Effect of the Combined Oral Contraceptive Pill and/or Metformin in the Management of Polycystic Ovary Syndrome

A Systematic Review With Meta-Analyses

Helena Teede; Eliza C. Tassone; Terhi Piltonen; Jaideep Malhotra; Ben W. Mol; Alexia Peña; Selma F. Witchel; Anju Joham; Veryan McAllister; Daniela Romualdi; Mala Thondan; Michael Costello; Marie L. Misso

Disclosures

Clin Endocrinol. 2019;91(4):479-489. 

In This Article

Abstract and Introduction

Abstract

Background: Polycystic ovary syndrome (PCOS) has a prevalence of 8%-13%. Given the prevalence, diverse health impacts and variation in care, rigorous evidence-based guidelines are needed in PCOS management. This systematic review with meta-analyses aimed to investigate the effect of the combined oral contraceptive pill (COCP) and/or metformin in the management of hormonal and clinical features of PCOS, to inform international guidelines.

Methods: Electronic databases were searched systematically from inception until 11 January 2017 to inform the guideline process. Eligible studies were randomized controlled trials which investigated the effect of COCPs and/or metformin alone or combined on hormonal and clinical features in women with PCOS. Outcomes were prioritized as critical for informing a decision about an intervention or important or not important, according to GRADE. Articles were assessed by one author against selection criteria, in consultation with a second author. Data were double extracted independently by four authors, and data quality appraisal was completed. Meta-analyses were conducted, where appropriate.

Results: Fifty-six studies were eligible for inclusion. Outcomes prioritized by women and health professionals included the following: irregular cycles, insulin resistance, weight, BMI, thromboembolic events and gastrointestinal effects. In low-quality evidence in adolescents, meta-analyses demonstrated that metformin was better than COCP for BMI (mean difference [MD] −4.02 [−5.23, −2.81], P < 0.001); COCP was better than metformin for menstrual regulation (MD −0.19 [−0.25, −0.13], P < 0.00001). In low-quality evidence in adults, meta-analyses demonstrated that metformin was better than placebo for BMI (MD −0.48 [−0.94, −0.02], P = 0.04); metformin was better than COCP for fasting insulin (MD 4.00 [2.59, 5.41], P = 0.00001), whereas COCP was better than metformin for irregular cycles (MD 12.49 [1.34, 116.62], P = 0.03). Combined oral contraceptive pill alone was better than the combination with an anti-androgen for BMI (MD −3.04 [−5.45, −0.64], P = 0.01). Metformin was associated with generally mild gastrointestinal adverse events. Differences in statistical significance were observed when outcomes were subgrouped by BMI.

Conclusions: This review identified that COCP therapy has benefits for management of hyperandrogenism and menstrual regulation. Metformin combined with the COCP may be useful for management of metabolic features. There is minimal evidence of benefits of adding an anti-androgen to COCP therapy.

Metformin alone has benefits for adult women for management of weight, hormonal and metabolic outcomes, especially for women with BMI ≥ 25 kg/m2. There is inadequate evidence to suggest the optimal COCP formulation, or dosing regimen and formulation of metformin.

Introduction

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, with a prevalence of 8%-13%.[1] Many women remain undiagnosed, and delays in diagnosis are common. Indeed, an international study reported that it took over 2 years and seeing 3 or more healthcare professionals for over one-third of the women to receive the diagnosis.[2] The most widely accepted diagnostic criteria internationally for PCOS, the Rotterdam criteria,[3] require that women fulfil at least two of the following three criteria for diagnosis of PCOS: oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries on ultrasound.[3–5]

The aetiology of PCOS is largely unknown, though available information suggests that genetics, in addition to environmental and lifestyle factors, contribute to its development.[6] The condition is heterogeneous, and women may present with a number of reproductive (menstrual dysfunction, infertility and pregnancy complications), endocrine (hyperandrogenism, hirsutism and acne), metabolic (insulin resistance, diabetes, weight gain and obesity) and psychosocial (anxiety, depression and poor quality of life) symptoms.[4,7–10]

Whilst lifestyle management is recommended as the first-line intervention for women with PCOS,[4] medical management including the combined oral contraceptive pill (COCP), insulin sensitizers, anti-androgens and/or anti-obesity medications may be required. Combined oral contraceptive pill s are often prescribed for adolescents and adults with PCOS to ameliorate clinical symptoms related to hormonal disturbances. Their effect on clinically important outcomes such as menstrual cycles, hirsutism, anthropometry, androgen levels and metabolic outcomes is variably reported. Additionally, metformin is an extensively used insulin sensitizer, which has been evaluated alone or in combination with COCPs, anti-androgens and/or lifestyle interventions in randomized controlled trials (RCTs) in adult women and adolescent girls with PCOS.[11] The role of metformin in clinical care, however, remains uncertain with small, short-term studies and variable end-points.[12] Metformin is not approved for use in PCOS; however, it is not restricted from use in PCOS either. There is variability in the use of metformin for PCOS adolescents and women according to the treating clinician specialty.[13]

Given the prevalence of PCOS, the impact it has on multiple aspects of a woman's health, the long-term complications, and the current gap and inconsistencies in diagnosis and care, rigorous, evidence-based guidelines have been developed to guide health care.[7–10] In this process, medical management of PCOS with the COCP and metformin were prioritized.[14] The Australian Centre for Research Excellence in PCOS partnered with leading international societies European Society of Human Reproduction and Embryology (ESHRE) and American Society of Reproductive Medicine (ASRM) and collaborated with 37 organizations including the US Endocrine Society to create the first International Evidence-based Guideline for Assessment and Management in PCOS.[7–10] This brought together representatives of an international network across six continents, with widespread engagement and international partnership to drive awareness, patient self-management, improved, evidence-based practices and better health outcomes in PCOS.[14]

This extensive systematic review directly informed the evidence-based guidelines, aiming to investigate the effect of the COCP and/or metformin, alone or in combination, in the management of consumer and health professional prioritized hormonal and clinical outcomes in PCOS.[7–10]

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