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Polycystic Ovary Syndrome (PCOS)                Polycystic Ovary Syndrome (2007 pdf file)         REF: ACP PIER 2007

Study all women with oligomenorrhea or amenorrhea. Consider PCOS for women in whom menstrual irregularity began at menarche and continued for >1 year. If symptoms began years after puberty or have suddenly worsened, consider other diagnoses more likely. Consider prolonged amenorrhea in women with PCOS as a risk factor for endometrial carcinoma. Consider PCOS in Women in whom menstrual irregularity began at menarche and continued for >1 year Women who present with infertility. Investigate patients with anovulatory infertility for PCOS. Women who show evidence of excess androgen. Investigate the likelihood of PCOS in women with hirsutism or acne that began with puberty. Women who present with central obesity. Note that an increased waist-to-hip ratio should lead to a directed history and physical exam on the other aspects of PCOS. Obtain serum androgen measurements in confirming the hyperandrogenemic state and for ruling out androgen-producing neoplasms. Measure total or free (bioavailable) testosterone level and possibly androstenedione level. Consider measuring gonadotropin level in some patients Measure LH and FSH levels, if necessary, to rule out other causes of amenorrhea or infertility. Obtain an ovarian ultrasound unless the diagnosis of PCOS is already clear. Perform ultrasound visualization of the ovaries to help make the diagnosis of PCOS. Look for evidence of insulin resistance. Obtain fasting glucose and serum lipid levels. Consider obtaining insulin level and a 2-hour oral glucose tolerance results as well. Consider other diagnoses in cases of severe hyperandrogenemia. If there is evidence of severe masculinizing features or exceedingly high androgen levels (e.g., testosterone >5.0 nmol/L [143 ng/dL], DHEAS >18.9 umol/L [700 µg/dL]), consider other diagnoses. Consider other causes of infertility and menstrual irregularities if there is no other evidence of PCOS. If symptoms do not begin at menarche or are not associated with hyperandrogenemia, exclude other diagnoses (e.g., hypothyroidism, hyperprolactinemia, late-onset congenital adrenal hyperplasia).

Diagnosis Study all women with oligomenorrhea or amenorrhea. Consider PCOS in women who present with infertility. Consider PCOS in women who show evidence of excess androgen. Consider women who present with central obesity to be at risk for PCOS. Obtain serum androgen measurements in confirming the hyperandrogenemic state and for ruling out androgen-producing neoplasms. Consider measuring gonadotropin level in some patients Obtain an ovarian ultrasound unless the diagnosis of PCOS is already clear. Look for evidence of insulin resistance. Consider other diagnoses in cases of severe hyperandrogenemia. Consider other causes of infertility and menstrual irregularities if there is no other evidence of PCOS.

History Menstrual irregularity Irregular menses begin at menarche, and a normal pattern is never established; chronic anovulation results in oligomenorrhea or amenorrhea and the absence of ovulatory symptoms Hirsutism First appears during early menarchal years and gradually worsens; the Ferriman–Gallwey scoring system may be used to document the degree of hirsutism; the psychosocial implications are important in developing treatment goals Acne Begins at menarche and may be more severe than in women without PCOS Family history There is a strong familial association both with PCOS and other manifestations of insulin resistance (e.g., diabetes, hypertension, CAD) Other cardiovascular risk factors It is essential to elicit other cardiovascular risk factors to determine overall morbidity risk Pregnancy history and desire for pregnancy in future n addition to the possibility of requiring assistance to become pregnant, women with PCOS are more likely to have their pregnancies complicated by gestational diabetes and hypertension (7; 8) The woman's desire for pregnancy affects treatment choice

Physical exam Blood pressure There is controversy as to whether there is an increased risk of hypertension in these women independent of body weight; nonetheless, it is important for assessing cardiovascular risk (9) Body mass index Waist-to-hip ratio A waist-to-hip ratio >0.85 and a waist circumference >100 cm are associated with cardiovascular morbidity (10) Hirsutism Location and severity of hirsutism should be recorded; ethnicity must be taken into account when assessing a normal pattern; generally, terminal hair on the sternum, upper abdomen, and upper back suggest hyperandrogenemia compared with hair on the upper lip and areolae Acne Severity and location should be documented Acanthosis nigricans Raised, velvety brown discoloration on the nape of neck, axilla, knuckles, and elbows is seen in all hyperinsulinemic syndromes Alopecia Although severe alopecia is uncommon, male-pattern baldness may be detected CAD = coronary artery disease; PCOS = polycystic ovary syndrome.

Laboratory and Other Studies for PCOS Serum testosterone Free (bioavailable) and total testosterone levels should be measured (13) Androstenedione Not as common a test but may have slightly better sensitivity in ultrasound proven PCOS LH, FSH High normal LH and normal FSH with ratio >1 consistent with diagnosis Serum prolactin May be slightly elevated in PCOS DHEAS Although usually increased, not helpful for diagnosis; if markedly increased, consider adrenal neoplasm Fasting glucose level and glucose tolerance test Approximately 50% of women with glucose intolerance have a normal fasting glucose level and an elevated level 2 hours after a 75-g glucose load. (19) However, the clinical significance and treatment benefits of isolated postprandial hyperglycemia require further study Fasting insulin:glucose ratio Insulin levels and insulin:glucose ratios are of interest but not yet helpful from either a diagnostic or therapeutic point of view (17) Fasting cholesterol, triglycerides, and HDL cholesterol For further assessment of cardiovascular risk DHEAS = dehydroepiandrosterone sulfate; HDL = high-density lipoprotein; PCOS = polycystic ovary syndrome

Differential Diagnosis of PCOS Late-onset congenital adrenal hyperplasia May have same clinical presentation as women with PCOS; may be more virilized than one would expect for PCOS and may have short stature; family history may be present A rare condition compared with PCOS; a screening 17-hydroxyprogesterone level may suffice; the benefits of diagnosis (other than symptom management) do not necessarily outweigh the costs and inconvenience of performing ACTH-stimulation tests on all women with PCOS Androgen-producing neoplasms Symptoms do not typically occur at menarche; they tend to be more severe and are progressive over a short period of time; tumors may be ovarian or adrenal in origin Androgen levels are extremely high (testosterone >5.0 nmol/L [143 ng/dL], DHEAS >18.9 µmol/L [700 µg/dL]) (14; 15); radiographic investigations are required to definitively rule out neoplasm Cushing's syndrome May present at any time, although usually in adulthood (not adolescence); may be slowly progressive; has symptoms similar to PCOS in mild cases. Best test for screening is a 24-hour urinary free cortisol test; if this is not possible, an overnight dexamethasone-suppression test can be performed Hyperprolactinemia Galactorrhea may or may not be present; does not usually present at menarche; hyperandrogenemic symptoms are not prominent Slightly high prolactin levels are seen with PCOS; if elevated, an MRI of the pituitary sella is warranted Pregnancy The possibility of pregnancy must be considered in all women with amenorrhea bHCG should be performed Hypothyroidism Hypothyroidism can lead to oligomenorrhea and/or amenorrhea and infertility Screen with TSH ACTH = adrenocorticotropic hormone; DHEAS = dehydroepiandrosterone sulfate; MRI = magnetic resonance imaging; PCOS = polycystic ovary syndrome; TSH = thyroid-stimulating hormone.

Non-drug Therapy Encourage weight loss through diet and exercise. Recommend local measures for hair removal when hirsutism is the major complaint. Drug Therapy Use drug therapy for hirsutism and acne if local measures do not provide acceptable results or if hirsutism is moderate to severe. Start with either oral contraceptives alone or in combination with an antiandrogen agent, depending on symptom severity and patient preference. Consider topical treatment with eflornithine to slow hair growth and reduce the frequency of the need for hair removal. Use drug therapy when there is anovulation that causes oligomenorrhea or amenorrhea after pregnancy has been excluded. Use an oral contraceptive in most women who do not desire pregnancy. Consider an insulin sensitizer such as metformin, particularly if there is evidence of insulin resistance. Tell women explicitly of the risks involved with becoming pregnant while using insulin sensitizers. When fertility is the primary concern, use agents that restore or induce ovulation. Refer patients to a reproductive endocrinologist or infertility specialist to induce ovulation. Drug Therapy for Polycystic Ovary Syndrome Metformin Insulin sensitizer (primarily at the liver) Dosage: 500-1000 mg bid Benefits: Improves glucose tolerance, promotes weight loss, may restore menstrual regularity, may improve clinical response to Clomid (clomiphene) in obese women; improves health-related quality of life, emotional distress, and sexuality; may also reduce testosterone levels Side Effects: GI upset, potential for lactic acidosis (although this population usually not at risk), long-term consequences not known Note: Most, but not all, evidence suggests a benefit with metformin ; all studies have been small, have had a short follow-up (6 months), have included only obese patients, and/or have lacked placebo control; larger long-term studies are necessary; fertility may be restored, so it is important that appropriate contraception is used if pregnancy is not desired Oral contraceptive Reduces ovarian androgen production, decreases LH production Dosage: Depends on formulation Benefits: Provides menstrual regularity and reduces hyperandrogenism manifestations while providing contraception; long-term benefits in PCOS may include improved body composition and insulin sensitivity and lower free testosterone levels compared with non-users (35) Side Effects: Same as with all oral contraceptives; more breakthrough bleeding occurs with triphasic preparations; there is potential for worsening insulin resistance (36) Note: Choose oral contraceptives with the least androgenicity; preparations that combine the antiandrogen cyproterone acetate with ethinyl estradiol are available in some countries (not the U.S.) Spironolactone Androgen-receptor inhibitor Dosage: 50–200 mg/d Benefits: Results in improvement in manifestations of hyperandrogenemia Side Effects: Hyperkalemia, breast tenderness, breakthrough bleeding; contraception is required because there is a potential for feminization of male infants Cyproterone acetate Androgen-receptor inhibitor Dosage: 25-50 mg/d on day 1-10 of menstrual cycle or 2 mg/d in combination with oral contraceptive (Diane) Benefits; Potent antiandrogen agent Side Effects: Abnormal LFTs, delayed menses for 2-3 days if on oral contraceptive; contraception is required because there is a potential for feminization of male infants Note:Not available in U.S. Finasteride 5-alpha-reductase inhibitor that reduces peripheral conversion of testosterone into DHT (active metabolite on the skin) Dosage: 5 mg/d Benefits: Potent antiandrogen agent Side Effects: Contraception is required because there is a potential for feminization of male infants Flutamide Nonsteroidal androgen-receptor inhibitor that has a possible effect on androgen synthesis Dosage: 250 mg bid Benefits: Reduces hirsutism and also may restore ovulation and improve lipid profile (37) Side Effects: Hepatotoxicity; Contraception is required because there is a potential for feminization of male infants Note: Long-term placebo-controlled trials are not yet available Eflornithine Blocks ornithine decarboxylase (required for growth and differentiation of the hair follicle) Dosage: Topical cream bid Benefits: Slows hair growth Side Effects: Acne, pseudofolliculitis barbae Rosiglitazone /Pioglitazone Insulin sensitizer (primarily at the liver) Dosage: 4 mg/d Rosiglitazone; 30 mg/d Pioglitazone Side Effects: No hepatic injury reported; tends to cause weight gain; may have adverse effect on lipids Note: Limited experience in PCOS to date bid = twice daily; DHT = dihydrotestosterone; GI = gastrointestinal; PCOS = polycystic ovary syndrome.

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