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.

Conclusion

This extensive systematic review with meta-analyses advances the literature as 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. It addresses key gaps on the role of these agents in PCOS and the role of metformin. We confirm that COCP therapy for women with PCOS improves hyperandrogenism and menstrual regulation. No type of COCP is adequately proven as superior, and aligned with general population recommendations and side effect profiles, higher dose oestrogen preparations should not be first line and lower dose preparations are recommended. We clarify the role of metformin alone or in combination with COCP showing it is useful for the management of metabolic features of PCOS specifically weight, hormonal and metabolic outcomes, especially in women with PCOS with a BMI ≥ 25 kg/m². We have directly informed international guideline recommendations and identified research gaps, including the need for additional high-quality RCTs to define optimal type and dose of both COCPs and metformin and to assess their impact on quality of life in PCOS.

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Acknowledgements
We thank Estifanos Baye and Ching Shan Wan for assisting with the data extraction and critical appraisals of studies included in this review. Ben W. Mol supported by a NHMRC Practitioner Fellowship (GNT1082548). BWM reports consultancy for ObsEva, Merck Merck KGaA and Guerbet. Michael Costello provided shares in Virtus Health and past sponsorship from Merck Serono for conference presentations.

Data Accessibility
The authors confirm that the data supporting the findings of this study are available within the article and the technical report of the international PCOS guideline, available at https://www.monash.edu/__data/assets/pdf_file/0020/1412282/PCOS-Guideline_Technical-report.pdf.

Funding information
The guideline was primarily funded by the National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Guideline evidence synthesis staff received salary from the institution (MM and ET). Travel expenses were covered by the sponsoring organizations.

Box 1. COCP recommendations in the international evidence-based guideline for the assessment and management of polycystic ovary syndrome*
The COCP alone should be recommended in adult women with PCOS for management of hyperandrogenism and/or irregular menstrual cycles (EBR) The COCP alone should be considered in adolescents with a clear diagnosis of PCOS for management of clinical hyperandrogenism and/or irregular menstrual cycles (EBR) The COCP could be considered in adolescents who are deemed "at risk" but not yet diagnosed with PCOS, for management of clinical hyperandrogenism and irregular menstrual cycles (EBR) Specific types or dose of progestins, oestrogens or combinations of COCP cannot currently be recommended in adults and adolescents with PCOS, and practice should be informed by general population guidelines (EBR) The 35 μg ethinyloestradiol plus cyproterone acetate preparations should not be considered first line in PCOS as per general population guidelines, due to adverse effects including venous thromboembolic risks (CCR) When prescribing COCPs in adults and adolescents with PCOS: ∘ various COCP preparations have similar efficacy in treating hirsutism ∘ the lowest effective oestrogen doses (such as 20–30 μg of ethinyloestradiol or equivalent), and natural oestrogen preparations should be considered, balancing efficacy, metabolic risk profile, side effects, cost and availability othe generally limited evidence on effects of COCPs in PCOS should be appreciated with practice informed by general population guidelines (WHO Guidelines) ∘ the relative and absolute contraindications and side effects of COCPs should be considered and be the subject of discussion oPCOS-specific risk factors such as high BMI, hyperlipidaemia and hypertension should be considered (CPP)

*These recommendations were informed by evidence, where evidence was inadequate clinical consensus recommendations were made as outlined in the international guideline on PCOS.^7–10 EBR, evidence-based recommendation; CCR, clinical consensus recommendation; CPP, clinical practice points.

Box 2. COCP in combination with metformin and/or anti-androgen pharmacological agents recommendations in the international evidence-based guideline for the assessment and management of polycystic ovary syndrome*
In combination with the COCP, metformin should be considered in women with PCOS for management of metabolic features where COCP and lifestyle changes do not achieve desired goals (EBR) In combination with the COCP, metformin could be considered in adolescents with PCOS and BMI ≥ 25 kg/m² where COCP and lifestyle changes do not achieve desired goals (EBR) In combination with the COCP, metformin may be most beneficial in high metabolic risk groups including those with diabetes risk factors, impaired glucose tolerance or high-risk ethnic groups (CPP) In combination with the COCP, anti-androgens should only be considered in PCOS to treat hirsutism, after 6 months or more of COCP and cosmetic therapy have failed to adequately improve symptoms (EBR) In combination with the COCP, anti-androgens could be considered for the treatment of androgen-related alopecia in PCOS (CCR) In PCOS, anti-androgens must be used with effective contraception, to avoid male foetal undervirilization. Variable availability and regulatory status of these agents are notable, and for some agents, potential liver toxicity requires caution (CPP)

Box 3. Metformin recommendations in the international evidence-based guideline for the assessment and management of polycystic ovary syndrome*
Metformin in addition to lifestyle could be recommended in adult women with PCOS, for the treatment of weight, hormonal and metabolic outcomes (EBR) Metformin in addition to lifestyle should be considered in adult women with PCOS with BMI ≥ 25 kg/m² for management of weight and metabolic outcomes (EBR) Metformin in additional to lifestyle could be considered in adolescents with a clear diagnosis of PCOS or with symptoms of PCOS before the diagnosis is made (EBR) Metformin may offer greater benefit in high metabolic risk groups including those with diabetes risk factors, impaired glucose tolerance or high-risk ethnic groups (CPP) Where metformin is prescribed the following should be considered ▪ adverse effects, including gastrointestinal side effects that are generally dose dependent and self-limiting, should be the subject of individualized discussion ▪ starting at a low dose, with 500 mg increments 1–2 weekly and extended release preparations may minimize side effects ▪ metformin use appears safe long-term, based on use in other populations; however, ongoing requirement should be considered and use may be associated with low vitamin B12 levels ▪ use is generally off label, and health professionals should inform women and discuss the evidence, possible concerns and side effects. (CPP)

Authors and Disclosures

Helena Teede^1,2, Eliza C. Tassone¹, Terhi Piltonen³, Jaideep Malhotra⁴, Ben W. Mol⁵, Alexia Peña⁶, Selma F. Witchel⁷, Anju Joham^1,2, Veryan McAllister⁸, Daniela Romualdi⁹, Mala Thondan^1,10, Michael Costello¹¹ and Marie L. Misso¹

¹Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Clayton, Victoria, Australia
²Department of Diabetes and Vascular Medicine, Monash Health, Clayton, Victoria, Australia
³Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
⁴Rainbow Hospital & Malhotra Nursing and Maternity Home, Agra, India
⁵Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
⁶Discipline of Paediatrics, Endocrinology and Diabetes Department, Women's and Children's Hospital, The University of Adelaide and Robinson Research Institute, North Adelaide, South Australia, Australia
⁷Peadiatric Endocrinology, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania
⁸Polycystic Ovary Association of Australia, Sydney, New South Wales, Australia
⁹Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
¹⁰HARP Family Medical, Kew, Victoria, Australia
¹¹University of New South Wales, Sydney, New South Wales, Australia

Correspondence
Helena Teede, Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Locked Bag 29, Clayton, Vic. 3168, Australia. Email: Helena.Teede@monash.edu

Authors' Contribution
All authors contributed to developing the questions and corresponding PICO, and prioritized the outcomes. M.M designed the search strategy (with input from HT), ran the database searches, screened articles, performed data extraction and critically appraisal, including risk of bias and GRADE, completed the statistical analyses and contributed to the write up of the manuscript. E.C.T performed data extractions, critically appraised articles and contributed to the write up of the manuscript. H.T designed the guideline project, obtained funding, chaired the evidence review workshop and guideline development group and contributed to the write up of the manuscript. T.P critically revised the manuscript. All authors assisted in interpretation of the synthesized literature and all approved the final version for submission.

Conflict of Interest
Eliza C Tassone, Tehri Piltonen, Jaideep Malhotra, Alexia Peña, Selma F Witchel, Anju Joham, Veryan McAllister, Daniela Romualdi, Mala Thondan and Marie Misso declared no conflicts of interest.

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