Ovulation inhibition by estetrol in an in vivo model

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.

Regularly cycling female rats were treated orally twice daily for four consecutive days, starting on the day of estrus, with E(4) (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 E(4) 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.

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 E4 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 ED(50) for the EE and the E(4) dose response curves shows that EE is 18 times more potent than E(4).

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.