1. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. Terms of Use  The In the Clinic ® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for- profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets constitutes copyright infringement.

2. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. * For Best Viewing: Open in Slide Show Mode (Click on in bottom right) or From the View menu, select the Slide Show option

3. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. in the clinic The Polycystic Ovary Syndrome

4. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. Who is at risk for PCOS? Factors that seem to increase risk  Family history  BMI >30 kg/m 2  >⅓ w/PCOS obese  ≈⅓ have impaired glucose tolerance  ≈20% w/ polycystic ovaries asymptomatic

5. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. What symptoms and signs should prompt clinicians to consider PCOS?  Hyperandrogenemia  Hirsutism, acne, alopecia, acanthosis nigricans  Menstrual irregularity  Infertility  Obesity (particularly abdominal)  Other signs and symptoms: Hypertension, hyperlipidemia, CVD; obstructive sleep apnea; depression

6. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. ESHRE/ASRM* criteria  First: exclude other medical conditions that cause irregular menstrual cycles and androgen excess  Then: confirm ≥2 of following present:  Oligoovulation or anovulation  Elevated levels of circulating androgens or clinical manifestations of androgen excess  Polycystic ovaries on ultrasonography *European Society for Human Reproduction and Embryology and American Society for Reproductive Medicine  NOTE: Polycystic ovaries alone ≠ PCOS  Most obese women w/oligomenorrhea have PCOS

7. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. What is the typical menstruation pattern in PCOS?  Oligomenorrhea  Typically ≥35 days between cycles  Only 4 to 9 periods/year  Occasionally, menstruation cycle more normal, but menses very light  Some w/PCOS do not menstruate at all  Consider PCOS: if menstrual irregularity began at menarche and continued >1 yr  Consider other diagnoses: if menstrual irregularity began years after puberty or suddenly worsened

8. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. How does PCOS affect fertility?  ≈90% anovulation infertility PCOS-related  No luteinizing hormone surge, so ovulation doesn’t occur  Pregnancy can often be achieved  With lifestyle modifications (weight loss), drug treatments, or surgical approaches to infertility  Infertility workup of both partners should precede drug therapy for infertility  Refer women w/PCOS and fertility concerns to specialist PCOS increases risk for pregnancy complications  Gestational diabetes, pregnancy-induced high BP and preeclampsia, preterm labor  Miscarriage (risk unclear)

9. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. Which lab tests are useful in diagnosis?  Serum testosterone  Free (bioavail) and total testosterone levels usually increased  Androstenedione  May have slightly better sensitivity in US-proven PCOS  LH, FSH  High normal LH & normal FSH with ratio >2 consistent with Dx  Serum prolactin  May be slightly elevated  Dehydroepiandrosterone (DHEA)  Often increased; if markedly so, consider adrenal neoplasia  Fasting glucose level and glucose tolerance test  Impaired glucose tolerance in ⅓ with PCOS  Fasting cholesterol, triglycerides, HDL (for assessment of CV risk)

10. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. Is an imaging study documenting cystic ovaries necessary for diagnosis?  Yes, unless diagnosis already clear  Polycystic ovary morphology on US: 1 of 3 criteria  Imaging advances allow improved measurement capabilities and resolution  Criteria defining polycystic ovaries:  ≥12 follicles in each ovary (2 to 9 mm diameter)  Or increased ovarian volume (>10 cm 3 )

11. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. What other diagnosis should clinicians consider?  Late-onset congenital adrenal hyperplasia  Androgen-producing neoplasms  Cushing syndrome  Hyperprolactinemia  Pregnancy  Hypothyroidism Alternate causes of oligo/amenorrhea  Chronic illness, stress, excessive exercise  Eating disorder, poor nutrition, low weight  Thyroid dysfunction, estrogen-secreting & pituitary tumor, illegal use of anabolic steroids

12. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1.  Consider PCOS: irregular menstruation, infertility, obesity, and hyperandrogenemia  Exclude other conditions causing similar symptoms  If androgen levels very high: ? adrenal/ovarian neoplasia  Make diagnosis: if ≥2 of following are present:  Oligoovulation or anovulation  Elevated levels of circulating androgens or clinical manifestations of androgen excess  Polycystic ovaries on ultrasonography  Most important part of history: symptom onset  If symptoms began years after puberty or have suddenly worsened, other diagnoses more likely CLINICAL BOTTOM LINE: Diagnosis...

13. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. What is the role of diet in the management of patients with PCOS?  Loss of abdominal fat helps restore ovulation  Just 2%-5% decrease in total body weight improves  Menstrual regularity and ovulatory function  Hirsutism  Insulin sensitivity  Response to fertility medication  Refer patients to dietician for dietary modifications

14. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. When is drug therapy appropriate, and what are available options?  Oral contraceptive  Regularizes menstruation, reduces hyperandrogenism; improves body composition and insulin sensitivity  Spironolactone  Improves hyperandrogenic manifestations  Cyproterone acetate  Potent antiandrogen agent; unavailable in U.S.  Finasteride  Potent antiandrogen agent  Eflornithine  Slows hair growth everywhere or just on face  Metformin  Improves ovulation & glucose tolerance; may reduce testosterone

15. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. When fertility is the primary concern, what treatment options are available?  Lifestyle modifications for weight loss  Clomiphene citrate  Estrogen-like hormone increases FSH and LH levels and improves ovulation chances  Clomiphene + metformin  Benefit of adding insulin sensitizer uncertain  Gonadotropins, if clomiphene-insensitive  Improves fertility, but often results in follicle overproduction  Laparoscopic ovarian surgery  Doesn’t trigger ovarian hyperstimulation

16. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. What are treatment options for hirsutism?  Local measures: shaving, waxing, lasers, electrolysis  Topical eflornithine cream  Retards hair growth  Oral contraceptives  May reduce hirsutism and acne  Cyproterone (antiandrogen agent) + oral contraceptives  Effective but reduces libido, causes liver function changes  Insulin-sensitizing agents  Not recommended for cosmetic purposes  Best result: combine systemic + nonsystemic therapies  Hirsutism slow to respond to therapy (≥6 months)

17. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. What are the risks for prolonged amenorrhea?  Elevated estrogen levels cause endometrial proliferation  Increases risk for endometrial carcinoma  Disorders with PCOS that  endometrial carcinoma risk:  Obesity  Hyperinsulinemia  Diabetes  Anovulatory cycles  High androgen levels  >3 months amenorrhea: consider progesterone challenge  ≥1 year amenorrhea In women with PCOS: ultrasound to measure endometrial thickness and possible biopsy if endometrium >14 mm

18. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1.  Cyclic progestin  Oral contraceptives with combo estrogen + progestin  Insulin-sensitizing drugs  Weight loss What interventions minimize the risks of prolonged amenorrhea?

19. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. How should clinicians manage follow-up care for women with PCOS?  Check menstrual pattern every 3-12 months  If menses >3 mo apart, initiate Provera challenge and/or oral contraceptive  Check hyperandrogenic symptoms every 3-6 months  Document acne severity and hirsutism, including topical measures  Ask about pregnancy plans as clinically appropriate  Planning needed so patient not on contraindicated drugs in pregnancy  Measure weight, waist circumference, and blood pressure regularly

20. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. Laboratory tests  Order fasting glucose or 2-hr glucose tolerance test annually  Check fasting total cholesterol, triglyceride, and HDL cholesterol levels every 1-3 years  Order Liver function tests only if patient is receiving a medication known to affect liver function  Nondrug therapy  Assess patient readiness to make changes in diet and/or exercise as clinically appropriate  Drug therapy  Check for adverse events as clinically appropriate

21. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1. Does pregnancy in women with PCOS carry specific risks?  Increased maternal risk for…  Gestational diabetes  Preeclampsia (possibly)  Hyperstimulation syndrome (if gonadotropins used)  Increased fetal risk for…  Preterm birth  Admission to neonatal ICU  Reduce risk factors before conception  Closer follow-up and more fetal monitoring needed during pregnancy

22. © Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (3): ITC2-1.  Focus on treating symptoms  If patient is overweight, encourage weight loss  If patient is not seeking pregnancy: consider oral contraceptives, sometimes combined with antiandrogen agent  If patient is seeking pregnancy: clomiphene commonly used  Insulin sensitizer (metformin) may also be beneficial  If patient is pregnant: beware increased complication risk  Women should report prolonged amenorrhea: so that a progesterone challenge or endometrial biopsy can be done CLINICAL BOTTOM LINE: Treatment...