Polycystic ovary syndrome (PCOS) is characterized by menstrual irregularity, hyperandrogenism, and polycystic ovaries. It affects 5-10% of women of reproductive age. Key features include ovarian dysfunction, hyperandrogenemia, polycystic ovaries on ultrasound, gonadotropin abnormalities, insulin resistance, dyslipidemia, and obesity. Treatment focuses on lifestyle modifications like diet and exercise as well as medications to address symptoms and underlying causes. Women with PCOS have an increased risk of diabetes and cardiovascular disease.

2. INTRODUCTION
 Classic syndrome originally described by
Stein and Levanthal in 1935
 Hyperandrogenism
 Menstrual irregularity
 Polycystic ovaries
 The most common endocrine disorder in
women of reproductive age (~ 5%-10%)
 Syndrome (association of several clinically
recognizable features), not a disease—
multiple potential etiologies with variable
clinical expression
Stein IF, Leventhal ML. 1935.
Dunaif A, et al. 2001

4.  NIH Criteria (1990)
(To include all of the following)
 Menstrual irregularity due to anovulation or oligo-
ovulation
 Evidence of clinical or biochemical
hyperandrogenism
 Hirsutism, acne, male pattern baldness
 High serum androgen levels
 Exclusion of other related disorders
Azziz 2007

5. EXCLUSION OF RELATED DISORDERS

6. FEATURES OF PCOS
 Ovulatory and menstrual dysfunction
 Hyperandrogenemia
 Polycystic ovaries
 Gonadotropin abnormalities (LH/FSH)
 Insulin Resistance and Hyperinsulinemia
 Dyslipidemia
 Obesity
 Type 2 diabetes
 Cardiovascular diseases
Mark O. et al 2011

7. OVULATORY AND MENSTRUAL
DYSFUNCTION
 75-85% PCOS patients diagnosed with
oligo-amenorrhea or abnormal uterine
bleeding
 40% PCOS patients with normal menses
have chronic anovulation
 20-50% hyperandrogenic women with
apparent eumenorrhea have chronic
anovulation, may be considered to be
affected by PCOS.
Azziz et al 2009

8. HYPERANDROGENEMIA
Refers to supranormal levels of circulating
endogenous androgens such as:
 Total, unbound, or free testosterone (T)
 Androstenedione (A4)
 Dehydroepiandrosterone (DHEA)
 DHEA metabolite DHEA sulphate (DHEAS)
Azziz R, Carmina E, Dewailly D, et
al. 2009

9. … HYPERANDROGENEMIA
 T circulates bound to SHBG and albumin and only free
fraction enters into target tissue. Assessment of free T
levels much more sensitive for diagnosis of
hyperandrogenemia. Elevated in ~70% PCOS patients
 Only few studies of prospective value available for using
A4 levels as a diagnostic criterion. However, ~10%
patients have elevated A4 levels
 ~20-30% PCOS patients have elevated DHEAS levels, but
also increased in other hyperandrogenic disorders and
DHEAS levels also decrease with age
 Therefore, serum androgen level cannot be used as sole
diagnostic criterion of PCOS
Azziz R, Carmina E, Dewailly D, et
al. 2009

10. MANIFESTATION OF
HYPERANDROGENISM
Clinically hyperandrogenism can manifest
itself in the form of:
 Hirsutism
 Acne
 Androgenic Alopecia

11. MANIFESTATION OF
HYPERANDROGENISM
Symptoms may include hirsutism,
acne, male pattern balding, and/or male
distribution of body hair
Hirsutism
Acne
Alopecia
Lobo RA, et al. 2000

12. HIRSUTISM
 Is the presence of terminal hair in a female body in a
male-type pattern, includes hair on 9 body areas:
upper lip, chin, chest, upper back, lower back, upper
and lower abdomen, upper arm and thigh
 Method to determine presence of hirsutism uses a
visual score, most common is modified FerrimanGallwey score
 0 score represents absence of terminal hair and score
of 4 represents extensive terminal hair growth.
Hirsutism is defined by an mGF score of ≥ 6
 However, prevalence of hirsutism varies according to
race and ethnicity of population
DeUgarte et al 2006

13. ACNE AND ANDROGENIC ALOPECIA
 Acne affects 15-25% PCOS patients but
unclear whether its prevalence is significantly
increased in these patients over general
population. No single scoring system used,
also varies with ethnicity
 Androgenic alopecia or scalp hair loss may
affect 5 – 50% PCOS patients but further
studies are needed to better define this
prevalence
Azziz R, Carmina E, Dewailly D,
et al. 2009

14. POLYCYSTIC OVARIES
 3 features used to define PCO:
 Ovarian size and volume
 Stromal volume
 Follicle size and number
 Rotterdam criteria defines PCO solely on total follicle
no. : presence of ≥ 12 follicles measuring 2-9 mm in
diameter and/or increased ovarian volume >10 mL in
at least one ovary
 Rotterdam definition of PCO cannot be applied to
women taking oral contraceptives as the have
modified ovarian morphology
Azziz R, Carmina E, Dewailly D,
et al. 2009

15. OVARIAN ABNORMALITIES
• Multiple follicles
in peripheral
location
• 80% of women
with PCOS have
classic cysts
ULTRASOUND IMAGE OF
POLYCYSTIC OVARIES
Smith R. 2006

16. GONADOTROPIC ABNORMALITIES
 Accelarated GnRH/LH pulse amplitude leads to
increased secretion of LH whereas FSH levels are
normal or even decreased
 >75% PCOS patients have a dysregulated
gonadotropin function
 Conceptually, increased surge of LH and
increased LH:FSH ratio during the follicular phase
of menstrual cycle has been considered as a
marker of PCOS. However, normal ratio may be
found in obese patients
Goodarzi, Dumesic et al 2011

17. Abnormal Pituitary Function Altered Negative Feedback
Loop
 Increased GnRH from hypothalamus
 Excessive LH secretion relative to FSH by
pituitary gland
 LH stimulates ovarian thecal cells - androgen
production
 Ineffective suppression of the LH pulse
frequency by estradiol and progesterone
 Androgen excess increases LH by blocking the
hypothalamic inhibitory feedback of
progesterone
Allahbadia, Merchant, 2010

18. GnRH
LH
hypothalamus
pituitary
X
Androgens
block
inhibitory
effect of
progesterone
ovary
androgens
Abnormal Pituitary Function—
Altered Negative Feedback

19. Abnormal steroidogenenesis
 Intraovarian androgen excess results in
excessive growth of small ovarian follicles
 Follicular maturation is inhibited
 Excess androgen causes thecal and stromal
hyperplasia

20. INSULIN RESISTANCE AND
HYPERINSULINEMIA
 50-70% women with PCOS have insulin resistance
 Defined as a subnormal target tissue response to a
given amount of insulin
 Results in Hyperinsulinemia, by the pancreatic islet
cells to maintain normal glucose homeostasis
 IR can lead to elevated circulating levels of glucose,
impaired glucose tolerance and eventually diabetes
 IR may not always be accompanied by elevated
circulating levels of insulin
Franks S. 1995.
Hopkinson 1998.

21. PATHWAYS LINKING HYPERINSULINEMIA AND
HYPERANDROGENEMIA
Maitra, Mukherjee, 2008

22. RELATIONSHIP B/W HYPERINSULINEMA &
HYPERANDROGENISM
 If hyperandrogenism caused insulin-resistance,
amelioration of hyperandrogenism would be
expected to improve insulin sensitivity
 But antiandrogen therapy has failed to produce
significant improvements in insulin resistance
 More support in literature that hyperinsulinemia
causes hyperandrogenism. Recent data suggest
that physiologic insulin levels enhance androgen
production from the granulosa cells of polycystic
ovaries and may act synergistically with LH.
Legro

23. Calculation of HOMA-IR
Glucose in Molar Units mmol/L
Glucose in mass units mg/dL
Matthews, 1935

24. DYSLIPIDEMIA AND OBESITY
Decreased levels of HDL-C
Increased levels of LDL-C
Increased levels of triyglycerides
A great reduction of (HDL) with higher increase
of both triglycerides & total cholesterol, may
make them prone to hypertension as well.
 Risk of atherosclerosis & premature
cardiovascular events increases
 About 50% PCOS women are obese, it appears
that risk of PCOS increases with obesity




Goodarzi, Dumesic, Azziz, 2011

25. MAJOR SIGNALING PATHWAYS OF
INSULIN ACTION

26.  Binding of insulin to its receptor results in autophosphorylation
and tyrosine kinase activation of the receptor which furthers
phosphorylates other downstream mediators [insulin receptor
substrate (IRS) and Src homology domain containing
transforming protein 2 (Shc)].
 These mediators then differentially activate various downstream
signaling proteins. Phosphatidylinositol 3-Kinase (PI3K) plays a
major role in glucose transport, glycogenesis and protein
synthesis.
 On the other hand, Grb2/SOS (growth factor receptor-bound
receptor 2/ Son of sevenless) complex activates mitogenactivated protein kinase pathway (MAPK) playing a crucial role
in mitogenic response.
 Another pathway via inositolglycan generation has been
suggested which may play a vital role in steroidogenesis.

27. OVARIAN STEROID BIOSYNTHETIC
PATHWAY
Wickenheisser, McAllister, 2007

28. ABNORMALITIES OF PCOS OVARY
 Increase in CYP17 leads to increased p450c17 enzyme and
hence increased androgen synthesis
 Decrease in CYP19 decreases aromatase enzyme activity
and conversion of androgens to E2 (Estradiol) is reduced
 Increased 5α-Reductase activity leads to increased
metabolism of ∆4-Androstenedione to 5αAndrostenedione, a competetive inhibitor of aromatase
activity
 This loss of aromatase and E2 biosynthesis has been
proposed to involve dysregulation of autocrine and
paracrine signaling within the follicle leading to follicular
arrest
Wickenheisser, McAllister, 2007

29. OVARIAN STEROID BIOSYNTHETIC
PATHWAY
Wickenheisser, McAllister, 2007

30. GENETIC LINK
Familial clustering of PCOS common
 1st degree relatives of patients with PCOS
may be at high risk for diabetes and glucose
intolerance
 Mothers and sisters of PCOS patients have
higher androgen levels than control subjects

31. INFERTILITY
 Intermittent ovulation or anovulation
 Inherent ovarian disorder—studies show reduced
rated of conception despite therapy with clomid

32. Treatment
 The first step is to help the patient understand that
this chronic disease process can be controlled by
changes in lifestyle.
 Lifestyle modification must be emphasized to
include appropriate diets & exercise program is
essential.
Azziz R, Carmina E, Dewailly D, et
al. 2009

33. …Treatment
 Metformin may complement the effects of
lifestyle modification, it causes marked
improvement in menstrual pattern & may
improve the response to ovulatory agents.
 Clomifene-citrate (competitive inhibitor of
estrogen receptor) is the standard method of
medical ovulation induction in anovulatory
women.
Azziz R, Carmina E, Dewailly D, et
al. 2009

34. …Treatment
 Anti-androgens: cyproterone acetate
 Spironolactone: alternative anti-androgen.
 Low dose of oral contraceptives are effective in
treating acne & hirsutism, minimum of 2 years &
cosmetic measures are needed to achieve good
results.
Azziz R, Carmina E, Dewailly D, et
al. 2009

35.  Susceptibility of PCOS patients to cardiovascular
diseases and diabetes
 Women with PCOS at ages 20–32 were more likely to
develop incident diabetes by the time they reached 38–
50 years of age
 Altered signaling pathways and susceptibility genes
 Marker genes for these diseases