FIGURE Twelve Or More Follicles on This Ovary Indicate That Polycystic Ovary Syndrome Is Likely

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FIGURE Twelve or more follicles on this ovary indicate that polycystic ovary syndrome is likely. The diagnosis is confirmed if the patient has anovulation or oligo-ovulation or hyperandrogenism (hirsutism or elevated androstenedione and/or dehydroepiandrosterone sulfate levels). ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT MARTENS KIMBERLY ILLUSTRATION:

8 OBG Management | April 2017 | Vol. 29 No. 4 obgmanagement.com Editorial

Treating polycystic ovary syndrome: Start using dual medical therapy Many clinicians treat polycystic ovary syndrome with oral estrogen− progestin (OEP) monotherapy. Dual therapy with OEP plus metformin or OEP plus spironolactone is more effective.

Robert Robert L. Barbieri, MD Editor in Chief, OBG Management Chair, Obstetrics and Gynecology Brigham and Women’s Hospital, Boston, Massachusetts Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology Harvard Medical School, Boston

sing the Rotterdam criteria, sex hormone−binding globulin metabolic abnormalities of PCOS. the diagnosis of polycystic (SHBG), which decreases free tes- Combination treatment with both U ovary syndrome (PCOS) is tosterone levels OEP plus metformin, along with diet made in the presence of 2 of the fol- • protection against the develop- and exercise, can best treat these lowing 3 criteria1: ment of endometrial hyperplasia combined abnormalities. 1. oligo-ovulation or anovulation • induction of regular uterine with- Data support dual therapy with 2. hyperandrogenism manifested by drawal bleeding. metformin. In one small, random- the presence of either hirsutism or However, OEP therapy neither ized trial in women with PCOS, OEP elevated hormone levels (including improves metabolic indices (insulin plus metformin (1,500 mg daily) serum testosterone androstene- sensitivity and visceral fat secretion resulted in a greater reduction in dione and/or dehydroepiandros- of adipokines) nor blocks androgen serum androstenedione and a greater terone sulfate) action in the skin. increase in SHBG than OEP mono- 3. ultrasonography evidence of multi- Dual medical treatment for therapy.3 In addition, weight loss and follicular ovaries (≥12 follicles with PCOS can address the issues that a reduction in waist-to-hip ratio only a diameter of 2 mm to 9 mm in one monotherapy cannot and, along with occurred in the OEP plus metformin or both ovaries; FIGURE) or ovarian providing guidance on improving group.3 In another small randomized stromal volume of 10 mL or more. diet and exercise, many experts sup- study in women with PCOS, OEP plus Among reproductive-age women, port the initial therapy of PCOS with metformin (1,500 mg daily) resulted the prevalence of PCOS has been dual medical therapy (OEP plus met- in a greater decrease in free androgen reported to range from 8% to 13% formin or spironolactone). index than OEP monotherapy.4 for different populations.2 Most cli- In my clinical opinion, women nicians initiate treatment for PCOS who may best benefit from OEP plus with oral estrogen−progestin (OEP) Advantages of OEP plus metformin therapy have one of the monotherapy. OEP treatment has metformin following factors indicating the pres- many beneficial hormonal effects, For many women with PCOS, ence of insulin resistance5: including: the syndrome is characterized by • body mass index >30 kg/m2 • a resulting decrease in pituitary abnormalities in both the reproduc- • waist-to-hip ratio ≥0.85 luteinizing hormone (LH) secre- tive (increase in LH secretion) and • waist circumference >35 in (89 cm) tion, which decreases ovarian metabolic (insulin resistance and • acanthosis nigricans androgen production increased adipokines) systems. OEP • personal history of gestational • an increase in liver production of monotherapy does not improve the diabetes

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• family history of type 2 diabetes mellitus (T2DM) in a first-degree Optimal dual therapy for PCOS when an OEP relative is contraindicated • diagnosis of the metabolic syndrome. An oral estrogen−progestin (OEP) may be contraindicated for the treatment of PCOS, for instance because of the presence of thrombophilia. In these cases, My preferred treatment alternative dual therapy options include a progestin plus a second agent. approach Options for progestin dual therapy include: Metformin is a low cost and safe • oral norethindrone acetate 5 mg daily (which can lower luteinizing hormone treatment for metabolic dysfunction levels and block ovulation) plus metformin • norethindrone acetate 5 mg plus spironolactone due to insulin resistance and excess • levonorgestrel-intrauterine device plus metformin or spironolactone. adipokines. I often start PCOS treat- These progestin therapies reduce the risk of pregnancy and decrease the ment for my patients with an OEP likelihood of endometrial hyperplasia development. plus metformin extended release (XR) 750 mg with dinner. If the patient tolerates this dose, I increase the dose to metformin XR 1,500 mg to the powerful intracellular andro- as “low quality” and additional con- with dinner. gen dihydrotestosterone.9 Women trolled trials of OEP monotherapy Adverse effects. The most com- with PCOS may present with a chief versus OEP plus spironolactone are mon side effects of metformin are problem report of hirsutism, acne, warranted. 12 gastrointestinal, including abdomi- or female androgenetic alopecia. nal discomfort, flatulence, bor- OEP plus spironolactone may be an My preferred treatment borygmi, diarrhea, and nausea. optimal initial treatment for women approach Metformin reduces serum vitamin with a dominant dermatologic man- Spironolactone is effective in the B12 levels by 5% to 10%; there- ifestation of PCOS. OEP treatment treatment of hirsutism at doses fore, ensuring adequate vitamin results in a decrease in pituitary LH ranging from 50 mg to 200 mg daily. B12 intake (2.6 µg daily) is helpful.6 secretion and ovarian androgen I routinely use a dose of spirono- Although metformin does reduce production. Spironolactone adds to lactone 100 mg daily because this vitamin B12 levels, there is no strong this therapeutic effect by blocking dose is near of the top of the dose- relationship between metformin androgen action in the skin. response curve and has few adverse and anemia or peripheral neuropa- The data on dual therapy with effects (such as intermittent uterine thy.7 Lactic acidosis is a rare compli- spironolactone. Many dermatolo- bleeding or spotting). With spirono- cation of metformin. gists recommend spironolactone in lactone monotherapy at a dose of Beneficial effects. In the treatment combination with cosmetic mea- 200 mg, irregular uterine bleeding of PCOS, metformin may have many sures for the treatment of acne, but or spotting is common, but con- beneficial effects, including8: there are only a few randomized tri- comitant treatment with an OEP • decrease in insulin resistance als that demonstrate its efficacy.10 In tends to minimize this side effect. • decrease in harmful adipokines one trial spironolactone was dem- In my practice I rarely have patients • reduction in visceral fat onstrated to be superior to placebo report irregular uterine bleeding or • reduction in the incidence of for the treatment of inflammatory spotting with the combination treat- T2DM. acne.10 Authors of multiple random- ment of an OEP and spironolactone ized trials report that the antiandro- 100 mg daily. gens, spironolactone, or finasteride Contraindications. Spironolactone OEP plus spironolactone are superior to metformin to treat should not be given to women with Many women with PCOS have hirsutism.11 In addition, a few small renal insufficiency because it can increased LH secretion and trials report that spironolactone plus cause hyperkalemia. However, it is increased androgen activity in the OEP is superior to either OEP or not necessary to check potassium skin due to increased 5-alpha reduc- metformin monotherapy for hirsut- levels in young women taking spi- tase enzyme activity, which cata- ism.11 Clinical trials of spironolac- ronolactone with normal creatinine lyzes the conversion of testosterone tone for hirsutism have been rated levels.13

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FIGURE Percentage of women reporting their contraceptive significantly improved their acne16

10 Percent of women Percent

DMPA

Etonogestrel Desogestrel-EE Etonogestrel-EEvaginal ring Drospirenone-EENorgestimate-EE Norethindrone-EE Levonorgestrel-EE Levonorgestrel-IUD subdermal implant

Abbreviations: DMPA, depot medroxyprogesterone acetate; EE, ethinyl estradiol; IUD, intrauterine device.

Triple therapy: OEP estradiol plus any synthetic progestin to 1% for those taking the etonoges- plus metformin plus suppresses pituitary secretion of LH trel subdermal implant (FIGURE).16 spironolactone and decreases ovarian androgen pro- The US Food and Drug Administra- Some experts strongly recommend duction. However, for the treatment tion has approved 4 OEP contra- the initial treatment of PCOS in ado- of acne, using a progestin that is less ceptives for the treatment of acne lescents and young women with androgenic may be beneficial.16 (TABLE). The OEPs with drospire- triple therapy: OEP plus an insulin In one study, 2,147 consecutive none, norgestimate, desogestrel, or sensitizer plus an antiandrogen.14 women who were taking a contra- norethindrone acetate may be opti- This recommendation is based in ceptive and presented for treatment mal choices for the treatment of acne part on the observation that OEP of acne were asked if their contra- caused by PCOS. monotherapy may be associated ceptive had a positive impact on with an increase in circulating adi- their acne. The percentage of women pokines and visceral fat mass as reporting that their contraceptive The bottom line determined by dual-energy x-ray significantly improved their acne PCOS is a common endocrine absorptiometry.15 By contrast, triple ranged from 26% for those taking disorder treated primarily by treatment with an OEP plus metfor- drospirenone-ethinyl estradiol (EE) obstetricians-gynecologists. Among min plus an antiandrogen is associated with a decrease in circulating TABLE FDA-approved estrogen−progestin contraceptives adipokines and visceral fat mass. for the treatment of acne Brand name Generic name What is the best Estrostep Norethindrone acetate-ethinyl estradiol plus ferrous fumarate progestin for PCOS? Ortho Tri-Cyclen Norgestimate-ethinyl estradiol Any OEP is better than no OEP, Yaz Drospirenone-ethinyl estradiol regardless of the progestin used to treat the PCOS because ethinyl BeYaz Drospirenone-ethinyl estradiol plus levomefolate

12 OBG Management | April 2017 | Vol. 29 No. 4 obgmanagement.com adolescents and young women with hypertension, T2DM, cardiovas- PCOS chief problem reports include cular disease, and endometrial irregular menses, hirsutism, obesity, cancer.17–19 To optimally treat the acne, and infertility. Among mid-life multiple pathophysiologic disorders women the presentation of PCOS manifested in PCOS, I recommend [email protected] often evolves into chronic medical initial dual medical therapy with an Dr. Barbieri reports no financial rela- problems, including obesity, meta- OEP plus metformin or an OEP plus tionships relevant to this article. bolic syndrome, hyperlipidemia, spironolactone.

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