This document discusses polycystic ovary syndrome (PCOS). It begins by defining PCOS as chronic anovulation and androgen excess not caused by other factors. The key pathophysiologic features are said to be insulin resistance, hyperandrogenism, and altered gonadotropin dynamics. The diagnostic approach involves assessing history and signs of irregular periods and excess hair growth or infertility. Treatment depends on presenting complaints and may include lifestyle changes, oral contraceptives, spironolactone or ovulation induction drugs. Women with PCOS have long term risks like diabetes and heart disease and require screening.

1. Polycystic Ovary Syndrome
DR JEREMIAH I
Department of Obstetrics and Gynaecology,
NDUTH.

2. Introduction
• Chronic anovulation and androgen excess not
attributable to another cause
• Occurs in approximately 4% of women
• Fundamental pathophysiologic defect
– Unknown
– Important characteristics ; insulin resistance,
hyperandrogenism, and altered gonadotropin dynamics
– Inadequate FSH ; hypothesized to be a proximate cause of
anovulation
– Obesity complicates PCOS but is not a defining
characteristic

3. Introduction
• Diagnostic approach ; should based on history
and physical exam
• Irregular bleeding, hirsutism and/or infertility
– Treated with OCs, OCs with spironolactone and
ovulation induction
• Higher prevalence of diabetes and increased risk
factors for cardiovascular ds.
– should also be screened
– for obese women with PCOS,
behavioral weight management ; central
component of the overall treatment strategy

4. Definition
• Since its first description in 1935, a variety of
histologic, biochemical, sonographic and
clinical characteristics ; associated with PCOS
• Practical and useful clinical definition of PCOS
in the United States
– If have chronic anovulation and evidence of
androgen excess for which there is no other cause
– Referred to as the "NIH Conference" definition,
despite wide variety of views regarding the clinical,
endocrinologic features (Table 1)

6. Prevalence
• Best prevalence study, reported in 1998, with
unselected sample of white and African-
American women between the ages of 18 and
45 years
– 277 women who consented to a history, physical
exam, and hormonal evaluation, overall
prevalence of PCOS
• 4-4.7% for white women
• 3.4% for African American women

7. Clinical Importance
• In clinical gynecologic practice,
– Primarily for menstrual irregularity, hirsutism, and
infertility
• Treatment is directed at the immediate presenting
complaint
• Long-term goals
– Prevent diabetes, coronary heart ds.
– Screen cancer
• Unopposed estrogen exposure -> increased risk of
endometrial ca.

8. Pathophysiology
• Fundamental pathophysiologic defect in PCOS
– Unknown
– Several interrelated characteristics ; insulin
resistance, hyperandrogenism, and altered
gonadotropin dynamics
– Hypothesis that inadequate FSH stimulation ;
proximate cause of anovulation in PCOS

9. Pathophysiology
• Insulin resistance
– Defined as a subnormal biological response to
insulin
– Associated with obesity
– Extent of insulin resistance - cannot be explained
entirely by obesity

10. Pathophysiology
• Hyperandrogenism
– strong correlation between insulin resistance and
hyperandrogenism
• HAIR-AN syndrome
– Acanthosis nigricans
• Strongly suggests insulin resistance
• Dermatologic disorder characterized by velvety
hyperpigmented skin, usually over the nape of the neck,
in the axillae, or beneath the breasts)

11. Pathophysiology
• what is the directionality of the relationship
between insulin resistance
and hyperandrogenism?
– Direction of causation is from insulin to androgen
and not reverse
• Administration of diazoxide -> results in reduction in
circulating androgen concentrations
• Weight loss and insulin sensitizers -> reduction in androgen
– in vivo effect on ovarian androgens by insulin
• insulin synergizes with LH to promote androgen production
by the thecal cells

12. Pathophysiology
• Altered gonadotropin-releasing hormone dynamics
– Another key pathophysiologic feature of PCOS
– Increased LH pulse frequency and amplitude, leading to
increased 24-hour mean concentrations in both lean and
obese women with PCOS
– Elevated LH levels
• Responsible for the excess androgen production
• Androgen production by theca cell is LH dependent
• Suppression of LH by GnRH agonists or by OCs reduces
circulating testosterone and androstenedione

13. Pathophysiology
• Inadequate concentrations of endogenous
FSH
– Absolute concentrations of FSH above a specified
threshold
• Essential for both the initiation of preovulatory follicle
development as well as the selection of a single
preovulatory follicle

14. Pathophysiology
• In PCOS,
– E2 production ; limited
• Follicles not mature fully
• Granulosa cells number and in aromatase activity decreased
• Therefore, E2 production is limited, in the range of 70-80
pg/mL higher than early follicular E2
– Suppressing FSH, but never reaching the levels needed to initiate
an LH surge
– Concentration of FSH
• Not rise above levels seen in the mid-follicular range
• Insufficient to stimulate preovulatroy follicle development
• Constrained by negative feedback inhibition of E2 which
never exceeds mid-follicular levels

15. Pathophysiology
• Currently lack a satisfactory integrative model
of PCOS pathophysiology
– Genetic factors are at the root of the condition
– In view of characteristics such as insulin resistance
and gonadotropin changes
• Likely that more than one genetic "hit"
• Influenced by environmental factors

16. Diagnostic Approach
• Relatively safe ground on combination of
chronic anovulation and androgen excess
• With respect to ovulatory history
– History of irregular menstrual cycles dating to
menarche
– Report 6 or fewer episodes of spontaneous
vaginal bleeding per year

17. Diagnostic Approach
• oily skin and acne
– subtle signs of androgen excess
• Hirsutism
– Most common manifestation of the androgen
component of PCOS
• should inquire about and examine for
– "male-pattern" hair(hair located on the upper lip,
chin, chest, lower abdomen, and inner aspects of
the thighs)

18. Diagnostic Approach
• Differing opinions on what laboratory studies
should be ordered in evaluating a woman with
PCOS
– Primarily a clinical diagnosis - few laboratory
studies are needed
– Only condition that needs to be excluded to
secure the diagnosis of PCOS - nonclassical CAH
– Diagnostic pathway in Figure 3

19. Diagnostic Approach
• Figure 3

20. Diagnostic Approach
• Ratio of LH to FSH greater than 2;1 - consistent
with PCOS
– LH ; FSH ratio often in the "normal range"
∵ pulsatile nature of gonadotropins, resulting in broad
range of LH ; FSH ratios in PCOS when a single blood
sample is drawn
• In author's practice, evaluating a women with
chronic anovulation since menarche and
hirsutism
– Only blood sample - 17-hydroxyprogesterone
concentration to rule out 21-hydroxylase-deficient
nonclassical adrenal hyperplasia

21. Diagnostic Approach
• Testosterone
– Not necessary for diagnosis when clear hirsutism is
present
– Sometimes helpful in evaluating a women with
chronic anovulation but who does not have clinical
evidence of hirsutism or other signs of androgen
excess
– Total testosterone concentration greater than 60
ng/dL ; consistent with PCOS

22. Diagnostic Approach
• Ovarian anatomy
– Show multiple, small, subcapsular cysts, reflecting
repeated episodes of incomplete follicular growth
– Dense, hyperplastic stroma, reflecting an active thecal
component that is over-secreting androgens
• Ultrasound picture
– Numerous, small subcapsular cysts that produces a
"string of pearls" sign(Figure 4)
– Small subcapsular cysts and hyperechogenic stroma

23. Diagnostic Approach
• Figure 4

24. Diagnostic Approach
• In summary,
– Best diagnosed clinically with a minimum of
laboratory tests
• History of chronic anovulation dating since menarche
• Evidence of androgen excess, principally hirsutism
• Blood sample for serum 17-
hydroxyprogesterone concentration to rule-out 21-
hydroxylase-deficient nonclassical adrenal hyperplasia
– Obesity in conjunction with anovulation and
androgen excess
• Increase further one's suspicion of PCOS

25. Diagnostic Approach
• In cases in which the clinical diagnosis is not
clear
– Chronic anovulation without hirsutism
– Hirsutism with a history of cyclic menses
• Obesity ; increases the clinical suspicion of PCOS
• Serum testosterone greater than 60 ng/dL ; suggests
diagnosis of PCOS

26. Long-term risk of PCOS
• Increased risk of endometrial cancer
∵ Unopposed estrogen that results from
chronic anovulation
• In recent years, diabetes and cardiovascular ds.

27. Long-term risk of PCOS
• Dramatically increased risk of impaired glucose
tolerance and non-insulin-dependent diabetes mellitus
– Fasting glucose concentrations - poor predictors of non-
insulin-dependent diabetes mellitus
∵ As shown in Figure 5, women with PCOS
- Normal fasting glucose concentration
- IGT and DM based on 2-hour oral glucose
tolerance test value
– 30% for IGT, 8-10% DM(Figure 6)

28. Long-term risk of PCOS

29. Long-term risk of PCOS
• Do the diabetes, adverse lipid profile and
preclinical atherosclerotic changes seen in
women with PCOS translate into an increase in
actual cardiovascular events?
– Limited and inconsistent
– Clear need for a prospective study

30. Treatment
• Figure 8

31. Treatment
• Patient's height and weight to calculate her
body mass index
• BP at the first visit
• Fasting lipid panel to evaluate cardiovascular
risk
• Fasting glucose concentration to evlauate the
possibility of IGT or non-insulin-dependent
diabetes mellitus
– 2-hour oral glucose tolerance test is preferable

32. Treatment
• In overweight patient(body mass index 26 or
higher),
major component of any treatment should be
directed at weight reduction
– Best weight loss strategy - integrated behavioral
program
• Include exercise, moderate calorie restriction
• Result in significant favorable impact on insulin, androgens,
and ovulation
– No data on long-term outcomes of such lifestyle
modification programs

33. Treatment
• Initial therapeutic strategy in the management
of PCOS
– Behavioral weight management in obese patients
follows directly from the patient's chief complaint
– Metformin - not sliver bullet for all aspects of
PCOS treatment

34. Treatment
• Irregular menstruation
– Without the additional concerns of hirsutism or
infertility
• OCs remain an excellent choice
– Present hirsutism
• OCs plus spironolactone, at a dose of 200 mg/d is
standard choice

35. Treatment
• Several clear benefits in the treatment of
irregular menstrual cycles in women with PCOS
– 1.Regular withdrawal bleeding
– 2. Reduction in the risk of endometrial hyperplasia or cancer because
of progestin opposition of estrogen
– 3. Reduction in LH secretion and consequent reduction of ovarian
androgens
– 4. Increased sex hormone binding globulin production and consequent
reduction in free testosterone
– 5. Improvement in hirsutism and acne
• Measruable decline in hirsutism after 6 months of
treatment, while no effect on hirsutism was seen
with metformin

36. Treatment
• Depends on theCommon reason for a
physician consultation ; infertility
– Assuming a normal semen analysis, ovulation
induction
– Recommended approach in Figure 9
– Hysterosalpingography to confirm a normal genital
tract if history of PID, endometriosis, or previous
abdominal surgery

37. Treatment
• Figure 9

38. Treatment
• Most physiologic approach to ovulation
induction ; weight loss
• Failing that -> clomiphene citrate
– Excellent initial pharmacologic strategy
– Use the lowest clomiphene citrate dose that will
initiate the smallest number of ovulatory
follicles(hopefully, only one!)
• Starting dose ; 50 mg/d for 5 days(usually days 5-9)
• approximately 50% ovulation on 50 mg

39. Treatment
• Ultrasound on day 13 to assess follicle development
– More than 2 preovulatory follicles on day 13 ; reduced to
25 mg/d in subsequent cycles
– No follicle development ; dose and duration of treatment
increased
• Never exceed 150 mg/d for 5 days
• Once regimen that induces ovulation if there is no
pregnancy
– Should repeat that regimen and not increase the dose in
subsequent cycles
-> Goal is ovulation, not superovulation
• Overall, approximately 80% of women with PCOS -
ovulate on clomiphene citrate

40. Treatment
• How should ovulation be induced in the 20% of
women who are refractory to clomiphene citrate?
– Use of metformin hydrochloride
• Common and effective strategy
• Used extensively in the treatment of non-insulin-dependent diabetes mellitus
– Helps with glycemic control by reducing hepatic glucose output and by
increasing peripheral uptake of glucose
– Kidney or liver ds., alcoholism, heart failure treated with furosemide
should not take metformin
∵ lactic acidosis risk ↑
• Begun at a dose of 500 mg/d to minimize
gastrointestinal side effects and increased
gradually as tolerated

41. Treatment
• Small percentage of women with PCOS (about 5-
10%) who are refractory to clomiphene citrate
alone and to metformin plus clomiphene citrate
or who cannot tolerate these medications
– Laparoscopic ovarian drilling or injectable
gonadotropin
• Gonadotropins
– Hypersensitive to exogenous FSH
• Risk of multiple pregnancy and hyperstimulation
• Should be used in conjunction with in vitro fertilization
; Number of embryos that are transferred to the uterine cavity
controlled

42. Follow-Up
• Women with PCOS who are being seen for
infertility
– Followed closely with regards to ovulation induction
– If no pregnancy after 6 months of documented
ovulation
• Additional infertility evaluation
– If no pregnancy after 9-12 months of documented
ovulation, and if no other infertility factors
• Blend with unexplained infertility
• Intrauterine insemination is added
– If lack of pregnancy despite multiple cycles of
ovulation induction and intrauterine insemination
• Lead to consideration of the use of gonadotropins

43. Follow-Up
• For women with PCOS who are not interested
in pregnancy
– Follow-up at 6 month intervals