Contraceptive effectiveness and safety of ormeloxifene: a systematic review

Objective To systematically review the contraceptive safety and effectiveness of ormeloxifene, a non-hormonal selective oestrogen receptor modulator, among reproductive-age women. Methods A comprehensive search was performed across MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar. No restrictions were applied regarding language, geography or publication year. Eligible studies included interventional and observational designs that evaluated the contraceptive effectiveness and/or safety of ormeloxifene. Two reviewers independently extracted data using a standardised form, assessed the risk of bias for individual studies, and graded the certainty of evidence using design-appropriate tools. Results The review included 14 studies on contraceptive use of ormeloxifene and 41 studies assessing its safety in non-contraceptive contexts. Twelve contraceptive studies reported Pearl Indices ranging from 0.48 to 4.2 per 100 woman-years, with failure rates between 0.8% and 10.1%. No serious adverse events such as thromboembolism or hepatotoxicity were reported. Two cases of benign endometrial hyperplasia were reported, and transient reductions in lactation were noted among 5.7% of women at 1 month, decreasing to 2% at 6 months among women using ormeloxifene as contraception. Infant exposure during breastfeeding remained below 10% of the maternal dose. The most common side effects were menstrual irregularities, leading to discontinuation in up to 31.5% of users. Continuation rates were high at 3–6 months (>85–100%), declining to 27–91% in larger cohorts involving longer follow-up extending beyond 12 months. Method satisfaction was consistently high (75–95%). All 14 studies on contraceptive use were conducted in India, had a high risk of bias, and only four were multicentre studies. Conclusions Ormeloxifene shows promise as a moderately effective, safe and user-acceptable contraceptive option. The current evidence is limited by methodological weaknesses and geographic concentration. High-quality, large-scale studies in diverse populations are essential to establish ormeloxifene’s comparative effectiveness and safety with greater certainty and support its inclusion in global contraceptive guidelines. PROSPERO registration number CRD42024622516.