(013) Estetrol Combined with Drospirenone: An Investigational Oral Contraceptive With A Selective Impact on Endocrine Parameters

Abstract

Abstract Introduction Combined oral hormone contraceptive use is associated with decreased circulating androgens (Burrows LJ, et al. J Sex Med. 2012) and increased hormone binding globulins (Mawet M, et al. Eu J Cont Rep Hlth Care. 2015). Estetrol (E4) is a human-specific estrogen produced by the fetal liver, and has selective action in different tissues. The combination of E4 and Drospirenone (DRSP) was evaluated in a Phase-2 study to determine the potential effects on endocrine parameters. Objectives To evaluate the change from baseline in serum concentration of various endocrine and liver protein markers at cycle 3 and 6 in subjects receiving E4/DRSP and two comparison combined oral contraceptive (COC) formulations. Methods In this randomized, open-label, three-arm parallel study, participants received E4 15 mg /DRSP 3mg (n = 38), or ethinyl-estradiol (EE) 30 g/Levonorgestrel (LNG) 150 g (n = 29) or EE 20 g/DRSP 3 mg (n = 31) in a 24/4-day regimen of 6 consecutive, 28-day treatment cycles. Changes from baseline in serum total testosterone (TT), free testosterone (FT), androstenedione, dehydroepiandrosterone sulfate (DHEA-S), cortisol binding globulin (CBG), sex hormone binding globulin (SHBG), and thyroxine binding globulin (TBG) were determined at cycle 3 and 6. Potential differences between baseline and cycle 3 and 6 for all treatments, as well as pairwise comparisons of E4/DRSP and each of the other two formulations are considered statistically significant with an exploratory P-value < 0.05. Results TBG was significantly increased with EE/LNG (47% and 37%) and EE/DRSP (80% and 70%) at cycle 3 and 6. TBG was also increased significantly but to a lesser extent with E4/DRSP (27% and 17%). CBG increased at cycle 6 in all treatments. The increase in CBG was significantly greater with EE/LNG (152%) and EE/DRSP (140%) than that noted for E4/DRSP (40%). A significant increase in SHBG was observed at cycle 3 (240%) and 6 (251%) with EE/DRSP as compared to baseline or E4/DRSP (52% and 55%). At cycle 3, a significant decrease in TT was observed for E4/DRSP (35%), EE/LNG (40.5%), and EE/DRSP (41%). FT was significantly reduced at cycle 3 for E4/DRSP, EE/LNG, and EE/DRSP at 50%, 60%, and 75%, respectively. At cycle 6, a similar pattern of significant reductions in both TT and FT was observed with each treatment. Pairwise comparison, revealed no significant differences in TT and FT among groups. There were significant decreases in androstenedione at cycle 3 and 6, with E4/DRSP (32% and 31%), EE/LNG (44% and 49%), and EE/DRSP (40% and 40%). DHEA-S was significantly reduced from baseline at cycle 3 and 6 in all treatments. There was a significant difference in DHEA-S at cycle 6 with EE/DRSP (27%) compared to E4/DRSP (11%). Conclusions E4/DRSP had lower increases in hormone binding globulins compared to EE/LNG or EE/DRSP. Increases in SHBG were significantly higher for EE/DRSP than E4/DRSP. A decrease in TT and FT with E4/DRSP was not significantly different from EE/LNG or EE/DRSP. E4/DRSP had a significantly lower impact on DHEA-S levels than EE/DRSP. Disclosure Yes - Mithra Women's Health. Industry initiated, executed and funded study – Yes.