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 (www.utahfertilitycenter.com)

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

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

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

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%

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

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

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

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

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

Hyperandrogenism Clinical hyperandrogenism: Hirsutism: excessive growth of terminal hair in women in a male like pattern Acne 10 -15% Alopecia: weak marker unless associated with anovulation 5%

Modified Ferriman-Gallwey scoring Androgen Excess and PCOS Society

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

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.

Ultrasonographic Polycystic ovaries

Ultrasonographic Polycystic ovaries

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

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

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

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

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

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

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

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

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

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

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)

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

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

Pathogenesis

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

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

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

Criteria for the metabolic syndrome in women with PCOS

Case Infertility Irregular periods Hirsutism

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

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

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

Metformin and weight reduction Metformin vs placebo Difference in BMI -0.04 (-0.29 - +0.22) Tang et al, Cochrane Database Syst Rev. 2009

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. 2009.

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

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

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

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

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

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 000056, 2000

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

Metformin: Ovulation induction Legro et al, NEJM, 2007

Laparoscopic ovarian drilling(LOD) Ovulation rate : 54 - 95% Pregnancy rates: 28 - 78 % Need for ovulation induction agent: 3-6 months 17.5 - 22.6% 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

LOD versus Gonadotropins Odds ratio 95% CI Ongoing pregnancy 1.08 0.69 - 1.71 Live birth 1.04 0.59 - 1.85 Miscarriage rate 0.81 0.36 - 1.86 Multiple pregnancy 0.13 0.03 - 0.52 Farquhar et al Cochrane Database Syst Rev. 2007

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