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

Discussion

This systematic review with meta-analyses is the most up to date, rigorous synthesis of peer-reviewed literature which has investigated the effect of the COCP and metformin on clinical, hormonal and metabolic features of PCOS, in both adolescents and adults. The 56 studies included here which met rigorous inclusion criteria and addressed clinically important comparisons were rated as low, moderate or high risk of bias. Some comparisons were limited by small sample sizes. Overall, COCP offers effective PCOS treatment ameliorating hyperandrogenism and cycle irregularity with no advantage of specific subtypes of COCP. Metformin improves metabolic, weight and other clinical features with mild side effects alone and in combination with COCP.

This systematic review was completed to directly inform recommendations in the recently launched international PCOS evidenced-based guideline, adopted across 38 societies and 71 countries. The systematic review presented here and the guideline address key gaps in the management of PCOS, and the guideline provides clear, rigorous and robust evidence-based recommendations which can be used internationally. In this review, we addressed specific clinical controversies on the type of COCP and the role of metformin in this common condition.

Here in this systematic review to inform the guideline, we confirm the role of COCP alone for the management of hyperandrogenism and menstrual regulation. Specific recommendations on dose and constituents of the COCP cannot be made based on studies in PCOS alone, due to a high degree of heterogeneity across studies on COCP in PCOS. We therefore defer to general population literature on COCP, highlighting that lower dose COCP and second-generation progestins offer a better safety profile.[24]

We highlight that in combination with metformin, COCP is useful for the management of metabolic features of PCOS in adults. We note that mild GI-related side effects were reported with the addition of metformin, which in practice could lead to reduced compliance with therapy. Like all medications, side effects and their potential impact on a woman's quality of life and day-to-day activities should be considered when recommending metformin; however, side effects are usually mild, self-limiting and may be minimized with a lower starting dose.[7] Extended release preparations and taking metformin with food might also decrease GI-related side effects.[25] Moving forward, we recommend that international evidence-based recommendations for COCP use should be followed in practice (Box 1 and Box 2).

With metformin compared with placebo for adults with PCOS, our meta-analyses demonstrate that there is a statistically significant difference post-treatment in favour of metformin for BMI, testosterone, total cholesterol and triglycerides, for participants across all BMI categories. For participants with a BMI > 25 kg/m2, results indicate that there may be additive benefits for weight, BMI, total cholesterol and LDL. Weight is the primary concern for women with PCOS,[2] and they are more likely to have rapid weight gain and obesity.[26] In line with the previous comparisons, GI-related side effects were more prevalent in the metformin groups, and thus, this should be taken into account by clinicians. We would therefore recommend metformin for adult women with PCOS for the prevention of weight gain, hormonal (testosterone) and metabolic outcomes (cholesterol and triglycerides), and for prevention of weight gain and metabolic outcomes (cholesterol and LDL), in women with PCOS with BMI ≥ 25. It has also been identified in this review that there is inadequate evidence to suggest whether one dosing regimen of metformin is superior to another. Additionally, the longest study duration was 24 months. We recommend that metformin use in practice should follow international evidence-based guideline recommendations (Box 3).

We recommend that future RCT research includes more detailed reporting of randomization methods, funding of research and conflict of interest statements, allocation concealment and blinding of participants, investigators and outcome assessors, conducts sample size calculations and publishes study protocols prior to the commencement of a trial. We also recommend future RCTs investigate whether there is an optimum dosing regimen for metformin, in which combination of the pill may be superior for managing features of PCOS, and further RCTs investigating combinations of these medications. Side effects need to be more accurately documented and key impacts on quality of life assessed.

Limitations

We did not contact study authors for missing information or data conversions; thus, if outcome data were presented in a form not usable in a meta-analysis (eg as a median and interquartile range), or where studies stated that they had conducted a RCT but then did not describe the method of randomization, or used an inadequate method of randomization, they were excluded. Additionally, in cases where data were obtained from an existing high-quality systematic review which reported risk of bias using an appropriate method, the systematic review's appraisal was adopted. We acknowledge that critical appraisal is individual judgement based, and therefore, those conducted by other systematic reviewers may not be aligned with the judgements of this evidence review team, thus limiting the confidence in the effect estimates of some of results. Furthermore, our systematic review is at risk of language bias, as studies conducted in languages other than English were not considered. Overall, the primary weakness was the quality of existing studies, which underpin this review.

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