenism• PCOS is responsible for over 20% of all cases of amenorrhea• PCOS is responsible for up to 75% of all cases of anovulatory

infertility.

Pathophysiology►Principal molecular defect that causes PCOS is

unknown

►Interaction of multiple genetic variants and environmental factors (diet, obesity)

evidences showed association between cytochrome P450 17-hydroxylase/17, 20-desmolase (CYP17) and PCOS.Cytochrome P450 side-chain cleavage enzyme (CYP11A) and PCOS.

Crosignani P, Nicolosi A. Polycystic ovarian disease: heritability and heterogeneity. Human reproduction update. 2001;7(1):3-7.

Pathophysiology►Principal genetic targets

•Gonadotropin secretion• Insulin secretion•Androgen biosynthesis•Weight and energy regulation

Gonadotropin secretion

PathophysiologyGonadotropin secretion► LH action enhanced at ovarian level► LH receptor is overexpressed in theca cells► LH increased relative to FSH levels► Follicular arrest and increased androgen production in the

ovarian theca cells► The most likely cause of anovulation is an FSH level too low

to fully mature the follicles► FSH levels may be suppressed by negative feedback

inhibition from mid-follicular estradiol level► Anovulation

PathophysiologyInsulin secretion and action

►Insulin resistance (IR)• Appears to be related to mutations in the insulin

receptor gene altered function

►50 to 70% PCOS patients have IR

PathophysiologyInsulin secretion and action

►IR leads to hyperandrogenism• Hyperinsulinemia and LH synergistically stimulates

theca cell secretion of androgens• Hyperinsulinemia inhibits hepatic sex-hormone binding

globulin (SHBG) production►Resulting in an increase in free androgens

PathophysiologyAndrogen biosynthesis and action

►Produced by ovaries and adrenal glands►Testosterone►70% bound to SHBG►20-30% bound to albumin►1% free - - biologically active

Serum Androgens

►Testosterone (T)• Majority made in ovary• Most potent circulating androgen• Biological activity determined by the amount of binding

to sex hormone binding globulin• Free testosterone is active

Serum Androgens

►Androstenedione (A) • Immediate precursor to testosterone• Ovary and adrenal production

►Dehyrdoepiandrosterone sulfate (DHEA-S)• Majority derived from adrenal glands• Small percentage from ovary

Serum Androgens

►Dihydrotestosterone (DHT)• Peripheral conversion in androgen responsive tissues• Intracellular 5-alpha reductase converts T to DHT• DHT binds to androgen receptor with affinity 10x greater than T• Women with PCOS have increased 5-alpha reductase activity

(converts T to DHT)• Resulting in increased activation of the pilosebaceous unit (hair

growth, sebum production) with increase in bioavailable testosterone

Ovarian Androgen Secretion►Androgens produced in the theca cells which respond to LH►Role of insulin

• Synergistic effect of LH and insulin to increase androgen secretion

►Theca cells synthesize mostly androstenedione and some testosterone

►They diffuse across the basement membrane to the granulosa cells

Ovarian Androgen Secretion(continued)►The granulosa cells, in response to stimulation by FSH,

produce aromatase which converts androgen precursors to estrone and estradiol (negative feedback to FSH)►Impeded normal follicular growth, resulting in follicular

arrest at the 4-8mm diameter size►A dominant follicle (18-25mm) does not develop therefore

ovulation does not occur

Ovarian Theca & Granulosa Cells

Adrenal Androgen Secretion

►Adrenal androgen secretion• Under control of ACTH• Over 50% of women with PCOS have evidence

of increased adrenal androgen secretion

PathophysiologyWeight and energy regulation►Obesity

►40-80% of PCOS are overweight or obese• Presence of obesity results in:

►Insulin resistance hyperinsulinemia►Hyperinsulinemia synergy with LH and drop in SHBG

Hyperandrogenism hirsuitism/acne►Arrest of follicular development chronic anovulation

• PCOS patients►31-35% have IGT (1.6% in non-PCOS)►7.5-10% have DM (2.2% in non-PCOS)

Obesity and insulin resistance

Clinical FeaturesAdolescence►No formal diagnostic criteria

• Obesity• Irregular cycles

►50% of cycles are anovulatory in first 2 years after menarche

►More Concerning…• Hyperandrogenism• Peripubertal girls with pubarche before age of 8

Clinical Features Reproductive age

►Anovulatory Symptoms

• 2/3 patients• Erratic cycles with breakthrough bleeding• Primary amenorrhea • Oligomenorrhea

►Hirsutism►Acne►Male pattern hair loss ►Polycystic Ovary

Clinical Features Reproductive age

►Obesity40-80% have BMI > 30

►Insulin Resistancemajority of PCOS patients regardless of obesity (30% lean and 70% obese)

►Diabetes (7.5 to 10% of PCOS patients)31-35 % of PCOS patients have glucose intolerance2-5 fold increase in developing DM

►Infertility75% of infertility causesPoor FSH stimulation and elevated LH levels impair follicle maturation and ovulation

►PregnancySpontaneous abortion rate 20-40% higherPregnancy complication rate (GDM 3.4x, GHTN 3.4x, Pre E 2.2x, PTB 1.9x)

Clinical Features Reproductive age►Endometrial Hyperplasia/Cancer

• Chronic exposure to unopposed estrogens►Dyslipidemia – low HDL, high triglycerides 70% of patients with

PCOS ►Metabolic syndrome – 30 to 40%►Nonalcoholic fatty liver disease – 30% in PCOS compared to 2% all

women and 5% women with DM2►Coronary heart disease►Sleep apnea ►Depression/anxiety►Eating disorders (binge eating)

Source of Image:http://fcionline.com/fertility/infertility-diagnosis-services/pcos

Differential Diagnosis

Menstrual Dysfunction in PCOS

• Irregular Menses -less than 21 days or greater than 35 days.• PCOS- typically have prolonged(>35 days) cycles.• Menstrual disturbances in PCOS classically have a

peripubertal onset• Both decreased menstrual cycle regularity and

dysfunctional uterine bleeding are clinical consequences of chronic anovulation.• Increased risk of endometrial

hyperplasia/carcinoma• Prolonged amenorrhea associated with endometrial

atrophy

Ovulatory and Menstrual Dysfunction per the Task Force of the AES 2006• 75% of patients have clinically evident menstrual

dysfunction, and 20% have a history of apparent eumenorrhea.• In women with hirsutism and eumenorrhea,

anovulation can be confirmed by measuring serum progesterone during days 20 through 24 of the cycle.

Clinical Hyperandrogenism• Hirsutism• Acne 15% to 25%• Male-pattern Balding• Acanthosis Nigricans- Occurs in up to 5% of women• - Mucocutaneous eruption characterized by hyperkeratosis,

papillomatosis and increased pigmentation.• Occurs in the axillae, nape of neck, under the breast and the flexures.• less common- Increased Muscle Mass, Deepening Voice,

Clitoromegaly

Labs►Goal is to exclude other etiologies►Androgens• Total Testosterone

►widely available►mildly elevated in PCOS►If >150 ng/dL (normal<70) consider androgen secreting tumor

• Free Testosterone►more sensitive test

• DHEA-S►marker for adrenal hyper androgenemia►If >800 mcg/dL (normal <270) consider androgen secreting tumor

• SHBG ??

Labs►LH – increased in PCOS, too variable to be useful

►FSH – Premature ovarian failurePCOS

►FSH levels low►LH levels high ►LH/FSH > 3

►PRL – hyperprolactinemia

►TSH – thyroid dysfunction

►17-hydroxyprogesterone• CAH• Random < 4 ng/mL• Morning fasting < 2 ng/mL• High levels should prompt an adrenocorticotropic hormone (ACTH)

stimulation test

►Dexamethasone suppression test• If suspicious of Cushing’s syndrome

Labs►Fasting glucose

• Fasting plasma glucose ►<100 mg/dL normal►100-125 mg/dL impaired fasting glucose/prediabetes►>126 mg/dL DM

►2 hour glucose level after 75gm oral glucose load• 140-199 mg/dL indicates impaired glucose tolerance• Above 199 mg/dL is diagnostic for type diabetes• Recheck every 2 years if IGT

Lipid Profile

Imaging►Ultrasound is the imaging modality of choice  ►Assessment of endometrial abnormalities►Pelvic U/S to rule out ovarian mass►PCOS ovaries are enlarged (>5cm)

• > 12 subcapsular follicles (2-9 mm) in one or both ovaries• Ovarian volume >10mL • Dense hyperechoic stroma• “string-of-pearls” appearance

Ovarian Morphology on Pelvic Ultrasound

• Ovarian pattern is both insufficient and unnecessary to make the diagnosis of PCOS per NIH Conference on PCOS criteria of l990

• However, it has been considered necessary to redefine PCOS and include with it an appropriate definition of the polycystic ovary per 2003 ESHRE/ASRM criteria

Polycystic Ovaries per the Task Force by AES 2006• 75% of patients have polycystic ovaries detected by

transvaginal ultrasonography

• The Dx of polycystic ovaries should not be based merely on a “polycystic” or “multicystic” appearance.• At least 1 ovary should have a volume of >10cm3

(mL), or there should be >= 12 follicles measuring 2 to 9 mm in diameter.

Additional Use for Pelvic Ultrasound

•To check the endometrium for hyperplasia and carcinoma

Goals of Treatment

►Lifestyle changes►Lower risk for DM and CV disease►Avoid effects of hyperinsulinemia►Reduce production and circulating levels of androgens►Protect the endometrium against effects of unopposed

estrogen►Induce ovulation to achieve pregnancy►Contraception – return of ovulation with treatment

Treatment for those NOT pursuing pregnancy

►Menstrual dysfunction and endometrial protection

►OCPs – first line• Cycle regulation –

predictable/regular withdrawal bleed• Contraception• Progestin antagonizes the

proliferative effect of estrogen and prevents endometrial hyperplasia

• Progestin only ►Cyclical or continuous oral

dosing►Progestin IUD►Progestin rod implant

• Metformin – second line►Restoration of ovulatory

cycles in 50% of women

Treatment for those NOT pursuing pregnancy

►Androgen excess• OCPs – first line

►Decreases LH secretion decrease ovarian androgen production

►Increases hepatic production of SHBG decrease in bioavailable testosterone

►Decrease in adrenal androgen secretion

Treatment for those NOT pursuing pregnancy►Anti-androgen – added if suboptimal effects after 6 months * *

MUST use contraception• Spironolactone – 50-100 mg BID

►Aldosterone antagonist diuretic►Competitive androgen receptor antagonist

• Finasteride, flutamide, GnRH agonist

►Eflornithin HCl (Vaniqa) 13.9% cream BID►Concomitant therapy (OC and anti-androgen)

• Cosmetic – mechanical (shaving, waxing, depilatories, electrolysis, laser

Treatment for those NOT pursuing pregnancy

►Metabolic abnormalities• Obesity – weight loss 5-10% to restart ovulatory patterns

(diet/exercise, pharmacotherapy, bariatric surgery)►Caloric restriction is main factor►No data supporting one diet over the other

• IR/risk of DM2 – metformin (first line)►thiazolidinediones (wt gain, less studied in PCOS)

• Dyslipidemia – exercise/weight loss, pharmacotherapy if needed• OSA – CPAP

Metformin►Major effect is to decrease hepatic glucose production thus less need

for insulin secretion►Target dose 1500-2000 mg/day (can use short acting or extended

dosing)►Side effects – diarrhea, nausea/vomiting, flatulence, indigestion,

abdominal discomfort►Avoid if risk for lactic acidosis (renal insufficiency)►“Off label” use – oligomenorrhea, hirsuitism, obesity, prevention of DM2

• A recent, uncontrolled, retrospective, observational study, showing that long-term treatment with metformin delays or prevents the development of impaired glucose tolerance and diabetes in women with PCOS, is certainly in keeping with this concept.*• Another study showed decreased weight and systolic blood pressure

as well as increased HDL in metformin-treated women with PCOS.* In this study, metformin was also shown to increase insulin sensitivity and lower testosterone in obese but not non obese PCOS women.

* Trolle B, Flyvbjerg A, Kesmodel U, Lauszus FF. Efficacy of metformin in obese and non-obese women with polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled, cross-over trial. Hum. Reprod. 22(11), 2967-2973 (2007)

* Sharma ST,Wickham III EP, Nestler JE. Changes in glucose tolerance with metformin treatment in polycystic ovary syndrome: a retrospective analysis. Endo. Prac. 13(4), 373-379 (2007).

Dosing of Metformin• “Start Low, Go Slow” • Starting dose 500 mg daily with food/dinner x 1 wk • 500 mg twice daily; breakfast, dinner x1 week • 500 mg am, 1,000 mg pm x 1 week • 1,000 mg BID; breakfast, dinner • Increasing q 1- 2 weeks to max 2+ gms day • Maximum 2250 mg total daily; 850 mg tid

• Garber et al. Am J Med 1997;103: Garber et al. Am J Med 1997;103: Ovulation improves w Single or Combination therapy Ovulation improves w Single or Combination therapy NEW: NEW: Research supports benefits even if NOT seeking pregnancy Research supports benefits even if NOT seeking pregnancy Secor 2011 

Metformin and OCPs►Metformin + OCPs

• Inadequate evidence to recommend routine addition of metformin as unclear whether this combination has important cosmetic or metabolic advantages over OCP monotherapy

►Metformin vs OCPs• OCPs first line for oligomenorrhea and hyperandrogenism. OCPs less

beneficial for insulin sensitivity while metformin better at reducing fasting insulin

Treatment for those pursuing pregancy►Weight loss – 5-10% loss yields resumption of ovulatory cycles ►Ovulation induction – be sure to do a semen analysis and HSG

to complete infertility• Clomiphene• Letrozole• Metformin• Gonadotropins

Treatment for those pursuing pregancy

►Ovulation induction agents• Clomiphene – first line

►Selective estrogen receptor modulator (SERM) – competitive inhibitor of estrogen binding to receptors in hypothalamus (blocks the negative feedback loop of estrogen) and results in increase in GnRH, FSH, and LH and influence follicular development.

►It is an estrogen agonist enhancing FSH stimulation of LH receptors in the granulosa cells

►50-150 mg per day orally 5 days: cycle days 3-7 ►Ovulate approx 10 days after last dose, Monitor for LH

surge starting day 12 ►80% will ovulate and 50% will conceive

Treatment for those pursuing pregancy►Ovulation induction agents

• Letrozole – aromatase inhibitor (off label use)►Aromatase catalyzes the rate limiting step in production of

estrogen thus suppresses ovarian estradiol secretion and rise in FSH and follicle production

►Also used as adjuvant endocrine therapy in postmenopausal breast cancer

►5-7.5 mg po daily day 2-6 x 5 days• Metformin – with or without clomiphene• GnRH – higher risk for ovarian hyperstimulation syndrome

Treatment for those pursuing pregancy

►Laparoscopic surgery• Wedge resection – abandoned secondary to adhesion

formation, better results with clomiphene• Ovarian drilling/diathermy

►In vitro fertilization (IVF)►Intracytoplasmic sperm injection (ICSI)

Laparoscopic Surgery for Ovulation Induction in PCOS►Majority with anovulatory infertility will ovulate in

response to clomiphene, however up to 30% remain anovulatory• Of 70% who do ovulate, only 50% will conceive• Addition of metformin can help ovulation %• Those that are still unresponsive/resistant move to

gonadotropin therapy►Issues: difficult to titrate the dose to achieve monofollicular

ovulation, 30% risk of multiples, risk of ovarain hyperstimulation syndrome, cost, SAB risk is higher

Laparoscopic Surgery for Ovulation Induction in PCOS►Dates to 1930’s – bilateral ovarian wedge resection

resulted in restoration of regular menses and pregnancy• fell out of favor secondary to post-op adhesion formation and

the introduction of clomiphene

►Ovarian drilling/electrocautery – less adhesions, similar pregnancy rates to gonadotropin with less multiple risk

Ovarian Drilling

►Create focal areas of damage to the ovarian cortex and stroma►Unipolar needle electrode

insulated down to 2 cm of exposed probe. 4-6 punctures of each ovary

Ovarian Drilling►Laparoscopic candidates – PCOS patients who have failed

clomiphene and metformin, non-obese BMI <30, and no other fertility factors

►Efficacy – similar conception rates to gonadotropin therapy• Advantages – no cyclical monitoring, more cost effective, no increase risk of

multiple gestations or OHSS• Disadvantages – anesthesia, surgical risk (bleeding, infection, damage to

surrounding tissues, adhesive disease)• Other considerations – often unsuccessful in obese women, patients should

have no other infertility factors (tubal, endometriosis, male factor), IVF success

Long Term Issues Associated with PCOS

Source of Image: Teede, Helena j. et al., Assessment and management of polycystic ovary syndrome: summary of an evidence-based guideline, Med J Aust 2011; 195 (6): S69.

The Metabolic Syndrome and PCOS• The prevalence of metabolic syndrome in women with PCOS is

approximately 43-46%.*

WHO• T2DM or IFG or IGT or insulin resistance plus ≥ 2 of the following:

• • BMI > 30 kg/m2

• • HDL < 1.0 mmol/L (< 40 mg/dL)

• • TG ≥ 1.7 mmol/L (150 mg/dL)

• • BP ≥ 140/90 mmHg or use of blood pressure medication

• • microalbuminuria > 20 pg/min

• • Alb/Crea ratio ≥ 30 mg/g

*Third report of the National Cholesterol Education Program. Expert panel on the detection, evaluation and treatment of high blood cholesterol in adults. Final report. Circulation 106, 3143-3421 (2002).

• Insulin resistance is the major underlying pathophysiologic abnormality linking the metabolic syndrome and PCOS.

• Weight loss with life-style modification is the safest and cheapest therapy that has shown benefit both in MetS and PCOS

Polycystic Ovary Syndrome and Cardiovascular Disease: Premature Association? Richard S. LegroEndocrine Reviews June 1, 2003; 24 (3): 302-312

• Women with polycystic ovary syndrome (PCOS) are often assumed, a priori, to be at increased risk

for cardiovascular disease (CVD), given the high prevalence of the metabolic syndrome X among them.

• Long-term studies of well characterized women with PCOS are lacking, and the link to primary cardiovascular events such as stroke or myocardial infarction remains more speculative than substantive.

• Epidemiological studies that have focused on isolated signs and stigmata of PCOS, such as polycystic ovaries, hyperandrogenism, or chronic anovulation, have found mixed results.

• There are studies that suggest a slight increase in cardiovascular events in women with polycystic ovaries, with perhaps stronger evidence between an increased risk of cardiovascular events in women with menstrual irregularity.

• However, there is little evidence for an association between hyperandrogenism per se and cardiovascular events.

• Furthermore, there are less data to substantiate an increased risk of events in women with PCOS identified on the basis of a combination of signs and symptoms, such as hyperandrogenic chronic anovulation.

• The existing data suggest that PCOS may adversely affect or accelerate the development of an adverse cardiovascular risk profile, and even of subclinical signs of atherosclerosis, but it does not appear to lower the age of clinical presentation to a premenopausal age group.

Cardiovascular Risk in PCOS

• Several studies using intima media thickness as a surrogate for cardiovascular risk evaluation have shown potential increased cardiovascular risk in women with PCOS.*

Talbot EO, Guzick DS, Sutton-Tyrrell K et al. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arterioscler. Thromb. Vasc. Biol. 20, 2414-2421 (2000).

* Vryonidou A, Papatheodorou A, Tauridou A et al. Association of hyperandrogenism and metabolic phenotype with carotid intima-media thickness in young women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 90, 2740-2746 (2005).

* Luque-Ramirez M, Mendieta-Azcona C, Alvarez-Blasco F, Escobar-Morreale HF. Androgen excess is associated with increased carotid intima-media thickness observed in young women with polycystic ovary syndrome. Hum. Reprod. 22, 3197-3203 (2007).

Coronary Artery Calcification and PCOS• A similar study using coronary artery calcification as risk stratification has shown increased risk in patients with PCOS.*

* Christian R, Dumesic DA, Behrenbeck T, Oberg AL, Sheedy PF, Fitzparick LA. Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 88, 2562-2568 (2003).

Sleep Apnea and Other Sleep Disorders• Multiple groups have documented an increased

risk for sleep apnea and other sleep disorders including increased daytime somnolence, such as sleep disordered breathing in women with PCOS.

Body Image and Quality of Life in PCOS Patients• There is little study of the psychopathology of women

defined as having PCOS in literature• PCOS disease-specific questionnaire known as the PCOSQ has

been developed to study the above questions. • Obesity and infertility cause the greatest degree of stress• Both anorexia nervosa and bulimia have been linked with

PCOS(etiological link?)• Many conditions co-exist with PCOS such as pelvic pain,

depression and altered mood but it is unclear where there is a casual or causal association.

Poly cystic ovarian syndrome and cancers

• Endometrial carcinoma- • The prevalence of endometrial hyperplasia with and without atypia in

women with PCOS varies from 1 to 48.8%

• chronic anovulation, which results in continuous estrogen stimulation of the endometrium unopposed by progesterone

• Obesity, hyperinsulinemia, and hyperandrogenism state in PCOS, results in increased bioavailability of unopposed estrogens by progesterone due to the increased peripheral conversion of endogenous androgen into estrogen

• Hardiman P, Pillay OS, Atiomo W. Polycystic ovary syndrome and endometrial carcinoma.

• The lancet. 2003;361(9371):1810-2.

Ovarian cancer and breast cancer

• women with PCOS had a 2.5-fold increased risk of developing ovarian cancer, • clomiphene citrate and gonadotropin therapy or ovulation induction was found

to increase the relative risk of ovarian tumors in women with PCOS around 4.1 x• meta analysis about the association between PCOS and breast cancer showed

that the risk of breast cancer was not significantly increased overall• However some studies showed that women with PCOS independently of age, age

at menarche or menopause, parity, using oral contraceptive pill, BMI and family history of breast cancer, have 1.8 times as likely to report benign breast disease

Schildkraut JM, Schwingl PJ, Bastos E, Evanoff A, Hughes C. Epithelial ovarian cancer risk among women with polycystic ovary syndrome. Obstetrics & Gynecology. 1996;88(4, Part 1):554-9.

Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Human reproduction update. 2014:dmu012.

•Polycystic ovary syndrome and pregnancy

PCOS and abortion• spontaneous Abortion occurs in 30 to 50% of PCOS women compared with

10 to 15% of normal women

• a metaanalysis showed Treatment with ovulation-inducing agents is associated with a higher incidence of abortion in PCOS women

• It is suggested that metformin therapies before and throughout pregnancy, could decrease the risk of early abortion, but more studies are needed

Kjerulff LE, Sanchez-Ramos L, Duffy D. Pregnancy outcomes in women with polycysticovary syndrome: a metaanalysis. American journal of obstetrics and gynecology.2011;204(6):558. e1-. e6.

PCOS and gestational diabetes mellitus• affects 4–7% of pregnancies overall.• There are 2.4-fold increased risks of GDM among PCOS women,

independent of age, race/ethnicity, and multiple gestations. • GDM complicates 40 to 50% of PCOS pregnancies.

Lo JC, Feigenbaum SL, Escobar GJ, Yang J, Crites YM, Ferrara A. Increased Prevalence of Gestational Diabetes Mellitus Among Women With Diagnosed Polycystic Ovary Syndrome A population-based study. Diabetes care. 2006;29(8):1915-7.

PCOS and hypertensive disorders in pregnancy• Hypertensive disorders occurs in 8% of PCOS pregnancies • Increased levels of androgens in PCOS have been

associated with the development of preeclampsia

Roberts JM, Pearson G, Cutler J, Lindheimer M. Summary of the NHLBI working group on research on hypertension during pregnancy. Hypertension. 2003;41(3):

PCOS-Key Points• PCOS is one of the commonest reproductive

endocrinopathies to affect women (5-10%).• PCOS is the most common cause of anovulatory infertility.• PCOS probably represents a spectrum of disease with

variable presentations- • Pathophysiology- Insulin resistance + androgen excess• Diagnosis –Clinical +/- labs, USG• Current treatment options- lifestyle, combination OCP

+insulin sensitizers• Is important to diagnose PCOS because of the potential

long-term consequences.• Further research is necessary in this syndrome.

Who Should Manage PCOS?• PCOS has evolved out of the purview of the

reproductive specialist and gynecologist.• PCOS is probably best managed by an internist, family practitioner or endocrinologist with subspecialists including gynecologists, fertility specialist, dermatologists and in the long run, cardiologists and oncologists as indicated.

References-• Berek & Novak’s Gynecology• Jeffcoate’s Principles of Gynecology• Clinical gynecology Bieber, Joseph S. Sanfilippo, Ira R. Horowitz• Uptodate.com• Polycystic ovary syndrome : a guide to clinical management / Adam Balen ...

[et al.]• Polycystic ovary syndrome / edited by R. Jeffrey Chang, Jerrold J. Heindel,

Andrea Dunaif.• ACOG practice bulletin, polycystic ovary syndrome• Clinical gynecologic endocrinology and infertility / Leon Speroff, Marc A. Fritz

• Comprehensive Gynecology. 4th Edition. Stenchever, Droegemueller, Herbst, Mishell.

• Clinical Gynecology. 1st Edition. Bieber, Sanfilippo, Horowitz. • Polycystic Ovary Syndrome. ACOG Practice Bulletin. Number 108.

October 2009. Reaffirmed 2013• A practical approach to the diagnosis of polycystic ovary syndrome.

American Journal of Obstetrics and Gynecology. Volume 191, Issue 3, Pages 713-717 (September 2004).

• Polycystic Ovarian Syndrome: 3 Key Challenges. Dale W. Stovall, MDOBG Management · June 2003 · Vol. 15, No. 6

• Polycystic ovary syndrome: How are obesity and insulin resistance involved?. OBG Management. October 2012 · Vol. 24, No. 10