Effect of the combined oral contraceptive pill and/or metformin in the management of polycystic ovary syndrome: A systematic review with meta‐analyses
Open accessAbstract
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/m 2 . There is inadequate evidence to suggest the optimal COCP formulation, or dosing regimen and formulation of metformin.
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Use of COCPs containing CPA is not recommended as first-line treatment due to increased risk of venous thromboembolism in the general population.
“however, the use of COCPs containing CPA is not recommended as first-line treatment due to the increased risk of venous thromboembolism in the general population (12, 16).”
From Metformin and Combined Oral Contraceptive Pills in the Management of Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis (2024) · cites this paper as [12]
Box 1 (p. 8) says that 35 μg ethinyloestradiol plus cyproterone acetate (CPA) preparations should not be first-line in PCOS because of adverse effects, including venous thromboembolic risk, in line with general-population guidelines. The citing sentence extends that recommendation to all COCPs containing CPA; the passage specifies one formulation. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCOCP are generally regarded as more effective than metformin for management of hyperandrogenism and menstrual regulation in PCOS.
“Generally combined oral contraceptive pills (COCP) are regarded as more effective than metformin for the management of hyperandrogenism and menstrual regulation in PCOS (11, 12).”
From Metformin and Combined Oral Contraceptive Pills in the Management of Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis (2024) · cites this paper as [12]
The COCP-versus-metformin results for adults (section 3.6, p. 6) favor COCP for androgen measures and irregular cycles. In adolescents (section 3.5, p. 6), COCP improved menstrual regulation more, but the review found no significant difference in the reported androgen measures. The claim is therefore supported for adults, but its broad hyperandrogenism comparison across PCOS is not fully supported. (LLM, conf=0.84)
Experimental — accuracy not yet measuredOur systematic review confirms that metformin is superior to COCP in lowering fasting insulin levels.
“Our systematic review confirms that metformin is superior in lowering fasting insulin levels, total cholesterol, and triglycerides compared with COCP, in line with findings reported previously (12).”
From Metformin and Combined Oral Contraceptive Pills in the Management of Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis (2024) · cites this paper as [12]
Section 3.6 (p. 6) reports significantly better fasting-insulin results with metformin than with COCP in adults with PCOS. The claim does not specify adults: Section 3.5 (p. 6) found no significant fasting-insulin difference in adolescents. The full citing sentence also claims superiority for total cholesterol, for which Section 3.6 reports no significant difference. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOur systematic review confirms that metformin is superior to COCP in lowering total cholesterol.
“Our systematic review confirms that metformin is superior in lowering fasting insulin levels, total cholesterol, and triglycerides compared with COCP, in line with findings reported previously (12).”
From Metformin and Combined Oral Contraceptive Pills in the Management of Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis (2024) · cites this paper as [12]
Section 3.6 (p. 6) reports that metformin improved fasting insulin compared with COCP, but found no statistically significant difference in total cholesterol. Thus the cited review supports the fasting-insulin part of the citing sentence, not its claim that metformin was superior at lowering total cholesterol. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOur systematic review confirms that metformin is superior to COCP in lowering triglycerides.
“Our systematic review confirms that metformin is superior in lowering fasting insulin levels, total cholesterol, and triglycerides compared with COCP, in line with findings reported previously (12).”
From Metformin and Combined Oral Contraceptive Pills in the Management of Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis (2024) · cites this paper as [12]
Section 3.11 (p. 7) reports lower triglycerides with metformin than with metformin plus COCP, but that is not the claimed comparison with COCP alone. For the direct comparison in adolescents, section 3.5 (p. 6) reports no statistically significant triglyceride difference; section 3.6 (p. 6) does not report triglyceride superiority in adults. (LLM, conf=0.84)
Experimental — accuracy not yet measured
When comparing metformin plus oral contraceptive pill to oral contraceptive pill alone, a better outcome on fasting glucose was shown in favour of metformin plus oral contraceptive pill, with mean difference 0.38 mmol/l (95% CI 0.22 to 0.54).
“When comparing metformin plus OCP to OCP alone, a better outcome on fasting glucose has been shown by Teede et al. [50] in favour of metformin plus OCP (MD 0.38 mmol/l; 95% CI0.22 to 0.54).”
From From Prediabetes to Type 2 Diabetes Mellitus in Women with Polycystic Ovary Syndrome: Lifestyle and Pharmacological Management (2020) · cites this paper as [50]
For many outcomes such as weight, WHR, and lipids, the certainty of available evidence was low and recommendations were conditional.
“However, for many outcomes such as weight, WHR, and lipids, the certainty of the available evidence was low and recommendations were conditional.”
In a prior systematic review, metformin appeared to lower BMI and decrease insulin resistance compared to placebo in PCOS.
“In a systematic review, 13 metformin appeared to lower BMI and decrease insulin resistance compared to placebo.”
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- Authors
- Teede, H., Tassone, E. C., Piltonen, T., Malhotra, J., Mol, B. W., Peña, A., Witchel, S. F., Joham, A., McAllister, V., Romualdi, D., Thondan, M., Costello, M., & Misso, M. L.
- Affiliations
- Monash Health (AU)
- Monash University (AU)
- Oulu University Hospital (FI)
- Rainbow Hospital & Malhotra Nursing and Maternity Home Agra India
- Women's and Children's Hospital (AU)
- University of Pittsburgh (US)
- Polycystic Ovary Association of Australia Sydney New South Wales Australia
- Agostino Gemelli University Polyclinic (IT)
- UNSW Sydney (AU)
- Corresponding author
- Teede, Helena
- ORCID
- Venue
- Clinical Endocrinology
- Publisher
- Wiley
- Published
- 2019-06-17
- Volume
- 91
- Issue
- 4
- Pages
- 479-489
- ISSN
- 0300-0664 (ISSN-L)
- 1365-2265
- OpenAlex
- W2945153056
- Cited by
- 79
- References
- 21
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 7 · 2023: 15 · 2022: 13 · 2021: 7 · 2020: 15 · 2019: 2
- FWCI
- 1.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Monash University Research Portal (Monash University) (acceptedVersion, other-oa)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- polycystic ovary syndrome, combined oral contraceptives, metformin, menstrual regulation, insulin resistance, body mass index, hyperandrogenism, androgen receptor antagonists, thromboembolic events, gastrointestinal adverse effects, adolescents, weight loss, fasting insulin, hirsutism, acne, rosacea, hypertriglyceridemia
- MeSH terms
- Contraceptives, Oral, Combined, Female, Humans, Hypoglycemic Agents, Metformin, Polycystic Ovary Syndrome
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