OR33-5 Low Systemic Levels of Segesterone Acetate are Required to Inhibit Ovulation in Women

Abstract

A one-year segesterone acetate (SA)/ethinyl estradiol (EE) contraceptive vaginal system (CVS; Annovera™) used to prevent pregnancy in women of reproductive age, was recently approved by the FDA (August 2018). Efficacy (Pearl Index of 2.98) and safety of the CVS were demonstrated in two phase 3, open-label, multicenter studies conducted in the US and internationally. The ring is self-inserted, left in place for 21 days and removed for 7 days in each cycle, and provides contraceptive efficacy for up to 13 cycles of use. It is designed to release 150 mcg SA and 13 mcg EE per day. This report reviews the evidence of systemic serum SA levels required for ovulation inhibition. SA is a potent synthetic progestin when given parenterally (eg, subcutaneous implant, transdermal gel, or vaginal ring), but, due to rapid inactivation by first-pass hepatic metabolism, is not biologically active when administered orally. SA specifically binds to progesterone receptors; it does not bind to sex hormone-binding globulin (SHBG) and has no estrogenic or androgenic activity. The effects of SA on ovulation inhibition were first examined in dose-finding studies of subdermal implants, which showed that the mechanism of ovulation inhibition was concentration dependent.1,2 Another study of subdermal implants releasing 45-50 mcg SA/day, showed ovulation did not occur with SA plasma levels >105 pmol/L; women who ovulated had SA levels ranging from 68 to <105 pmol/L.3 The effects of SA on ovulation inhibition were also evaluated in vaginal rings delivering 3 different doses (50, 75, 100 mcg/day) of SA for 6 months.4 These doses effectively inhibited ovulation, with SA serum levels remaining fairly constant through the study at ~125, 200 and 250 pmol/L, respectively, decreasing slightly over time.4 A study using a SA/estradiol transdermal gel demonstrated full suppression of ovulation and follicle growth at SA levels of 250 pmol/L.5 For better cycle control, EE was added to the vaginal ring for SA/EE (mcg/mcg per day) dosages of 50/10, 50/20, 150/15 (actual delivery 150/13), 150/20 and 200/15; ovulation inhibition was also evaluated in two trials with these doses.6,7 Overall, serum SA levels achieved with these rings were in the range of 200-300 pmol/L, well above levels required to inhibit ovulation.6,7 In both trials, body weight/BMI was inversely correlated with SA levels.6,7 The SA/EE CVS prevents ovulation when SA serum levels remain above 105 pmol. SA/EE CVS is novel, procedure-free and long-acting reversible contraceptive that can be used for up to one year. 1. Lahteenmaki PL, et al. Fertil Steril. 1985;44:20-24. 2. Haukkamaa M, et al. Contraception. 1992;45:49-55. 3. Diaz S, et al. Contraception. 1995;51:33-38. 4. Brache V, et al. Contraception. 2001;63:257-261. 5. Brache V, et al. Contraception. 2015;92:289-297. 6. Fraser IS, et al. Contraception. 2005;72:40-45. 7. Sivin I, et al. Contraception. 2005;71:122-129.