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
3.
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
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
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
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.
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
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
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.
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
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
Editor's Notes
Clinical Features of PCOS. Hyperandrogenism.
Hyperandrogenemia is a key feature of PCOS, and it may appear as hirsutism, acne, male pattern balding, and/or male distribution of body hair.1
Reference
1. Lobo RA, et al. Ann Intern Med. 2000;132:989-993.
Heritability. Due to the observable trends within families concerning insulin resistance, the question remains whether PCOS has a genetic connection. For instance, first degree relatives inherit B-cell dysfunction (secretory deficits). Franks and colleagues offered the following hypothesis: Linage analysis-syndrome inherited in autosomal recessive fashion; heterogeneous disorder-need to focus on hyperandrogenism to assign phenotype.
Infertility Treatments. Another complicating feature of PCOS is the effects it has on ovulation and fertility. Since there are so many facets to PCOS, there are also multiple options for treating infertility based upon the patient’s characteristics. First line of treatment in overweight patients is weight loss through lifestyle modification. Another cautious approach is administering CC as first line then insulin sensitizer if REGNANCY desired outcome. However, only short-term treatment with sensitizer and although CC has demonstrated benefit it should be limited to three cycles (Gysler et al. Fert Ster 37:161; 1982). The infertility industry has developed multiple treatment protocols to offer women with PCOS. The following slides review two studies demonstrating the published success.