Polycystic Ovary Syndrome

1. Polycystic Ovary Syndrome Obstetrics & Gynecology Vol 103, No 1, Jau 2004 부산백병원 산부인과 R4 강영미

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 treatmentstrategy

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 andhyperandrogenism? • Direction of causation is from insulin to androgen and not reverse • Administration of diazoxide -> results in reduction in circulating androgenconcentrations • 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 thecalcells

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 circulatingtestosterone 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 aromataseactivity decreased • Therefore, E2 production is limited, in the range of 70-80 pg/mL higher thanearly follicular E2 • Suppressing FSH, but never reaching the levels needed toinitiate 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 feedbackinhibition 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 • Mostcommon manifestation of the androgen component of PCOS • should inquire about and examine for • "male-pattern" hair(hair locatedon 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 ratiosin 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 out21-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 doesnot have clinical evidence of hirsutism or other signs of androgen excess • Total testosteroneconcentration 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(Figure4) • 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 androgenexcess, principally hirsutism • Blood sample for serum 17-hydroxyprogesteroneconcentration to rule-out 21-hydroxylase-deficient nonclassical adrenal hyperplasia • Obesity in conjunction with anovulation and androgen excess • Increase furtherone's suspicion of PCOS

25. Diagnostic Approach • In cases in which the clinical diagnosis is not clear • Chronic anovulation withouthirsutism • 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-dependentdiabetes 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 womenwith PCOS • 1.Regular withdrawal bleeding • 2. Reduction in the risk of endometrial hyperplasia or cancer because ofprogestin 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 noeffect on hirsutism was seen with metformin

36. Treatment • Common 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 numberof 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 insubsequent 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 clomiphenecitrate

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 otherinfertility factors • Blend with unexplained infertility • Intrauterine insemination is added • If lack of pregnancy despite multiple cycles of ovulation induction andintrauterine 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