1. Polycystic ovarian syndrome
Ahmad O. Hammoud MD, MPH
Assistant Professor
Obstetrics and Gynecology
Reproductive Endocrinology and Infertility
University of Utah
Medical Director
Utah Center for Reproductive Medicine (

2. Case
A 32-year-old woman was evaluated because of oligomenorrhea and difficulty becoming pregnant
Menarche had occurred at 12 years of age and menses were regular until the patient began taking oral contraceptives at 20 years of age

3. Case
At 25 years of age, she discontinued oral contraceptives and irregular menstrual cycles developed, ranging from 31 to 51 days, with menstrual flow of 7 days' duration.
Between the ages of 28 and 32 years, she had unprotected coitus with her husband but did not conceive
She reported frequent acne and facial hair that she removed manually

4. Positive elements Young women Irregular periods Inability to conceive
Acne and increased facial hair

5. Polycystic ovarian syndrome
In 1935, Stein and Leventhal published a paper on their findings in seven women with
Amenorrhea
Hirsutism
Obesity
Characteristic polycystic appearance of the ovaries
The most common reproductive endocrinopathy of women during their childbearing years: 4% to 8%

6. Consensus on diagnostic criteria for PCOS
1992 NIH criteria 1 and 2
Chronic anovulation
Clinical and/or biochemical signs of hyperandrogenism
Exclusion of other etiologies
NIH,1992
Rotterdam 2003 criteria 2/3
Oligo- and/or anovulation
Clinical and/or biochemical signs of hyperandrogenism
Polycystic ovaries on ultrasound
Exclusion of other etiologies
ESHRE and ASRM 2003

7. Consensus on diagnostic criteria for PCOS
The 2003 criteria introduced the “Non-NIH PCOS”
Hyperandrogenism but ovulatory
Non hyperadrogenic with anovulation
Criteria
NIH PCOS
Non-NIH PCOS
Anovulation +
Hyperandrogenism
PCO

8. Consensus on diagnostic criteria for PCOS
Androgen Excess Society Guidelines 2006:
PCOS is a hyperandrogenic disorder: Hirsutism or elevated free testosterone and
PCO morphology 75% or
Ovulatory dysfunction
Exclusion of other etiologies
Azziz et al, JCEM, 2006

9. Consensus on diagnostic criteria for PCOS
Rotterdam criteria
Criteria
NIH PCOS
Non-NIH PCOS
Anovulation +
Hyperandrogenism
PCO
Androgen Excess Society

10. Menstrual dysfunction
Oligomenorrhea fewer than nine menses per year or amenorrhea
Anovulatory cycles may lead :
Dysfunctional uterine bleeding
Decreased fertility
Endometrial hyperplasia
Usually start at menarche and the postpubertal phase

11. Hyperandrogenism Clinical hyperandrogenism:
Hirsutism: excessive growth of terminal hair in women in a male like pattern
Acne %
Alopecia: weak marker unless associated with anovulation 5%

12. Modified Ferriman-Gallwey scoring
Androgen Excess and PCOS Society

13. Hirsutism Visual scoring: modified Ferriman-Gallawey score 6-8
50% of women with unwanted hair score< 5 had PCOS
Less prevalent in East Asian or in adolescence
Souter et al , Am J Obstet Gynecol. 2004

14. Hyperandrogenism Biochemical hyperandrogenism
Total Testosterone is not a sensitive marker
Free testosterone T: equilibrium dialysis or calculated:
Isolated elevations in DHEA-S 10% or elevated Androstenedione 10%
20-40% will have normal androgens.

15. Ultrasonographic Polycystic ovaries

16. Ultrasonographic Polycystic ovaries

17. Ultrasonographic Polycystic ovaries
Presence of 12 or more follicles in each ovary measuring 2 ± 9 mm or
Increased ovarian volume >10 ml
PCO is present in 75% of women with PCOS
PCO is present in 22% of women in the general population
Azziz et al, JCEM, 2006
Farquhar el al, Aust N Z Obstet Gynecol 1994

18. Ultrasonographic Polycystic ovaries
This definition does not apply to women taking OCP
Only one ovary fitting this definition is sufficient
If there is a dominant follicle >10 mm or a corpus luteum, the scan should be repeated the next cycle
The presence of an abnormal cyst or ovarian asymmetry necessitates further investigation

19. Other manifestation Acanthosis nigricans is common in obese PCOS
neck
axilla
area beneath the breasts
Intertrigenous areas
elbows and knuckles
Women with PCOS may experience increased skin oiliness resulting from excessive stimulation of the pilosebaceous unit by increased androgen production

20. Case What about our patient: 1-Irregular periods
2-Clinical hyperandrogenism
3-No ultrasound
She may have PCOS if there is no other abnormalities.

21. Obesity Obesity : 50% PCOS
Increased waist-to-hip ratio, or ‘‘android’’
UK, n = 1741
USA,n= 398

22. Insulin resistance Insulin resistance: 50% in obese and non obese
A defect in the insulin signaling pathway in muscle and adipose tissue
No validated clinical test

23. ADA criteria for the diagnosis of diabetes mellitus, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG)
IFG
IGT 
Diabetes 
Fasting glucose 
≥110 to 125
≥126 
2-hour glucose
≥140 and <200
≥200 
HbA1 C
≥6.5
Random glucose
>200 with symptoms

24. LH and LH/FSH ratio
Both the absolute level of circulating LH and its relationship to FSH levels are significantly elevated in PCOS
LH levels should not be considered necessary for the clinical diagnosis of PCOS
Useful as a secondary parameter especially in lean women with amenorrhea, or in research

25. Exclusion of related disorders
Initial work-up may also include :
FSH and estradiol E2 : hypogonadotropic hypogonadism or premature ovarian failure
Prolactin to exclude hyperprolactinemia
NB: many hyperandrogenic patients may have prolactin levels slightly above normal
TSH: exclude hypothyroidism

26. Exclusion of related disorders
Non-classic adrenal hyperplasia
Basal morning 17-hydroxyprogesterone
Cut-off values 2 and 3 ng/ml
Values in excess of 3 ng/mL warrant further evaluation by an ACTH stimulation test
Cushings syndrome:
24-hour urinary free cortisol
A value in excess of 3 times the normal assumes the diagnosis
Intermediate values warrant a repeat of the test

27. Exclusion of related disorders
Ovarian hyperthecosis
Obese and exhibit acanthosis nigricans , severe Hirsutism, virilizing signs
Nests of luteinized theca cells scattered throughout the stroma
The ovary is enlarged and of an extremely firm texture
The absence of follicle formation
High serum androgen concentrations
Syndromes of severe insulin resistance (e.g. for the diagnosis of the hyperandrogenic insulin-resistant acanthosis nigricans or HAIRAN syndrome)

28. Exclusion of related disorders
Androgen-secreting neoplasm
May arise from the ovary and the adrenal gland
Best predictor is clinical presentation
Total T and DHEA-S .
Neoplasm should be considered if testosterone >200 ng/dL and DHEA-S >700 ng/ mL
High dose exogenous androgens

29. Case Test to order on our patient: Pelvic ultrasound
FSH, Estradiol day 3 of cycle
Prolactin, TSH
17 OH progesterone, free and totalTestosterone, DHEAS if severe or rapid hirsutism.
Lipid profile and 2 hour glucose tolerance test

30. Pathogenesis

31. Cardiovascular Coronary and other vascular disease
Hypertension
Develops in some women with the polycystic ovary syndrome during their reproductive years
Reduced vascular compliance and vascular endothelial dysfunction
Coronary and other vascular disease
Hypertriglyceridemia, increased levels of very low- density lipoprotein and low-density lipoprotein cholesterol, and decreased levels of high-density lipoprotein cholesterol

32. Obstructive sleep apnea
Cannot be explained by obesity alone
The risk of sleep-disordered breathing was increased by a factor of 30
Insulin resistance appears to be a stronger predictor of sleep-disordered breathing than is age, body mass index, or the circulating testosterone concentration

33. Association with cancer
Increased prevalence of endometrial hyperplasia and carcinoma
Attributed to the persistent stimulation of endometrial tissue by estrogen (mainly estrone) without the progesterone
Breast and ovarian cancer have been variably associated with the polycystic ovary syndrome

34. Criteria for the metabolic syndrome in women with PCOS

35. Case
Infertility
Irregular periods
Hirsutism

36. Treatment Insulin resistance and glucose intolerance
Hirsutism and acne
Oligomenorrhea and amenorrhea
Ovulation Induction

37. First line therapy
Weight reduction is important in treating overweight patients
No unique weight-loss regimen targets excess adiposity specific to the syndrome: Hypocaloric diet
Modest reductions in body weight (2 to 7 percent) through lifestyle modification have been associated with reductions in androgen levels and improved ovulatory function

38. Metformin Inhibit hepatic glucose production
Started at 500mg daily , titrating up to 500mg three time daily over 7-10 days.
Max 1000 mg BID
Outcome within 2-4 months

39. Metformin and weight reduction
Metformin vs placebo
Difference in BMI ( )
Tang et al, Cochrane Database Syst Rev. 2009

40. Metformin Adverse effects : Nausea and diarrhea 10-15% of patients
Lactic acidosis
Troglitazone: report of fatal liver toxicity
Pioglitazone: (Vs Placebo) little evidence of effect on any outcome , It does induce weight gain
Tang et al, Cochrane Database Syst Rev

41. Hirsutism and acne Oral Contraceptives:
Suppress LH and androgen production
Increase SHBG: reducing free testosterone
The choice of OCP is controversial
Levonorgesterel and Norethindrone
Norgestimate and desogestrel
Drosperinone
Potential adverse effects on insulin resistance, glucose tolerance, vascular reactivity, and coagulability

42. Hirsutism and acne
Spironolactone: has moderate antiandrogenic effects : 100 to 200 mg daily.
Caution when used with drosperinone
Antiandrogens :
Cyproterone acetate competitively inhibits the binding of testosterone and 5a-dihydrotestosterone,
Flutamide is a potent nonsteroidal antiandrogen that is effective in the treatment of hirsutism. hepatocellular dysfunction
Finasteride inhibitor of type 2 5α reductase to treat hirsutism

43. Oligomenorrhea and amenorrhea
PCOS : 36% endometrial hyperplasia:25% cytologic atypia
Cyclic progestin or oral contraceptives
Endometrial biopsy in patients who have not had menstrual bleeding for 3 month or longer
Use of ultrasonography to determine endometrial thickness: 7mm

44. Ovulation induction: Clomiphene
Start 50 mg daily on day 2 ,3,4 or 5 for five days
If failed , increased to 100 daily , followed by 150 daily
Ovulation monitoring
Temperature charting
Serum Progesteorne (day 21)
LH kit
Transvaginal ultrasound

45. Clomiphene: Step-up protocol
Hurst et al, Am J Obstet Gynecol. 2009

46. Clomiphene citrate Clinical outcome 60 – 85 % will ovulate
30-40% will become pregnant
Cumulative pregnancy rate over 12 month: 70%
Hughes et al. Cochrane Database Sys Rev CD , 2000

47. Clomid resistant patients
Dexamethasone
Letrozole (Femara) or other aromatase inhibitors
Tamoxifen
Gonadotropins

48. Metformin: Ovulation induction
Legro et al, NEJM, 2007

49. Laparoscopic ovarian drilling(LOD)
Ovulation rate : %
Pregnancy rates: %
Need for ovulation induction agent:
3-6 months %
Failure rates: 20-30%
Obese
Hyperandrogenism
Infertility of more than 3 years
Unlu C, Atabekoglu CS.Curr Opin Obstet Gynecol. 2006
Amer et al Hum Reprod 2004

50. LOD versus Gonadotropins
Odds ratio
95% CI
Ongoing pregnancy
1.08
Live birth
1.04
Miscarriage rate
0.81
Multiple pregnancy
0.13
Farquhar et al Cochrane Database Syst Rev. 2007

51. Case Short term treatment : Diet and weight loss Clomid ± Metfromin
Long term treatment
Metformin
OCP