By Robert W. Rebar, MD

Professor and Founding Chair Emeritus, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo

Dr. Rebar reports no financial relationships relevant to this field of study.

SYNOPSIS: This systematic review documents the effectiveness of combined oral contraceptive pills in treating hyperandrogenism and irregular menses, and of metformin in addressing the metabolic disturbances in women with polycystic ovary syndrome.

SOURCE: Teede H, Tassone EC, Piltonen T, et al. Effect of the combined oral contraceptive pill and/or metformin in the management of polycystic ovary syndrome: A systematic review with meta-analyses. Clin Endocrinol (Oxf) 2019;91:479-489.

In part, this systematic review was used as evidence for the development of the international evidence-based guidelines for polycystic ovary syndrome (PCOS) adopted across 38 societies and 71 countries.¹ A total of 56 randomized controlled trials identified from electronic databases prior to Jan. 11, 2017, were included in this systematic review. Researchers evaluated data about the effects of combined oral contraceptive pills (COCPs) and/or metformin alone or combined on hormonal and clinical features in PCOS. The length of treatment varied from three to 24 months in those included studies, and sample sizes varied from 10 to 253 participants. Fully 48 of the included studies were conducted in adults, six were in adolescents, and two did not report age. Mean body mass index (BMI) varied across studies, from the normal range (18.50-24.99 kg/m²) to obese class III (≥ 40.00 kg/m²). In general, side effects of therapy were inadequately detailed. Overall, the literature was found to be of poor quality, limiting the ability to draw firm conclusions.

In low-quality evidence in adults, meta-analyses indicated that metformin was better than placebo for reducing BMI (P < 0.04); metformin was better than COCPs with regard to fasting insulin levels (P = 0.00001); but COCPs were better than metformin for irregular bleeding (P = 0.03). COCPs alone were more effective than COCPs with an anti-androgen for BMI (P = 0.01). In low-quality evidence in adolescents, meta-analyses indicated that metformin was better than COCPs for controlling BMI (P < 0.001), but COCPs were better than metformin for menstrual irregularity (P < 0.00001). The studies documented that metformin typically was associated with mild gastrointestinal adverse events.

The authors concluded that COCPs have benefits for the management of hyperandrogenism and menstrual irregularity and that metformin combined with COCPs might be useful for the management of metabolic abnormalities. There was little evidence that anti-androgen added to COCPs provided additional benefit. Metformin alone benefited women for management of weight and metabolic features, particularly for women with BMI ≥ 25 kg/m². The authors were unable to reach any conclusions about the types and dosages of COCPs that were most appropriate or about the dosing and formulation of metformin that was most effective.

COMMENTARY

Quite frankly, this systematic review is neither very definitive nor informative, largely because of the poor quality of the studies. This is the case despite the fact that it has been noted that PCOS is the most common endocrine disorder in women of reproductive age, with a prevalence of 8% to 13%.² However, this less-than-perfect study provides me with the opportunity to offer some of my thoughts about the management of women with PCOS.

To my way of thinking, management has been complicated by the publication and widespread adoption of the diagnostic criteria developed at the Rotterdam consensus conference.³ This viewpoint has been echoed by conclusions reached at a conference conducted by the National Institutes of Health in 2012, which I attended, but not formally published in the scientific literature.⁴ The Rotterdam criteria did not separate women affected by PCOS by BMI or by the presence or absence of evidence of hyperandrogenism or irregular or absent menses. All the affected women are typically “lumped together,” making it more difficult to assess what specific treatments are best for which phenotypes. The same is true of the randomized trials that formed the basis for the systematic review by Teede et al and served as the evidence for some of the published international guidelines. To be sure, this systematic review examined the effect of BMI, but it was unable to look in-depth at all of the individual features associated with PCOS.

In an international consensus workshop sponsored by the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology in Amsterdam, it was noted that not all PCOS phenotypes have similar metabolic risk.⁵ It was further appreciated that women affected with both hyperandrogenemia and oligomenorrhea are at most risk; this is the group most likely to benefit from metformin. Thus, it is important to remember that metformin need not — and I say should not — be administered to all women with a diagnosis of PCOS. It should be reserved for those in high metabolic risk groups, including those with diabetes risk factors, impaired glucose tolerance, or high-risk ethnic groups, as actually spelled out in the international guidelines. Administration of metformin is associated with the possibility of real and common side effects, including nausea and diarrhea. Lactic acidosis is an extremely rare but significant potential side effect as well. Consequently, judicious use is warranted. Over the years, I have had a significant number of women refuse to continue metformin for the long term because of the bothersome gastrointestinal side effects.

Treatment of women with PCOS aims to address the major complaints of those affected. First and foremost, lifestyle modification is advised and encouraged, but it alone is seldom effective therapy. Medically, COCPs provide first-line therapy for those complaining of menstrual irregularity and signs and symptoms of hyperandrogenemia. There is no evidence that any one low-dose COCP is better than another in women with PCOS. Although not addressed specifically in the study by Teede et al, the addition of an anti-androgen, most commonly spironolactone, has long been known to have a positive effect on the hyperandrogenism.⁶ No anti-androgen should be administered to women with hirsutism who are not also using effective contraception because of the potential effect on any developing female fetus. Clomiphene citrate (Food and Drug Administration [FDA]-approved) or letrozole, not FDA-approved but with documented efficacy,^1,7 is first-line therapy for affected women with infertility.

It is important to remember that not all women who meet the diagnostic criteria for metabolic syndrome have PCOS, and not all women with PCOS have the features of metabolic syndrome. Metformin is not a miracle drug, but merely one that belongs in the armamentarium of clinicians tasked with treating women with PCOS.

REFERENCES

1. Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 2018;110:364-379.
2. 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.
3. 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.
4. National Institutes of Health. Final report. Evidence-based methodology workshop on polycystic ovary syndrome. Dec. 3-5, 2012. Available at: https://prevention.nih.gov/sites/default/files/2018-06/FinalReport.pdf. Accessed Dec. 4, 2019.
5. Fauser BC, Tarlatzis BC, Rebar RW, 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.
6. Cumming DC, Yang JC, Rebar RW, Yen SS. Treatment of hirsutism with spironolactone. JAMA 1982;247:1295-1298.
7. 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.