Ovulation inhibition by estetrol in an in vivo model

Background: Currently, the synthetic steroid ethinylestradiol (EE) is the preferred estrogen in combined oral contraceptives. The aim of the present study was to evaluate the effectiveness of the natural steroid estetrol (E-4) as an ovulation inhibitor in rats when compared to EE. Study Design: Regularly cycling female rats were treated orally twice daily for four consecutive days, starting on the day of estrus, with E4 (0.03, 0.1, 0.3, 1.0 or 3.0 mg/kg), EE (0.0003, 0.001, 0.003, 0.01 or 0.03 mg/kg) or vehicle control (eight animals per group). In a second experiment conducted under the same experimental protocol, 2.0 mg/kg of E4 was administered as a single daily dose or as a dose of 1.0 mg/kg twice daily. In both studies, the primary end point was the number of ovulated oocytes in the genital tract. Results: Estetrol at the twice daily dose of 0.3 mg/kg and above inhibited ovulation. This effect was statistically significant (P<.05). The comparator, EE, significantly inhibited ovulation (p<.05) at the highest dose (0.03 mg/kg) administered twice daily. An E-4 dose of 2.0 mg/kg administered once daily for four consecutive days inhibited ovulation in four of eight rats. In contrast, when the same dose was administered in two separate doses, that is, 1.0 mg/kg twice daily, ovulation was inhibited in eight of eight rats. The ED50 for the EE and the E-4 dose response curves shows that EE is 18 times more potent than E-4. Conclusion: Twice daily administration of E-4 effectively inhibits ovulation in cycling rats. The effect is dose-dependent. The relative potency of E-4 is about 18 times less compared to that of EE. We conclude that based on these data, combined with available pharmacological and clinical data on the safety and efficacy of E-4, the human fetal estrogenic steroid estetrol is a potential candidate to replace EE in combined oral contraceptives. (c) 2008 Elsevier Inc. All rights reserved.