Estetrol as estrogen in a combined oral contraceptive, from the first in-human study to the contraceptive efficacy

Abstract

Even though the use of combined oral contraceptive (COC) has numerous health benefits, it is associated with an increased risk of venous thromboembolism (VTE). Currently, the second generation COCs [ethinylestradiol (EE) with levonorgestrel (LNG)] are considered as the safest regarding the VTE risk but the androgenicity of LNG is responsible for undesirable side effects (acne, hirsutism and mood alteration) jeopardizing compliance. In the opposite, the use of less androgenic progestins or anti-androgenic progestins such as drospirenone (DRSP) is better tolerated but doubles the risk of VTE in comparison with EE/LNG. Replacing EE by a natural estrogen has been suggested to improve the VTE risk. Estetrol (E4) is a natural estrogen only produced by the human fetal liver. In-vivo and in-vitro fundamental studies suggest that E4 is safer than EE and estradiol (E2) on important estrogenic targets such as breast tissue and synthesis of liver proteins (responsible for hemostasis impairments associated with the use of estrogens). A vast clinical program has recently been conducted in order to evaluate the use of E4 as estrogen in a COC. A dose-finding program studied different combinations of E4 with DRSP or LNG. Ovulation inhibition, bleeding pattern, and tolerance were used to select the best E4-COC for further evaluation. All the E4-COCs tested were safe and capable of blocking ovulation. However, 15 mg E4 with 3 mg DRSP was associated with the best bleeding pattern and the highest tolerance. In addition, the changes in hemostasis parameters elicited by 15 mg E4/DRSP were significantly less pronounced than those recorded with EE/ DRSP, and similar or even lower than those seen with the safe EE/LNG. This combination was therefore selected to be further evaluated in a Phase 3 program where it confirmed its excellent safety and contraceptive efficacy.

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