Polycystic ovary syndrome

Dr. Bulent Urman

PCOS

• A short story of a girl named Polly Sistic

Stein-Leventhal Syndrome

• 1935: Dr. Irving Stein and Dr. Michael Leventhal published the article:

– Seven women with amenorrhea, hirsutism, obesity, and polycystic appearing ovaries

Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J ObstetGynecol 1935; 29:181-191.

Epidemiology

• Polycystic ovary syndrome (PCOS) is recognized as one of the most common endocrine/metabolic disorders of women

• Prevalence is between 6 and 12 percent depending on the studied population

High risk groups

• Women with oligoovulatory infertility

• Women with obesity and/or insulin resistance

• Women with Type 1, Type 2 or GDM

• A history of premature adrenarche

• Women with relatives having PCOS

Pathogenesis

• Polycystic ovary syndrome (PCOS) is now thought to be a complex genetic trait, similar to cardiovascular disease, type 2 diabetes mellitus, and the metabolic syndrome, where multiple genetic variants and environmental factors interact to foster the development of the disorder

Genetic influences

• The largest twin study documented monozygotic correlation of 71% and a dizygotic correlation of 38%; the authors estimated that genetic influences account for as much as 70% of the variance in the pathogenesis of PCOS

• Principal genetic targets include genes regulating– gonadotropin secretion and action

– insulin secretion and action

– weight and energy regulation

– androgen biosynthesis and action

Pathophysiology

Altered LH action

• Altered LH action may be involved in the pathogenesis of PCOS:– PCOS patients often have higher serum LH

concentrations and increased LH pulse frequency and amplitude

– LH action at the ovarian level may be enhanced in PCOS, as the LH receptor is overexpressed in thecal and granulosa cells from polycystic ovaries

– Genetic variants of the LH beta-subunit have been reported in women with PCOS

Insulin secretion and action

• Insulin resistance, and the development of compensatory hyperinsulinemia, is a frequent finding in PCOS

• Insulin-sensitizing agents have been found to improve these features in many patients

• Theca cells in PCOS women are hyper-responsive to the stimulatory effects of insulin on androgen secretion

Weight and energy regulation

• The presence of obesity worsens – insulin resistance

– degree of hyperinsulinemia,

– severity of ovulatory and menstrual dysfunction, and pregnancy outcome in polycystic ovary syndrome (PCOS)

• Obesity is associated with an increasing prevalence of metabolic syndrome, glucose intolerance, cardiovascular risk factors, and sleep apnea

Diagnosis of PCOS

Chronic Anovulation

–Oligomenorrhea

• 8 or fewer cycles per year

–Secondary amenorrhea

• No menstrual cycles for 3 or more consecutive months

Polycystic Ovaries

• Not all women with PCOS have polycystic ovaries

• Not all polycystic ovaries are caused by PCOS

• Transvaginal ultrasound preferred method

• ≥ 12 follicles measuring 2-9mm in diameter

• Increased ovarian volume (> 10cm3)

Androgen Excess: Hirsutism

• Present in 75% of women with PCOS of white or black race

• Infrequent in women of Scandinavian and East Asian origin

• Ethnic differences likely due to differences in sensitivity of pilo-sebaceous unit to circulating androgens

• No difference in androgen levels between PCOS women with and without hirsutism

Azziz et al. JCEM 2004;89:453-462. Chang et al. Fertil Steril 2005;83:1717-1723.

Phenotypic expressions of PCOS

Useful for screening –but not mandatory

• LH – most likely to be raised on day 10 - 12

• Waist circumference >88 cm

• Test for insulin resistance – not necessary

for diagnosis or treatment selection

BUT

screen for metabolic syndrome if obese

Metabolic syndrome

• Abdominal obesity- > 88cm

• Triglycerides > 150 mg/dL

• HDL Cholesterol < 50 mg/dL

• BP > 130/85

• Glucose-fasting>110, 2hr PP>140 mg/dL

Any 3 out of 5

Prevalence of metabolic syndrome

• In general population 23%

• In PCOS 43%

• In PCOS < 20 23%

• In PCOS 30-39 53%

Symptoms of PCOS

• Hyperandrogenic symptoms– Hirsutism

– Seborrhea

– Acne

– Hair loss

• Anovulation or oligoovulation

• Infertility

• Recurrent abortion

• Obesity

• Dysfunctional uterine bleeding

Differential diagnosis

• Ovarian hyperthecosis– Proliferation of nests of lutenized granulosa cells

• Congenital adrenal hyperplasia– Incomplete form of late onset CAH

• Cushings syndrome– Excessive cortisol production form an adrenal

neoplasm or ACTH secreting tumor

• Androgen producing neoplasms– Ovary or the adrenal gland– These neoplasms induce rapid virilization

Treatment

Treatment in adolescents

• Treatment for PCOS in adolescents is directed at the following clinical manifestations:– Menstrual irregularity

• OCs, Progestins

– Cutaneous hyperandrogenism, primarily hirsutismand acne• OCs with antiandrogenic progestins• Antiandrogens

– Obesity and insulin resistance• Weight loss• Insulin sensitizers

– Metformin

Weight loss

• Improves signs of hyperandrogenism

• Loss of > 5% weight

– Reduces insulin levels

– Reduces androgens

– Circulating free T levels

– Increases SHBG and IGFBP

Pharmacological treatment

• OCs

• Antiandrogens

– Sprinolactone

– Cyproterone acetate

– Flutamide

– Finasteride

Treatment in adults

• Measures directed against the treatment or alleviation of obesity and IR

• Treatment directed against the treatment of anovulation and infertility

Treatment options for anovulatory infertility

• Clomiphene Citrate

– Add Metformin if obese or insulin resistant

• Gonadotropin treatment or laparoscopic ovarian drilling

• IVF

72%

Long term consequences of PCOS

• Cancer

• Diabetes mellitus

• Dyslipidemia

• Cardiovascular disease

• Hypertension

Cancer

• Endometrial hyperplasia and endometrial cancer

– OR for endo Ca 5.3 (1.55-18.6)

• Breast cancer

– Vast majority of the studies have not been able to define a positive association between PCOS and breast Ca

• Ovarian cancer

– PCOS does not appear to increase the risk of breast Ca

Diabetes mellitus

• 20-40% of women with insulin resistance will have Type II DM by the fourth decade of life

• 27-52% of premenopausal women with Type II DM were found to have PCOS

• The prevalence rates for impaired glucose tolerance and and DM in mothers and fathers of women with PCOS were 46 and 58%

Dyslipidemia

• Circulating levels of Total Cholesterol, LDL Cholesterol and triglycerides are increased in women with PCOS

• HDL levels were significantly lower

• These increase the risk of plaque generation in coronary vessels, heart attacks and hypertension

Why is there PCOS from and

evolutionary point of view?

An evolutionary concept of polycystic ovarian disease

• Does evolution favor reproductive success over survival?

• Why has PCOD been able to maintain such a high prevalence, worldwide, over thousands of years?

• As a condition closely linked to the metabolic syndrome, and therefore to premature and increased mortality, one would expect evolution to select aggressively against such a genetic predisposition

• Evolution traditionally favors reproductive success over continuity of life. This means, when having to make a choice nature will value the creation of new over the maintenance of old life

• With PCOD being widely considered a condition that causes infertility, it, on first glance, would not appear to qualify as supportive of reproductive success

• Consequently, evolution should have in all ethnic populations selected against its survival

• PCOD can therefore, from an evolutionary point of view, be seen as a ‘fertility storage condition’, which will guarantee survival of the species even during periods of distress and famine

• It has been recently suggested that women with PCOD demonstrate later menopause than controls

• PCOD expands the potential fertile, reproductive years for affected women, and such an expansion, once again, has to be seen as an overall fertility-enhancing characteristic of PCOD which, in adverse times, clearly benefits the survival of the species