4TH YEAR CLERKSHIP STUDENT LECTURE

1. Polycystic ovary syndrome
Dr. Bulent Urman

2. PCOS
• A short story of a girl named Polly Sistic

3. 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 Obstet
Gynecol 1935; 29:181-191.

4. 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

5. 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

6. 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

7. 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

8. Pathophysiology

10. 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

11. 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

12. 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

15. Diagnosis of PCOS

16. Chronic Anovulation
–Oligomenorrhea
• 8 or fewer cycles per year
–Secondary amenorrhea
• No menstrual cycles for 3 or more
consecutive months

17. 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)

18. 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.

20. Phenotypic expressions of PCOS

21. 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

22. 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

23. Prevalence of metabolic syndrome
• In general population 23%
• In PCOS 43%
• In PCOS < 20 23%
• In PCOS 30-39 53%

26. Symptoms of PCOS
• Hyperandrogenic symptoms
– Hirsutism
– Seborrhea
– Acne
– Hair loss
• Anovulation or oligoovulation
• Infertility
• Recurrent abortion
• Obesity
• Dysfunctional uterine bleeding

27. 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

28. Treatment

30. Treatment in adolescents
• Treatment for PCOS in adolescents is directed at
the following clinical manifestations:
– Menstrual irregularity
• OCs, Progestins
– Cutaneous hyperandrogenism, primarily hirsutism
and acne
• OCs with antiandrogenic progestins
• Antiandrogens
– Obesity and insulin resistance
• Weight loss
• Insulin sensitizers
– Metformin

31. Weight loss
• Improves signs of hyperandrogenism
• Loss of > 5% weight
– Reduces insulin levels
– Reduces androgens
– Circulating free T levels
– Increases SHBG and IGFBP

32. Pharmacological treatment
• OCs
• Antiandrogens
– Sprinolactone
– Cyproterone acetate
– Flutamide
– Finasteride

33. Treatment in adults
• Measures directed against the treatment or
alleviation of obesity and IR
• Treatment directed against the treatment of
anovulation and infertility

34. Treatment options for anovulatory infertility
• Clomiphene Citrate
– Add Metformin if obese or insulin resistant
• Gonadotropin treatment or laparoscopic
ovarian drilling
• IVF

35. 72%

36. Long term consequences of PCOS
• Cancer
• Diabetes mellitus
• Dyslipidemia
• Cardiovascular disease
• Hypertension

37. 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

38. 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%

39. 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

41. Why is there PCOS from and
evolutionary point of view?

42. 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

43. • 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

44. • 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