What Is Optimal Hormonal Treatment for Women with Polycystic Ovary

EDITORIAL

What is optimal hormonal treatment for women with polycystic ovary syndrome? In my practice, I commonly prescribe 3 hormone treatments for PCOS: combination estrogen-progestin contraceptive, metformin, and spironolactone. In combination, these medications rebalance the 3 system abnormalities commonly seen in women with PCOS, including reproductive, metabolic, and dermatologic dysfunction.

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

olycystic ovary syndrome LH pulse amplitude and LH pulse Given that PCOS is caused by (PCOS) is the triad of oligo- frequency, suggesting a primary abnormalities in the reproductive, P ovulation resulting in oli- hypothalamic disorder metabolic, and dermatologic sys- gomenorrhea, hyperandrogenism • an increase in ovarian secretion of tems, it is appropriate to consider and, often, an excess number of androstenedione and testosterone multimodal hormonal therapy that small antral follicles on high-reso- due to stimulation by LH and pos- addresses all 3 problems. In my prac- lution pelvic ultrasound. One meta- sibly insulin tice, I believe that the best approach analysis reported that, in women of • oligo-ovulation with chronically to the long-term hormonal treatment reproductive age, the prevalence of low levels of progesterone that can of PCOS for many women is to pre- PCOS was 10% using the Rotterdam- result in endometrial hyperplasia scribe a combination of 3 medicines: European Society of Human Repro- • ovulatory infertility. a combination estrogen-progestin duction and Embryology/American Metabolic abnormalities com- oral contraceptive (COC), an insulin Society for Reproductive Medi- monly observed in women with sensitizer, and an antiandrogen. cine (ESHRE/ASRM) criteria1 and PCOS include5,6: The COC reduces pituitary secre- 6% using the National Institutes of • insulin resistance and hyperinsu- tion of LH, decreases ovarian andro- Health 1990 diagnostic criteria.2 (See linemia gen production, and prevents the “The PCOS trinity—3 findings in one • excess adipose tissue in the liver development of endometrial hyper- syndrome: oligo-ovulation, hyper- • excess visceral fat plasia. When taken cyclically, the androgenism, and a multifollicular • elevated adipokines COC treatment also restores regular ovary” on page 12.)3 • obesity withdrawal uterine bleeding. PCOS is caused by abnormalities • an increased prevalence of glucose An insulin sensitizer, such as in 3 systems: reproductive, metabolic, intolerance and frank diabetes. metformin or pioglitazone, helps and dermatologic. Reproductive Dermatologic abnormalities to reduce insulin resistance, glucose abnormalities commonly observed in commonly observed in women with intolerance, and hepatic adipose women with PCOS include4: PCOS include7: content, rebalancing central metab- • an increase in pituitary secre- • facial hirsutism olism. It is important to include tion of luteinizing hormone (LH), • acne diet and exercise in the long-term resulting from both an increase in • androgenetic alopecia. treatment of PCOS, and I always

10 OBG Management | January 2020 | Vol. 32 No. 1 mdedge.com/obgyn encourage these lifestyle changes. In the same study, the percent of bothersome uterine bleeding while However, my patients usually report women reporting that a birth control spironolactone at a dose of 100 mg that they have tried multiple times pill made their acne worse was 3% for daily is seldom associated with to restrict dietary caloric intake and pills containing drospirenone, 6% irregular bleeding. I believe that spi- increase exercise and have been for pills containing norgestimate, ronolactone at a dose of 100 mg daily unable to rebalance their metabo- 2% for pills containing desogestrel, results in superior clinical efficacy lism with these interventions alone. 8% for pills containing norethin- than a 50-mg daily dose, although Of note, in the women with PCOS drone, and 10% for pills containing studies report that both doses are and a body mass index >35 kg/m2, levonorgestrel.9 Given these findings, effective in the treatment of acne and bariatric surgery, such as a sleeve when treating a woman with PCOS, I hirsutism. Spironolactone should gastrectomy, often results in marked generally prescribe a contraceptive not be prescribed to women with improvement of their PCOS.8 that does not contain levonorgestrel. renal failure because it can result in The antiandrogen spironolactone severe hyperkalemia. In a study of provides effective treatment for the Why is a spironolactone dose spironolactone safety in the treat- dermatologic problems of facial hir- of 100 mg a good choice for ment of acne, no adverse effects on sutism and acne. Some COCs con- PCOS treatment? the kidney, liver, or adrenal glands taining the progestins drospirenone, Spironolactone, an antiandrogen were reported over 8 years of use.12 norgestimate, and norethindrone and inhibitor of 5-alpha-reductase, acetate are approved by the US Food is commonly prescribed for the What insulin sensitizers are and Drug Administration for the treat- treatment of hirsutism and acne at useful in rebalancing the ment of acne. A common approach I doses ranging from 50 mg to 200 mg metabolic abnormalities use in practice is to prescribe a COC, daily.10,11 In my clinical experience, observed with PCOS? plus spironolactone 100 mg daily plus spironolactone at a dose of 200 mg Diet and exercise are superb metformin extended-release 750 mg daily commonly causes irregular and approaches to rebalancing metabolic to 1,500 mg daily.

Which COCs have low androgenicity? I believe that every COC is an effective treatment for PCOS, regardless of the androgenicity of the progestin in the contraceptive. However, some dermatologists believe that combination contraceptives containing progestins with low androgenicity, such as drospirenone, norgestimate, and desogestrel, are more likely to improve acne than contraceptives with an androgenic progestin such as levonorgestrel. In one study in which 2,147 women with acne were treated by one dermatologic practice, the percentage of women reporting that a birth control pill helped to improve their acne was 66% for pills containing drospirenone, 53% for pills containing norgestimate, 44% for pills containing desogestrel, 30% for pills containing norethindrone, and 25%

ILLUSTRATION: JOHN J. DENAPOLI / IMAGES: SCIENCEPICS/ SUPREEYA-ANON/ ORAWAN PATTARAWIMONCHAI/SHUTTERSTOCK ORAWAN JOHN J. DENAPOLI / IMAGES: SCIENCEPICS/ SUPREEYA-ANON/ ILLUSTRATION: for pills containing levonorgestrel.

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mdedge.com/obgyn Vol. 32 No. 1 | January 2020 | OBG Management 11 EDITORIAL

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The PCOS trinity—3 findings in one syndrome: oligo-ovulation, hyperandrogenism, and a multifollicular ovary

The two approaches most commonly used to diagnose polycystic ovary syndrome (PCOS) are the 1990 National Institutes of Health (NIH) criteria and the 2003 Rotterdam-European Society of Human Reproduction and Embryology/ American Society for Reproductive Medicine (ESHRE/ASRM) criteria (TABLE).1,2 In one meta-analysis, the prevalence of PCOS in women of reproductive age was 6% and 10% when using the NIH and ESHRE/ASRM criteria, respectively.3

TABLE Two diagnostic systems for identifying women with PCOS 1990 NIH Definition1 2003 Rotterdam-ESHRE/ASRM Definition2 ALL REQUIRED TWO OUT OF 3 REQUIRED Hyperandrogenism (physical examination or laboratory testing) Hyperandrogenism (physical examination or laboratory testing) Oligo-ovulation, typically manifested as oligomenorrhea Oligo-ovulation, typically manifested as oligomenorrhea Exclude other hyperandrogenic disorders, including: Multifollicular morphology on ultrasonography (presence of nonclassical adrenal hyperplasia, ovarian tumors, ≥ 12 follicles in each ovary measuring 2 to 9 mm in diameter) Cushing syndrome, and hyperprolactinemia or increased ovarian volume ( >10 mL)

References 1. Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In Dunaif A, Givens JR, Haseltine FP, et al. Polycystic ovary syndrome. Boston, MA: Blackwell Scientific; 1992:377-384. 2. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81:19-25. 3. Bozdag G, Mumusoglu S, Zengin D, et al. The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2016;31:2841-2855.

abnormalities, but for many of my congestive heart failure and non- in women with the Factor V Leiden patients they are insufficient and treat- fatal myocardial infarction. Piogli- mutation. The prevalence of this ment with an insulin sensitizer is war- tazone is also associated with a risk mutation varies by race and eth- ranted. The most commonly utilized of hepatotoxicity. However, at the nicity. It is present in about 5% of insulin sensitizer for the treatment of pioglitazone dose commonly used white, 2% of Hispanic, 1% of black, PCOS is metformin because it is very in the treatment of PCOS (7.5 mg 1% of Native American, and 0.5% of inexpensive and has a low risk of seri- daily), these serious adverse effects Asian women. In women with PCOS ous adverse effects such as lactic aci- are rare. In practice, I initiate metfor- who are known to be carriers of the dosis. Metformin increases peripheral min at a dose of 750 mg daily using mutation, dual therapy with met- glucose uptake and reduces gastroin- the extended-release formulation. formin and spironolactone is highly testinal glucose absorption. Insulin I increase the metformin dose to effective.13-15 For these women I also sensitizers also decrease visceral fat, 1,500 mg daily if the patient has no offer a levonorgestrel IUD to provide a major source of adipokines. One bothersome gastrointestinal symp- contraception and reduce the risk of major disadvantage of metformin is toms on the lower dose. If the patient endometrial hyperplasia. that at doses in the range of 1,500 mg cannot tolerate metformin treatment to 2,250 mg it often causes gastroin- because of adverse effects, I will use Combination triple medication testinal adverse effects such as borbo- pioglitazone 7.5 mg daily. treatment of PCOS rygmi, nausea, abdominal discomfort, Optimal treatment of the reproduc- and loose stools. Treatment of PCOS in women tive, metabolic, and dermatologic Thiazolidinediones, including who are carriers of the problems associated with PCOS pioglitazone, have been reported Factor V Leiden mutation requires multimodal medications to be effective in rebalancing cen- The Factor V Leiden allele is associ- including an estrogen-progestin tral metabolism in women with ated with an increased risk of venous contraceptive, an antiandrogen, and PCOS. Pioglitazone carries a black thromboembolism. Estrogen-proges- an insulin sensitizer. In my prac- box warning of an increased risk of tin contraception is contraindicated tice, I initiate treatment of PCOS by

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12 OBG Management | January 2020 | Vol. 32 No. 1 mdedge.com/obgyn EDITORIAL CONTINUED FROM PAGE 12

offering patients 3 medications: a Although triple medication treatment COC, spironolactone 100 mg daily, of PCOS has not been tested in large and metformin extended-release for- randomized clinical trials, small trials

mulation 750 mg daily. Some patients report that triple medication treat- [email protected] elect dual medication therapy (COC ment produces optimal improvement plus spironolactone or COC plus in the reproductive, metabolic, and metformin), but many patients select dermatologic problems associated Dr. Barbieri reports no financial rela- treatment with all 3 medications. with PCOS.16-18 tionships relevant to this article.

References 1. Rotterdam ESHRE/ASRM-Sponsored PCOS Con- 7. Housman E, Reynolds RV. Polycystic ovary syn- (PCOS): a six-month, open-label randomized sensus Workshop Group. Revised 2003 consensus drome: a review for dermatologists: Part I. Diag- study. J Clin Endocrinol Metab. 2013;98:3599-3607. on diagnostic criteria and long-term health risks nosis and manifestations. J Am Acad Dermatol. 14. Mazza A, Fruci B, Guzzi P, et al. In PCOS patients related to polycystic ovary syndrome. Fertil Steril. 2014;71:847.e1-e10. the addition of low-dose spironolactone induces a 2004;81:19-25. 8. Dilday J, Derickson M, Kuckelman J, et al. Sleeve more marked reduction of clinical and biochemi- 2. Zawadski JK, Dunaif A. Diagnostic criteria for gastrectomy for obesity in polycystic ovarian syn- cal hyperandrogenism than metformin alone. polycystic ovary syndrome: towards a rational drome: a pilot study evaluating weight loss and Nutr Metab Cardiovascular Dis. 2014;24:132-139. approach. In Dunaif A, Givens JR, Haseltine FP, et fertility outcomes. Obes Surg. 2019;29:93-98. 15. Ganie MA, Khurana ML, Eunice M, et al. Compar- al. Polycystic ovary syndrome. Boston, MA: Black- 9. Lortscher D, Admani S, Satur N, et al. Hormonal ison of efficacy of spironolactone with metformin well Scientific; 1992:377-384. contraceptives and acne: a retrospective analysis in the management of polycystic ovary syndrome: 3. Bozdag G, Mumusoglu S, Zengin D, et al. The of 2147 patients. J Drugs Dermatol. 2016;15:670- an open-labeled study. J Clin Endocrinol Metab. prevalence and phenotypic features of polycystic 674. 2004;89:2756-2762. ovary syndrome: a systematic review and meta- 10. Brown J, Farquhar C, Lee O, et al. Spironolactone 16. Ibanez L, de Zegher F. Low-dose combination flu- analysis. Hum Reprod. 2016;31:2841-2855. versus placebo or in combination with steroids for tamide, metformin and an oral contraceptive for 4. Baskind NE, Balen AH. Hypothalamic-pituitary, hirsutism and/or acne. Cochrane Database Syst non-obese, young women with polycystic ovary ovarian and adrenal contributions to polycystic Rev. 2009;CD000194. syndrome. Hum Reprod. 2003;18:57-60. ovary syndrome. Best Pract Res Clin Obstet Gynae- 11. Shaw JC. Low-dose adjunctive spironolactone in 17. Ibanez L, de Zegher F. Flutamide-metformin plus col. 2016;37:80-97. the treatment of acne in women: a retrospective an oral contraceptive (OC) for young women with 5. Gilbert EW, Tay CT, Hiam DS, et al. Comorbidities analysis of 85 consecutively treated patients. J Am polycystic ovary syndrome: switch from third- to and complications of polycystic ovary syndrome: Acad Dermatol. 2000;43:498-502. fourth-generation OC reduces body adiposity. an overview of systematic reviews. Clin Endocri- 12. Shaw JC, White LE. Long-term safety of spirono- Hum Reprod. 2004;19:1725-1727. nol (Oxf). 2018;89:683-699. lactone in acne: results of an 8-year follow-up 18. Ibanez L, de Zegher F. Ethinyl estradiol-drospi- 6. Harsha Varma S, Tirupati S, Pradeep TV, et al. study. J Cutan Med Surg. 2002;6:541-545. renone, flutamide-metformin or both for adoles- Insulin resistance and hyperandrogenemia inde- 13. Ganie MA, Khurana ML, Nisar S, et al. Improved cents and women with hyperinsulinemic hyper- pendently predict nonalcoholic fatty liver disease efficacy of low-dose spironolactone and metformin androgenism: opposite effects on adipocytokine in women with polycystic ovary syndrome. Diabe- combination than either drug alone in the manage- and body adiposity. J Clin Endocrinol Metab. tes Metab Syndr. 2019;13:1065-1069. ment of women with polycystic ovary syndrome 2004;89:1592-1597.

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