Effects of estetrol/drospirenone versus ethinyl estradiol/drospirenone on glucose tolerance in women with polycystic ovary syndrome: A randomised controlled trial

AIMS: To compare the effects of estetrol/drospirenone (E4/DRSP) and ethinyl estradiol/drospirenone (EE/DRSP) on glucose tolerance in women with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: This open-label, randomised crossover trial was conducted from January 2024 to January 2025. Women with PCOS, diagnosed according to the modified 2003 Rotterdam criteria, received three cycles of either E4 15 mg/DRSP 3 mg or EE 30 mcg/DRSP 3 mg. After a 2-month washout, participants crossed over to the alternate regimen for three further cycles. Glucose tolerance (via 75 g oral glucose tolerance test [OGTT]), insulin levels and homeostatic model assessment for insulin resistance (HOMA-IR) were compared between treatments. RESULTS: Of 66 women enrolled, 61 completed both treatment phases. Baseline characteristics were comparable. No significant differences were observed in the mean changes in 2-h OGTT (E4/DRSP: 4.65 mg/dL [95% confidence interval (CI) -2.37 to 11.66] vs. EE/DRSP: 14.40 mg/dL [95% CI 7.50-21.29]; p = 0.05; upper boundary for non-inferiority margin of 14.29), 1-h insulin levels (-1.04 μU/mL [95% CI -25.94 to 23.86] vs. -0.77 μU/mL [95% CI -25.24 to 23.70]; p = 0.99; upper boundary for non-inferiority margin of 50.72) or HOMA-IR (0.28 [95% CI -0.24 to 0.80] vs. 0.60 [95% CI 0.09-1.11]; p = 0.39; upper boundary for non-inferiority margin of 1.06). CONCLUSION: E4/DRSP was not inferior to EE/DRSP in its effects on glucose tolerance, insulin levels and HOMA-IR, supporting its use as a potential oral contraceptive option in women with PCOS.