Estetrol (E4): A Comprehensive Monograph on a Novel Native Estrogen

Executive Summary

Estetrol (E4) is a naturally occurring human estrogenic steroid hormone that represents a significant innovation in women's health therapeutics. Produced exclusively by the fetal liver during pregnancy, its unique biological origin formed the basis for its development as a pharmaceutical agent with a potentially superior safety profile.[1] Estetrol is the first compound to be classified as a Native Estrogen with Selective Tissue activity (NEST), a designation stemming from its unique pharmacological mechanism. This mechanism involves the differential modulation of estrogen receptors, specifically uncoupling the activation of nuclear estrogen receptor alpha (ERα), which mediates desired estrogenic effects, from the activation of membrane ERα, which is implicated in adverse effects in tissues such as the breast and liver.[2]

Its primary approved indication is for oral contraception, in a fixed-dose combination with the progestin drospirenone, marketed under brand names including Nextstellis® and Drovelis®.[6] This approval marks the introduction of the first new estrogen for contraceptive use in the United States in over 50 years, offering a novel alternative to formulations based on the long-standing synthetic estrogen, ethinylestradiol.[1]