Estetrol, a Natural Estrogen with Selective Tissue activity (NEST)

Abstract

ABSTRACT Introduction Current contraceptives can pose an increased risk of venous thromboembolism and breast cancer due to their pharmacological profile. Estetrol (E4) is a native estrogen produced by the human fetus during pregnancy, which has a pharmacological profile different from that of other estrogens. Objective Additional studies were conducted to better characterize the unique pharmacological and pharmacokinetic profile of E4. Methods E4 has been characterized in nonclinical studies, investigated in clinical trials as a component of contraceptives and is being evaluated for treatment of menopausal symptoms. Results E4 is quickly absorbed after oral administration and does not exhibit an extensive binding to plasma proteins in contrast to other estrogens. It has a half-life of at least 24h. It is transformed into inactive sulfo- and glucurono-conjugates, primarily excreted in urine. No potentially carcinogenic metabolites have been identified after E4 metabolization. E4 does not significantly affect CYP450 liver enzymes and has minimal impact on hemostatic parameters, plasma levels of lipids and glucose. In cell, human and animal studies, E4 has limited effects on normal and malignant breast tissue. At the cellular level, E4 like other estrogens, binds and activates the nuclear estrogen receptor α (ERα) and recruits the same coregulators, while selective estrogen receptor modulators (SERMs) recruit other coregulators. However, unlike the other estrogens, E4 induces very limited activity on membrane ERα and antagonizes this pathway in the presence of estradiol, thereby uniquely uncoupling nuclear and membrane activation. Conclusions Based on its unique structure, pharmacokinetic/dynamic properties and distinctive mode-of-action, E4 is considered a Natural Estrogen with Selective Tissues activity (NEST), with a favorable benefit-to-risk ratio. Disclosure Yes, this is sponsored by industry/sponsor: Estetra SRL (an affiliate company of Mithra Pharmaceuticals, Belgium; Publication support by Mayne Pharma Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Estetra SRL (an affiliate company of Mithra Pharmaceuticals, Belgium; Publication support by Mayne Pharma