I POLYCYSTIC OVARY SYNDROME ^273 ^567

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyper- androgenism, ovulatory dysfunction, and polycystic ovaries. Its etiology remains unknown, and treatment is largely symptom based and empirical.

Definition and Diagnostic Criteria

Polycystic ovary syndrome is a group of symptoms for which the definition has been somewhat controversial. In 1990, the National Institutes of Health (NIH) developed diagnostic criteria for PCOS, and subsequently revised criteria were proposed by the Rotterdam PCOS Consensus Workshop Group in 2003 and the Androgen Excess Society in 2006 (Table 4-4). The rationale behind the newer recommendations is that PCOS encompasses a broader clinical presentation than that defined by the NIH criteria. Critics of the Rotterdam criteria point out that polycystic ovaries demonstrated on ultrasonography are a nonspecific finding and may be found in women without endocrine or metabolic abnormalities. It should be noted that insulin resistance and elevated ratios of luteinizing hormone to follicle­stimulating hormone have been seen in many women with PCOS, but they are not part of any of the diagnostic criteria. In addition, medical conditions that can mimic and be confused with PCOS, such as nonclas- sical (late-onset) congenital adrenal hyperplasia, hyperprolactinemia, and androgen-secreting neoplasms, need to be ruled out (Box 4-8).

The suggested diagnostic evaluation for PCOS is included in Box 4-9. Although patients generally present to the obstetrician-gynecologist reporting symptoms, such as menstrual irregularity, infertility, or hirsutism,

Table 4-4. Recommended Diagnostic Schemes for Polycystic Ovary Syndrome by Varying Expert Groups ^

Abbreviations: R, required for diagnosis; NR, possible diagnostic criteria but not required to be present.

*All criteria recommend excluding other possible etiologies of these signs and symptoms and more than one of the factors present to make a diagnosis.

^tDunaif A, Givens JR, Haseletine FP, Merriam GR, editors. Polycystic ovary syndrome. Boston (MA): Blackwell Scientific Publications; 1992.

¹Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Fertil Steril 2004;81:19-25.

§Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. Androgen Excess Society. J Clin Endocrinol Metab 2006;91:4237-45.

IlHyperandrogenism may be either the presence of hirsutism or biochemical hyperandrogen- emia.

Reprinted from Polycystic ovary syndrome. ACOG Practice Bulletin No. 108. American College of Obstetricians and Gynecologists. Obstet Gynecol 2009;114:936-49.

a critical element of caring for the patient with PCOS is addressing the sub­stantial metabolic sequelae associated with the condition. Patients often develop diabetes or cardiovascular disease and have dyslipidemia; thus, all patients with PCOS should be screened for metabolic abnormalities. Patients also have an increased risk of endometrial carcinoma related to anovulation and unopposed estrogen.

Box 4-8. Factors to Consider in the Differential Diagnosis of Polycystic Ovary Syndrome ^

Androgen-secreting tumor

Exogenous androgens

Cushing syndrome

Nonclassical congenital adrenal hyperplasia

Acromegaly

Genetic defects in insulin action

Primary hypothalamic amenorrhea

Primary ovarian failure

Thyroid disease

Prolactin disorders

Reprinted from Polycystic ovary syndrome. ACOG Practice Bulletin No. 108. American College of Obstetricians and Gynecologists.

Box 4-9. Suggested Evaluation for Patients With Polycystic Ovary Syndrome ^

Physical Examination

• Blood pressure

• Body mass index (calculated as weight in kilograms divided by height in meters squared): 25-29.9 = overweight; 30 or greater = obese

• Waist circumference: value greater than 35 in. = abnormal

• Presence of stigmata of hyperandrogenism and insulin resistance: acne, hirsutism, androgenic alopecia, acanthosis nigricans

Laboratory

• Documentation of biochemical hyperandrogenemia: total testosterone and sex hormone-binding globulin or bioavailable and free testosterone

• Exclusion of other causes of hyperandrogenism

— Thyroid-stimulating hormone levels (thyroid dysfunction)

— Prolactin (hyperprolactinemia)

(continued)

Box 4-9. Suggested Evaluation for Patients With Polycystic Ovary Syndrome (continued)

• Exclusion of other causes of hyperandrogenism (continued)

— 17-hydroxyprogesterone (nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency)

Random normal level less than 4 ng/mL or morning fasting level less than 2 ng/mL

— Consider screening for Cushing syndrome and other rare disorders, such as acromegaly

• Evaluation for metabolic abnormalities: 2-hour oral glucose tolerance test (fasting glucose less than 110 mg/dL = normal; 110-125 mg/dL = impaired; greater than 126 mg/dL = type 2 diabetes mellitus) followed by 75 g oral glucose ingestion and then 2-hour glucose level (less than 140 mg/dL = normal glucose tolerance; 140-199 mg/dL = impaired glucose tolerance; greater than 200 mg/dL = type 2 diabetes mellitus)

• Fasting lipid and lipoprotein level: total cholesterol greater than 200 mg/ dL = abnormal, high-density lipoproteins less than 50 mg/dL = abnormal; triglycerides greater than 150 mg/dL = abnormal

Ultrasound Examination

• Determination of polycystic ovaries: in one or both ovaries, either 12 or more follicles measuring 2-9 mm in diameter, or increased ovarian volume (greater than 10 cm³).

• Identification of endometrial abnormalities

Optional Tests to Consider

• Gonadotropin determinations to determine cause of amenorrhea

• Fasting insulin levels in younger women, those with diagnostic signs of insulin resistance and hyperandrogenism, or those undergoing ovulation induction

• 24-hour urinary free-cortisol excretion test or a low-dose dexametha­sone suppression test in women with late onset of polycystic ovary syn­drome symptoms or stigmata of Cushing syndrome

Modified from Polycystic ovary syndrome. ACOG Practice Bulletin No. 108. American College of Obstetricians and Gynecologists. Obstet Gynecol 2009;114:936-49.

Management

The treatment of patients with PCOS often depends on the presenting signs and symptoms.

Obesity

In overweight and obese women, weight loss can result in spontaneous return of menses, improved pregnancy rates, decreased hirsutism, and improved glucose and lipid levels. Weight loss should be attempted first by exercise and nutrition interventions (see also the “Fitness” section in Part 3). Although weight loss of as little as 5% of initial weight has resulted in these benefits, the effects of weight loss in normal-weight women are not known. The use of pharmacologic weight-loss agents and gastric bypass surgery also has demonstrated benefit in women with reproductive and metabolic abnormalities.

Risk of Cardiovascular Disease and Diabetes

Overall, lifestyle modifications that include increased exercise and reduced caloric intake are the best first-line approach to decreasing the risk of cardiovascular disease and diabetes. Data are insufficient to recommend insulin-sensitizing agents to prevent diabetes in women with PCOS; women found to have impaired glucose tolerance or metabolic syndrome may, however, receive some benefit from active management with phar­macologic agents (see also the “Cardiovascular Disorders” section and the “Diabetes Mellitus” section in Part 3).

Menstrual Disorders

In women not attempting to conceive, low-dose combined oral contracep­tives remain the mainstay of long-term treatment for menstrual irregulari­ties because they provide a progestin, suppress androgen secretion, increase sex hormone-binding globulin, and reduce the potential for endometrial cancer. There is insufficient evidence to determine the most effective com­bined hormonal contraceptive to treat menstrual disorders in women with PCOS. Progestin-only contraceptives or progestin-containing intrauterine devices are an alternative for endometrial protection, but they are associ­ated with abnormal bleeding patterns in 50-89% of users. Small studies over 3-6 months using metformin have shown an improvement in ovula­tory function in approximately one half the women studied. Serious but rare adverse effects of metformin may include lactic acidosis, but this is seen chiefly in patients with preexisting renal or hepatic disease, which are contraindications to this medication. Lactic acidosis also may occur with marked dehydration. Metformin administration should be discontinued before radiologic procedures that use iodinated contrast material, such as intravenous pyelography. Common adverse effects of metformin, such as bloating and diarrhea, may be decreased by initiating therapy at low doses and gradually increasing the amounts until therapeutic levels are attained.

There is currently no single accepted algorithm to guide ovulation induc­tion in women with PCOS who are attempting to conceive. Patients should always first be counseled about lifestyle modification with weight loss and exercise. Clomiphene citrate is still the recommended first-line pharmaco­logic agent for ovulation induction. The third joint consensus conference on PCOS sponsored by the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology con­cluded that there is no evidence for improved live-birth rates or decreased pregnancy complications associated with the use of metformin either before conception or during pregnancy.

Hirsutism

In patients reporting hirsutism, combined therapy with an ovarian suppres­sion agent and an antiandrogen, such as spironolactone, appears effective, though caution must be used when combining a contraceptive containing drospirenone with spironolactone. Mechanical hair removal with shaving, plucking, waxing, depilatory creams, electrolysis, and laser vaporization are often the first-line treatment options for most women with PCOS.

Bibliography

Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. Positions statement: criteria for defining polycystic ovary syn­drome as a predominantly Hyperandrogenic syndrome: an Androgen Excess Society guideline. Androgen Excess Society. J Clin Endocrinol Metab 2006;91:4237-45. [PubMed] [Full Text]

Dunaif A, Givens JR, Haseletine FP, Merriam GR, editors. Polycystic ovary syn­drome. Boston (MA): Blackwell Scientific Publications; 1992.

Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005;352:1223-36. [PubMed] [Full Text]

Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, et al. Consensus on women's health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril 2012;97:28-38.e25. [PubMed] [Full Text]

Polycystic ovary syndrome. ACOG Practice Bulletin No. 108. American College of Obstetricians and Gynecologists. Obstet Gynecol 2009;114:936-49. [PubMed] [Obstetrics & Gynecology]

Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Fertil Steril 2004;81:19-25. [PubMed] [Full Text]

Resources

American College of Obstetricians and Gynecologists. Polycystic ovary syndrome. Patient Education Pamphlet AP121. Washington, DC: American College of Obste­tricians and Gynecologists; 2011.

American College of Obstetricians and Gynecologists. Treating infertility. Patient Education Pamphlet AP137. Washington, DC: American College of Obstetricians and Gynecologists; 2012.

American Society for Reproductive Medicine. Medications for inducing ovulation: a guide for patients. Birmingham (AL): ASRM; 2012. Available at: http://www.asrm. org/uploadedFiles/ASRM_Content/Resources/Patient_Resources/Fact_Sheets_and_ Info_Booklets/ovulation_drugs.pdf. Retrieved August 12, 2013.

American Society for Reproductive Medicine. Polycystic ovary syndrome (PCOS). Fact sheet. Birmingham (AL): ASRM; 2012. Available at: http://www.reproductive- facts.org/uploadedFiles/ASRM_Content/Resources/Patient_Resources/Fact_Sheets_ and_Info_Booklets/PCOS.pdf. Retrieved August 12, 2013.

Department of Health and Human Services, Office on Women's Health. Polycystic ovary syndrome (PCOS) fact sheet. Washington, DC: HHS; 2010. Available at: http://www.womenshealth.gov/publications/our-publications/fact-sheet/poly cystic-ovary-syndrome.pdf. Retrieved August 12, 2013.