Polycystic Ovary Syndrome: Treatment Option Pros and Cons

Adolescents with polycystic ovary syndrome (PCOS) are at risk for such complications as dyslipidemia, hypertension, type 2 diabetes mellitus (DM), and potentially coronary artery disease (CAD). Prompt diagnosis is crucial, as are therapeutic efforts to establish healthy diet and exercise habits. This is the second of 2 articles on PCOS in adolescents and is an update to a previous report on this subject. In part 1 we focused on PCOS diagnosis. Here we concentrate on treatment options and outline management strategies that can reduce symptoms and associated long-term health risks. Among the most important clinical updates in the management of adolescent PCOS is the growing recognition that the levonorgestrel intrauterine device (LNG-IUD) is a suitable treatment for dysfunctional uterine bleeding associated with the syndrome.

MANAGEMENT
Patient education and lifestyle modification are crucial to addressing the acute presenting symptoms and ameliorating the associated long-term health risks. Acute symptoms of PCOS can be managed primarily with combined oral contraceptives (OCs) and antiandrogens. In addition to OCs, multiple delivery systems (transdermal contraceptive patch and vaginal contraceptive ring) of combined hormonal contraceptives achieve similar treatment results in adolescents. Insulin sensitizing drugs are best incorporated into the treatment of adolescents with DM and could contribute to the management of impaired glucose tolerance. Given the broad range of symptoms in affected patients, a multidisciplinary approach to treatment is generally required.

Obesity. Weight reduction is the central component of treatment of overweight patients with PCOS.¹ Weight loss ameliorates many of the associated endocrine derangements, including insulin resistance, depressed sex hormone–binding globulin (SHGB) levels, and hyperandrogenism. Modest weight reduction of 2% to 5% of total body weight has been shown to improve cycle regularity and reduce free testosterone indices.^2,3 The most effective approach appears to be a combination of caloric restriction, exercise, and behavior modification. Low-carbohydrate diets do not appear to confer a distinct metabolic benefit over other types of diets.⁴ Weight loss should be emphasized, regardless of whether medications are incorporated into treatment.

Hirsutism and acne. Effective treatment of hirsutism in PCOS requires a multimodal approach, including reduction of androgen synthesis, blocking androgen action, and mechanical removal of excess hair. The medications described here for hirsutism do not eliminate established hair, but rather reduce new hair growth. Thus, when only medical management is used, up to 6 months may pass before a significant change in hair distribution is noted.^2,5 The incorporation of mechanical treatments (eg, electrolysis, depilatories, and laser hair removal) with medical therapy can be extremely beneficial. Only one of the medications described below (eflornithine) is FDA-approved for the treatment of hirsutism but all have demonstrated efficacy. The absence of pregnancy must be confirmed before initiation of any medical treatments and a reliable contraceptive method must be used in combination with these drugs.

Androgen suppression. Combination OCs are first-line therapy for acne and hirsutism because they safely diminish androgen production through several mechanisms. Transdermal and vaginal contraceptives reduce androgen levels through identical mechanisms. Specifically, OCs diminish ovarian androgen production by suppressing pituitary gonadotropins and by up-regulation of SHBG, which binds bioactive free testosterone. Both of these actions reduce the amount of testosterone available to stimulate terminal hair growth and cause acne.^1,2,5,6 In addition, OCs reduce androgen production from the adrenal gland by an as yet unspecified mechanism.⁵

In addition to cosmetic benefits, OCs regulate menstrual bleeding, reduce the likelihood of endometrial hyperplasia, and are effective contraception for sexually active teenagers.^1,2

The potential deterioration of insulin sensitivity in adolescents with PCOS using OCs has been suggested. However, to date, a substantial clinical risk has not been confirmed, and the clear benefits of OCs overshadow this possibility.^6,7 An OC containing a minimally androgenic progestin, such as norgestimate or desogestrel is a preferred initial treatment option. Of note, etonogestrel, the progestin in the contraceptive vaginal ring is the active metabolite of desogestrel; norelgestromin the progestin in the contraceptive path is the active metabolite of norgestimate. Drospirenone, an analogue of spironolactone, is available in combination OCs (Yasmin) and may prove to be of particular benefit in patients with PCOS.⁶ When OCs are contraindicated or declined by the patient, medroxyprogesterone acetate may be used as an alternative to reduce androgen levels. We recommend the intramuscular route of administration (depot medroxyprogesterone acetate, 150 mg IM every 3 months), which also provides excellent contraception. Compared with OCs, the relative efficacy of medroxyprogesterone acetate to control excess hair growth may be limited by a less dramatic impact on SHBG and free testosterone levels.^2,8

MANAGEMENT, cont'd

Androgen blockade. Medications that block or reduce the action of androgens on terminal hair production should always be used with reliable contraception as these medications are teratogens that could feminize a male fetus.^2,9 Spironolactone is first-line among this class of drugs and has multiple antiandrogenic effects. Most important, spironolactone is an androgen receptor blocker and is believed to have synergistic treatment effects when used with OCs.^1,2,6 Because it is also a potassium-sparing diuretic, patients using this medication may be at risk for hyperkalemia, especially those with underlying renal dysfunction. Make sure that serum potassium and creatinine levels are normal before starting treatment. Although some patients benefit from a daily dose of 100 mg, the optimal dosage appears to be 200 mg/d (divided 100 mg bid).^1,2,6 Common adverse effects, such as polyuria and headaches, are minimized by starting at a dosage of 25 mg/d and gradually increasing to the final dose over several weeks.⁵ Alternative antiandrogen preparations have benefit for treatment of hirsutism in women but their use is less widespread than spironolactone. Flutamide is a powerful antiandrogen that is FDA-approved for prostate cancer treatment but has been associated with rare instances of fatal hepatotoxicity.⁸ Finasteride blocks the conversion of testosterone to the more powerful androgen dihydrotestosterone-the hormone primarily responsible for influencing hair growth; the effectiveness of finasteride to control new hair growth appears to be limited compared with flutamide or spironolactone.^8,9

Mechanical and topical treatments. Eflornithine (Vaniqa) is a topical ornithine decarboxylase inhibitor that prevents hair growth and is FDA-approved for the treatment of excess facial hair. It has been shown to be highly effective after approximately 6 to 8 weeks of use; its benefits appear to be short-lived after discontinuation. Adverse effects are limited. Its effect on excess nonfacial hair has not been thoroughly investigated.^5,8,9 Unfortunately, eflornithine can be expensive and is rarely covered by insurance plans. Mechanical treatments of hirsutism have been used as monotherapy and as adjuncts to hormonal therapies. Common approaches include shaving, hair bleaching, and chemical depilation. Waxing or plucking of hair in areas of androgenized skin may increase the risk of folliculitis, ingrown hairs, and skin damage.⁵

The objective of electrolysis and laser hair removal is to permanently destroy hair follicles that produce unwanted hair.^5,10 The best results are achieved when initiated after at least 6 months of medical inhibition of new hair growth.^2,10,11 Electrolysis produces electrocoagulation of the base of the hair follicle. Laser hair removal causes selective thermal damage of the follicle while sparing adjacent tissues.^5,10 Persons with lighter skin and dark hair obtain best results from laser therapy.^2,5,10 Although both electrolysis and laser therapy aim to permanently destroy hair follicles, repeated treatments are required and complete hair removal is not always achieved. Thus, a description of these methods as “permanently reducing” rather than “permanently removing” unwanted hair has been suggested.¹⁰ When comparing these treatments, it has been demonstrated that electrolysis is less comfortable¹² and less costly than laser hair removal. Early evidence from small randomized trials suggests that electrolysis may be less effective than laser hair removal but more outcomes research is required.¹³

Abnormal bleeding. If no contraindications exist, OCs and transdermal and vaginal contraceptives are a highly effective means of achieving cycle regularity in patients with PCOS. Oral medroxyprogesterone acetate (Provera), 5 to 10 mg daily, can also be used for the first 12 days of each month. While Provera prevents endometrial hyperplasia and dysfunctional uterine bleeding, the dose of hormone used for this purpose is not adequate to provide contraception. Alternatively, depot medroxyprogesterone acetate (Depot provera, DMPA) may be used to address dysfunction bleeding in adolescents who desire long-term contraception or in whom OCs are contraindicated.^1,2

We also recommend greater use of the LNG IUD (Mirena) for the management of abnormal bleeding in adolescents with PCOS. OC continuation rates in adolescents are as low as 12% 1 year after initiation.¹⁴ Comparable continuation rates have been observed in adolescent users of the transdermal patch (11%) and DMPA (16%), with slightly higher rates in users of the contraceptive vaginal ring (30%).¹⁵ Despite the contraceptive efficacy of IUDs, highly favorable adverse-effect profile, and superior continuation rates (72% to 85%), many physicians are reluctant to recommend placement in adolescents and nulliparous women.¹⁵ Provider concerns about risk of subsequent infertility and increased risk of pelvic inflammatory disease with use of IUDs are not supported by follow-up of adolescent and adult IUD users. As a result of local delivery of levonorgestrel to the uterus and subsequent endometrial atrophy, adolescents with the LNG IUD in place can anticipate a diminished pattern of bleeding over time, with up 50% to 80% becoming amenorrheic at 12 months.¹⁶ LNG IUD users can safely continue therapy for up to 5 years, during which time symptoms are controlled and endometrial protection from unopposed estrogen stimulation occurs.^16,17

Insulin Resistance, Impaired Glucose Tolerance, and Diabetes Mellitus 
Currently, the primary role of insulin sensitizers such as metformin and the thiazolidinediones in the management of adults with PCOS is to address DM and impaired glucose tolerance (IGT).^1,2,6 In recent years, the use of insulin sensitizers for ovulation induction in infertile women with PCOS has diminished. This shift in clinical practice relates to the results of a recent, large randomized trial demonstrating the superiority of clomiphene citrate to metformin in this regard.¹⁸ Nevertheless, women with PCOS have a higher risk of developing IGT and DM; adolescents are also at risk.¹⁹ We believe that insulin sensitizers can play a role in the management of select adolescents with PCOS who are at high risk for DM or who already have the disease.

Metformin. In addition to its role as an insulin sensitizer, metformin has been shown to reduce blood pressure and low-density lipoprotein cholesterol levels in patients with PCOS, independent of changes in weight.^20,21 Although a few studies on the effects of metformin in adolescents have demonstrated almost universal improvement in metabolic derangements (including oligomenorrhea, insulin resistance, androgen levels, and lipid profiles) and the drug has been shown to be well tolerated and effective in both lean and obese adolescents, the available data are limited by a lack of randomized controlled trials and long-term follow-up.^22,23

We do not recommend metformin as first-line treatment of PCOS in adolescents. It may be reasonable to consider the drug as an adjuvant in select groups with DM and possibly IGT, or those with multiple metabolic abnormalities.¹⁹

Thiazolidinediones. Pioglitazone and rosiglitazone reduce androgen levels and increase ovulatory frequency in women with PCOS.^24,25 Given the limited experience-relative to metformin-with these drugs for PCOS and the concern for potential liver toxicity, they are not recommended for the treatment of PCOS in adolescents.⁹

SCREENING AND MONITORING FOR LONG-TERM HEALTH RISKS

Cardiovascular Risk Factors
Adolescents with PCOS must be screened and monitored for long-term sequelae associated with the syndrome. The risk of IGT and DM in PCOS is 10% and 30%, respectively, by the fourth decade of life.²⁶ Women with PCOS are also at increased risk for dyslipidemia and vascular dysfunction, which suggests a potential association between PCOS and CAD onset.^1,6 At present, the data regarding a definitive association between PCOS and CAD remain controversial. Several studies have demonstrated higher levels of inflammatory biomarkers, increased endothelial dysfunction and coronary artery calcium in women with PCOS.^2,27 Results from observational studies such as the Nurses Health Study lend epidemiologic support to an association between menstrual irregularity, features of PCOS, and CAD.²⁸ Data contradicting these findings also exist, making additional long-term follow-up of patient cohorts necessary to draw firm conclusions.²⁹

A baseline assessment of risk factors for CAD and type 2 DM is recommended.^1,6 Screen all adolescents with newly diagnosed PCOS with a fasting lipid panel and blood pressure measurement; follow-up is dictated by the results of these tests and by cardiovascular risk factors. Given the significant prevalence of glucose intolerance and occult type 2 DM among women with PCOS, adolescents should also be screened with a 2-hour oral glucose tolerance test. The provocative test has better sensitivity for glucose intolerance in PCOS than does a fasting glucose assessment. We do not recommend evaluation of insulin resistance. The commonly used tests (eg, the fasting glucose to insulin ratio) lack accuracy when compared with the diagnostic gold standard: the euglycemic hyperinsulinemic clamp. Furthermore, assessment of insulin resistance has shown no clinical value in determining the need for treatment or response to insulin-lowering therapies.⁶ Adolescents who have PCOS and diabetes can be treated with medical and lifestyle intervention. In those with glucose intolerance, lifestyle modifications can help prevent overt diabetes. The role of insulin sensitizers in the prevention of diabetes in patients with PCOS remains unresolved.

Follow-up
• Evaluate adolescents with PCOS as frequently as is clinically warranted when active medical issues are being addressed. Otherwise, follow-up twice yearly is prudent to monitor weight, blood pressure, and long-term medical interventions.
• Screening overweight patients annually for glucose intolerance and type 2 DM lifestyle modification, especially in overweight patients, is key to reducing the symptoms of PCOS, the risk of type 2 DM, and the development of conditions that could lead to CAD.
• Emotional pain and depression associated with the physical stigmata of PCOS may best be addressed by a mental health professional.

References
1. Guzick DS. Polycystic ovary syndrome. Obstet Gynecol. 2004;103:181-193.
2. Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility. Philadelphia: Lippincott Williams and Wilkins.
3. Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab. 1999;84:1470-1474.
4. Moran LJ, Noakes M, Clifton PM, et al. Dietary composition in restoring reproductive and metabolic physiology in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88:812-819.
5. Azziz R. The evaluation and management of hirsutism. Obstet Gynecol. 2003;101:995-1007.
6. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005;352:1223-1236.
7. Godsland IF, Walton C, Felton C, et al. Insulin resistance, secretion, and metabolism in users of oral contraceptives. J Clin Endocrinol Metab. 1992;74:64-70.
8. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists: number 41, December 2002. Obstet Gynecol. 2002;100:1389-1402.
9. Michelmore KF, Balen AH, Dunger DB, Vessey MP. Polycystic ovaries and associated clinical and biochemical features in young women. Clin Endocrinol (Oxf). 1999;51:779-786.
10. Sanchez LA, Perez M, Azziz R. Laser hair reduction in the hirsute patient: a critical assessment. Hum Reprod Update. 2002;8:169-181.
11. Plouffe LJ. Disorders of excessive hair growth in the adolescent. Obstet Gynecol Clin North Am. 2000;27:79-99.
12. Wagner RF Jr, Flores CA, Argo LF. A double-blind placebo controlled study of a 5% lidocaine/prilocaine cream (EMLA) for topical anesthesia during thermolysis. J Dermatol Surg Oncol. 1994;20:148-150.
13. Haedersdal M, Wulf HC. Evidence-based review of hair removal using lasers and light sources. J Eur Acad Dermatol Venereol. 2006;20:9-20.
14. Abma JC, Martinez GM, Copen CE. Teenagers in the United States: sexual activity, contraceptive use, and childbearing, national survey of family growth 2006-2008. Vital Health Stat23. 2010;(30):1-47.
15. Committee opinion no. 539: adolescents and long-acting reversible contraception: implants and intrauterine devices. Obstet Gynecol. 2012;120:983-988.
16. ACOG Practice Bulletin No. 110: noncontraceptive uses of hormonal contraceptives. Obstet Gynecol. 2010;115:206-218.
17. ACOG Practice Bulletin No. 121: Long-acting reversible contraception: implants and intrauterine devices. Obstet Gynecol. 2011;118:184-196.
18. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551-566.
19. Driscoll DA. Polycystic ovary syndrome in adolescence. Ann N Y Acad Sci. 2003;997:49-55.
20. Crave JC, Fimbel S, Lejeune H, et al. Effects of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women. J Clin Endocrinol Metab. 1995;80:2057-2062.
21. Lord JM, Flight IH, Norman RJ. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Cochrane Database Syst Rev. 2003:CD003053.
22. Ibanez L, Valls C, Ferrer A, et al. Sensitization to insulin induces ovulation in nonobese adolescents with anovulatory hyperandrogenism. J Clin Endocrinol Metab. 2001;86:3595-3598.
23. Freemark M, Bursey D. The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Pediatrics. 2001;107:E55.
24. Belli SH, Graffigna MN, Oneto A, et al. Effect of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome. Fertil Steril. 2004;81:624-629.
25. Romualdi D, Guido M, Ciampelli M, et al. Selective effects of pioglitazone on insulin and androgen abnormalities in normo- and hyperinsulinaemic obese patients with polycystic ovary syndrome. Hum Reprod. 2003;18:1210-1218.
26. Ehrmann DA, Barnes RB, Rosenfield RL, et al. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22:141-146.
27. Shroff R, Kerchner A, Maifeld M, et al. Young obese women with polycystic ovary syndrome have evidence of early coronary atherosclerosis. J Clin Endocrinol Metab. 2007;92:4609-4614.
28. Solomon CG, Hu FB, Dunaif A, et al. Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab. 2002;87:2013-2017.
29. Pierpoint T, McKeigue PM, Isaacs AJ, et al. Mortality of women with polycystic ovary syndrome at long-term follow-up. J Clin Epidemiol. 1998;51:581-586.