By Jeffrey T. Jensen, MD, MPH, Editor
Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland
Dr. Jensen reports he is a consultant for Teva Pharmaceuticals, MicroChips, and Evofem; is a consultant for and receives grant/research support from Bayer Healthcare, Merck, Agile Pharm, Population Council, AbbVie, ContraMed, and FHI360; and receives grant/research support from HRA Pharma and Medicines 360.
SYNOPSIS: Emerging evidence supports that two metabolic phenotypes exist among women with polycystic ovary syndrome (PCOS). For metabolically healthy PCOS patients, managing menstrual symptoms, anovulation and androgen excess with combined oral contraceptives (COCs) provides a simple and well-tolerated treatment regimen. In contrast, PCOS patients with metabolic syndrome are at high risk for type 2 diabetes, and COC use may contribute to hyperinsulinemia, adverse lipid changes, and endothelial changes associated with adverse cardiovascular risk. The use of a levonorgestrel intrauterine device combined with spironolactone (to manage hyperandrogenism) and metformin (to manage hyperinsulinism) may offer advantages to metabolically unhealthy PCOS patients.
Recent advances in the treatment of polycystic ovary syndrome (PCOS) support therapeutic interventions that address the key disturbances of the condition: combined oral contraceptive pills (COCs) to suppress ovarian androgens and induce regular menstrual bleeding, metformin to treat hyperinsulinemia and improve glucose tolerance, and lifestyle modification of diet and exercise for weight loss. Although all of these have supportive data, not all patients present with the same complaints, and some treatments, such as contraception or prevention of metabolic disturbances, are better tolerated or offer additional benefits.
As a syndrome, PCOS encompasses a heterogeneous group of women who present with hyperandrogenism, anovulation, and polycystic ovarian morphology. Recently, the Endocrine Society recommended new guidelines for the diagnosis and treatment of PCOS.1 For adults, a diagnosis of PCOS can be made if two of the three Rotterdam criteria are met: androgen excess, ovulatory dysfunction, or polycystic ovaries (PCO). Disorders that mimic the clinical features of PCOS (thyroid disease, hyperprolactinemia, and nonclassic congenital adrenal hyperplasia) must be excluded. In adolescents, the diagnosis must include the clinical or biochemical evidence of hyperandrogenism (after exclusion of other causes) in the presence of persistent oligomenorrhea. Since anovulation and polycystic appearance of ovaries on ultrasound occur commonly during adolescence, neither provides evidence for PCOS in the absence of hyperandrogenism. Although obesity and metabolic dysfunction are not included in the diagnosis of PCOS, both occur commonly. About one-third of adolescents with PCOS meet criteria for metabolic syndrome compared with only 5% without PCOS.2 The risk of metabolic syndrome seems correlated with increasing androgen levels independent of obesity and insulin resistance.2 Metabolic syndrome increases the risk of cardiovascular disease.
Role of Combined Oral Contraceptives
COCs act to decrease gonadotropins that stimulate ovarian steroid hormone production. This results in a decrease in ovarian androgen production, a prime factor that drives the PCOS phenotype. Progestins also decrease the conversion of testosterone to the more potent and peripherally active 5-hydrotestosterone that is associated with acne and hirsutism. Drospirenone offers the unique property of inhibiting the androgen receptor directly. The estrogen competent of all combined pills provides an additional therapeutic effect by increasing sex hormone binding globulin, further lowering free androgen levels. A large literature supports the beneficial effect of COCs on the phenotypic symptoms of hyperandrogenism.3 Although low androgen progestins result in the greatest decrease in free and total androgens,4 the clinical benefit has not been shown in women with PCOS. A randomized study by Kriplani et al compared oral drospirenone/ethinyl estradiol (EE) to desogestrel/EE in Indian women with PCOS.5 Both groups showed similar improvement in acne. Treatment with the drospirenone pill resulted in a reduction of body mass index (BMI) (-0.52 kg/m2) and blood pressure compared to slight increases with desogestrel. The lipid profile improved, and fasting/postprandial blood sugar, insulin, and total testosterone all decreased compared to the desogestrel pill.
However, COCs also increase the risk of thrombosis, a risk also elevated by obesity. Some studies suggest that COCs increase the risk of insulin resistance and coronary heart disease. A cohort study of 31-year-old women from Finland found that after adjusting for BMI, income, and area of residence, users of COCs had higher systolic and diastolic blood pressure, increased levels of inflammatory indices (C-reactive protein), and impaired insulin sensitivity compared to users of the levonorgestrel-releasing intrauterine device.6 This raises the question of safety for COC use in women with PCOS.
Mastorakos et al randomized adolescent girls with PCOS to treatment with a COC containing desogestrel 150 mcg plus EE 30 mcg or cyproterone acetate (CPA) 2 mg/EE 35 mcg.7 CPA pills are commonly prescribed in Europe for acne and are considered to be non-androgenic. After 12 months of treatment, insulin resistance increased significantly in both groups, but insulin levels increased only among teens using the CPA pill. Battaglia et al compared oral drospirenone/EE to the etonogestrel/EE vaginal ring (CVR).8 Although fasting insulin, glucose, and C-peptide did not change with either treatment, the area under the curve (AUC) for both insulin and glucose significantly decreased in users of the CVR. A recent study by Adeniji et al compared the metabolic response following initiation of triphasic norgestimate/EE COC in obese (BMI > 30 kg/m2) women with and without PCOS.9 The obese PCOS subjects were more insulin resistant, had higher fasting insulin and glucose levels, and had higher AUC insulin at baseline. After three months of COC use, glucose tolerance deteriorated further only in the PCOS group, but there was no additional increase in insulin resistance. This study confirmed the previously noted positive correlation of androgen levels to insulin resistance and cardiovascular risk.10,11
When to Use Insulin Sensitizers
Metformin reduces hepatic glucose output and increases insulin-stimulated glucose uptake in skeletal muscle and adipocytes. It also has been used to improve fertility in women with PCOS. Although clinical pregnancy rates are improved for metformin (alone or with clomiphene) vs. placebo, a recent Cochrane review concluded that there was no evidence that metformin improved live birth rates.12 Costello and colleagues reviewed the evidence comparing metformin to combined pills in non-diabetic women with PCOS and concluded that there is no evidence of a difference in effect between the two therapies on reducing fasting glucose levels, total cholesterol levels, or severe adverse events.13 Among obese teenagers with PCOS, the addition of metformin did not add improvement to quality-of-life measures above those observed with lifestyle modification and COC treatment alone.14 Taken together, these data do not support a role for metformin in the treatment of non-diabetic women with PCOS.
Lifestyle Modifications
A growing literature supports the value of lifestyle modification with diet and exercise for women with PCOS. Hoeger and colleagues randomized obese adolescent women with PCOS to receive either metformin, a lifestyle modification program, a COC, or placebo.15 They followed this study with a randomized combination trial of lifestyle modification and COC with and without metformin. In the single intervention study, both lifestyle modification (-59%) and COCs (-86%) significantly reduced the free androgen index, and COC use decreased BMI (mean decrease 1.4 kg/m2). The addition of metformin to lifestyle modification and COCs in the combination trial resulted in a further reduction of total testosterone and central obesity, but did not enhance overall weight reduction.
Dokras et al evaluated quality of life in women with PCOS randomized to a continuous COC, intensive lifestyle modification, or a combination of both approaches.16 All three interventions resulted in significant improvement in health-related quality of life. Orio et al randomized women with PCOS to a drospirenone/EE COC, a structured exercise program, or a multivitamin (control).17 The primary outcome was change in intima-media thickness (IMT) and flow mediated dilation (FMD). After six months of treatment, the IMT was significantly lower and reduced from baseline in the exercise group, with no changes observed in the COC and control groups. FMD also significantly improved only in the exercise group. Similarly, BMI significantly reduced only in the exercise group, while menstrual regularity improved in both the exercise and COC group. Fasting glucose and AUC for glucose did not change with any of the treatments. Acne scores, free testosterone, and the free androgen index improved only with COC treatment.
The Levonorgestrel Intrauterine System
The levonorgestrel intrauterine system provides reliable, long-acting, and highly effective contraception. For women with PCOS, intrauterine levonorgestrel provides protection from anovulation-related endometrial hyperplasia and carcinoma, and effective treatment for heavy menstrual bleeding.18 The local mechanism of action results in a neutral metabolic profile19 and no increase in thrombosis.20 However, since gonadotropins generally are not suppressed with the levonorgestrel intrauterine system, there is no reduction in ovarian androgen production or treatment of androgen excess. Thus, effective treatment of androgen excess requires the addition of spironolactone or an alternative anti-androgen.
Clinical Recommendation
Women with PCOS should undergo detailed evaluation for signs of type 2 diabetes and metabolic syndrome. Growing evidence supports lifestyle modification, with diet and exercise as a cornerstone of therapy for both prevention and a primary treatment for metabolic syndrome and type 2 diabetes. Metformin is indicated as treatment for women with PCOS who have clinical diabetes. Healthy women with PCOS can safely use combined hormonal contraception. Combined hormonal contraception also will manage symptoms of hyperandrogenism effectively. Although there may be theoretical advantages to low-androgen progestins, there is an absence of supportive comparison studies in PCOS women. Since obesity is an independent risk factor for venous thrombosis, and greatly increases the risk of thrombosis with combined hormonal contraception, use of COCs is not recommended. The levonorgestrel intrauterine system provides endometrial protection for obese women with PCOS, but does not manage androgen excess.
REFERENCES
- Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and treatment of polycystic ovary syndrome: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2013;98:4565-4592.
- Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance. J Clin Endocrinol Metab 2006;91:492-497.
- Mes-Krowinkel MG, Louwers YV, Mulders AG, et al. Influence of oral contraceptives on anthropomorphometric, endocrine, and metabolic profiles of anovulatory polycystic ovary syndrome patients. Fertil Steril 2014;101:1757-1765.e1.
- De Leo V, Di Sabatino A, Musacchio MC, et al. Effect of oral contraceptives on markers of hyperandrogenism and SHBG in women with polycystic ovary syndrome. Contraception 2010;82:276-280.
- Kriplani A, Periyasamy AJ, Agarwal N, et al. Effect of oral contraceptive containing ethinyl estradiol combined with drospirenone vs. desogestrel on clinical and biochemical parameters in patients with polycystic ovary syndrome. Contraception 2010;82:139-146.
- Morin-Papunen L, Martikainen H, McCarthy MI, et al. Comparison of metabolic and inflammatory outcomes in women who used oral contraceptives and the levonorgestrel-releasing intrauterine device in a general population. Am J Obstet Gynecol 2008;199:529.e1- e10.
- Mastorakos G, Koliopoulos C, Deligeoroglou E, et al. Effects of two forms of combined oral contraceptives on carbohydrate metabolism in adolescents with polycystic ovary syndrome. Fertil Steril 2006;85:420-427.
- Battaglia C, Mancini F, Fabbri R, et al. Polycystic ovary syndrome and cardiovascular risk in young patients treated with drospirenone-ethinylestradiol or contraceptive vaginal ring. A prospective, randomized, pilot study. Fertil Steril 2010;94:1417-1425.
- Adeniji AA, Essah PA, Nestler JE, Cheang KI. Metabolic effects of a commonly used combined hormonal oral contraceptive in women with and without polycystic ovary syndrome. J Womens Health (Larchmt) 2016;25:638-645.
- Macut D, Antic IB, Bjekic-Macut J. Cardiovascular risk factors and events in women with androgen excess. J Endocrinol Invest 2015;38:295-301.
- Azziz R. Androgen excess is the key element in polycystic ovary syndrome. Fertil Steril 2003;80:252-254.
- Tang T, Lord JM, Norman RJ, et al. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea, and subfertility. Cochrane Database Syst Rev 2012:CD003053.
- Costello MF, Shrestha B, Eden J, et al. Metformin versus oral contraceptive pill in polycystic ovary syndrome: A Cochrane review. Hum Reprod 2007;22:1200-1209.
- Harris-Glocker M, Davidson K, Kochman L, et al. Improvement in quality-of-life questionnaire measures in obese adolescent females with polycystic ovary syndrome treated with lifestyle changes and oral contraceptives, with or without metformin. Fertil Steril 2010;93:1016-1019.
- Hoeger K, Davidson K, Kochman L, et al. The impact of metformin, oral contraceptives, and lifestyle modification on polycystic ovary syndrome in obese adolescent women in two randomized, placebo-controlled clinical trials. J Clin Endocrinol Metab 2008;93:4299-4306.
- Dokras A, Sarwer DB, Allison KC, et al. Weight loss and lowering androgens predict improvements in health-related auality of life in women with PCOS. J Clin Endocrinol Metab 2016:jc20161896.
- Orio F, Muscogiuri G, Giallauria F, et al. Oral contraceptives versus physical exercise on cardiovascular and metabolic risk factors in women with polycystic ovary syndrome: A randomized controlled trial. Clin Endocrinol (Oxf) 2016; May 24. doi: 10.1111/cen.13112. [Epub ahead of print].
- Kaunitz AM, Bissonnette F, Monteiro I, et al. Levonorgestrel-releasing intrauterine system or medroxyprogesterone for heavy menstrual bleeding: A randomized controlled trial. Obstet Gynecol 2010;116:625-632.
- da Silva AV, de Melo AS, Barboza RP, et al. Levonorgestrel-releasing intrauterine system for women with polycystic ovary syndrome: Metabolic and clinical effects. Reprod Sci 2016;23:877-884.
- Lidegaard O, Nielsen LH, Skovlund CW, et al. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ 2011;343:d6423.
Emerging evidence supports that two metabolic phenotypes exist among women with PCOS. For metabolically healthy PCOS patients, managing menstrual symptoms, anovulation and androgen excess with COCs provides a simple and well-tolerated treatment regimen. In contrast, PCOS patients with metabolic syndrome are at high risk for type 2 diabetes, and COC use may contribute to hyperinsulinemia, adverse lipid changes, and endothelial changes associated with adverse cardiovascular risk. The use of a levonorgestrel intrauterine device combined with spironolactone (to manage hyperandrogenism) and metformin (to manage hyperinsulinism) may offer advantages to metabolically unhealthy PCOS patients.
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