Low-Dose Hormonal Contraceptives Do Not Increase Metabolic Syndrome Risk in Obese Women With PCOS: COMET-PCOS Trial
USA: Researchers have reported that low-dose combined hormonal contraceptives (CHCs) can effectively control symptoms of polycystic ovary syndrome (PCOS) without increasing the burden of metabolic syndrome in women with hyperandrogenic PCOS and overweight or obesity.
The findings are from the COMET-PCOS randomized clinical trial, published in PLOS Medicine by Anuja Dokras from the Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, and colleagues.
PCOS is a common endocrine disorder, frequently accompanied by obesity, insulin resistance, and a higher risk of cardiovascular disease. Combined oral contraceptive pills and metformin are widely used as first-line therapies. Yet, their long-term cardiometabolic safety—particularly their impact on metabolic syndrome (MetS), a key predictor of diabetes and heart disease—has remained uncertain. The COMET-PCOS trial was designed to address this evidence gap by directly comparing these commonly prescribed treatments.
In this multicenter, double-blind, double-dummy trial, 240 women aged 18 to 40 years with hyperandrogenic PCOS and a body mass index between 25 and 48 kg/m² were randomized to receive one of three interventions for 24 weeks: low-dose CHCs, extended-release metformin, or a combination of both. Hyperandrogenic PCOS was defined using the Rotterdam criteria. The primary outcome was the prevalence of metabolic syndrome at the end of the study, while secondary outcomes included changes in individual MetS components such as waist circumference, lipid levels, blood pressure, and glucose.
The study led to the following findings:
- At baseline, nearly one-third of participants met the criteria for metabolic syndrome, with similar proportions across all treatment groups.
- At study completion, metabolic syndrome prevalence remained comparable between groups, affecting 26.2% in the metformin group, 28.6% in the combined therapy group, and 28.8% in the CHC group.
- Statistical analysis showed no significant increase or decrease in metabolic syndrome prevalence with any of the interventions.
- Participants receiving low-dose CHCs showed modest but statistically significant reductions in waist circumference, body mass index, and central (android) fat mass from baseline.
- Metformin monotherapy did not result in significant improvements in waist circumference, BMI, or central fat measures.
- Gastrointestinal adverse effects were frequent with metformin, with over 64% of participants in metformin-containing groups reporting diarrhea.
- Abnormal uterine bleeding was the most commonly reported side effect among participants treated with CHCs.
The investigators acknowledged several limitations, including higher-than-anticipated dropout rates, which were partly attributed to medication side effects and disruptions caused by the COVID-19 pandemic. The study was also not powered to detect small differences in secondary outcomes, and the relatively short follow-up limits conclusions about long-term cardiovascular events.
Despite these constraints, the COMET-PCOS trial represents the largest randomized study to date examining the impact of CHCs and metformin on metabolic syndrome in this population. The results challenge the routine use of metformin—either alone or in combination with contraceptives—solely to reduce cardiometabolic risk in women with hyperandrogenic PCOS and obesity.
The authors suggest that low-dose CHCs may offer a more patient-centered first-line approach for symptom control without worsening metabolic risk, while emphasizing the need for longer and more personalized studies to guide future PCOS management.
Reference:
Dokras A, Coutifaris C, Remaley AT, Mehta NN, Playford MP, Kunselman AR, et al. (2025) Impact of combined hormonal contraceptives and metformin on metabolic syndrome in women with hyperandrogenic polycystic ovary syndrome and obesity: The COMET-PCOS randomized clinical trial. PLoS Med 22(12): e1004662. https://doi.org/10.1371/journal.pmed.1004662
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