The history of the discovery of estetrol

The three major estrogens, estrone (E1), estradiol (E2) and estriol (E3) were identified and characterized in the 1930s; it then took more than 30 years before a new major estrogen, estetrol (15α-hydroxyestriol, E4) was identified. Here we try to highlight the pioneering work of a small group of scientists who made the new discovery possible. The formal identification of E4 was made by a group led by Egon Diczfalusy at the Karolinska Institute, Stockholm in 1967, but was preceded by a series of progressive steps beginning in 1955. Besides isolating the new steroid from maternal and neonatal urine, they were able to determine two unique characteristics of E4: it is present only during pregnancy and in the neonate, and it is produced by the fetal/neonatal liver using E2 as the substrate (phenolic pathway). Following the formal identification of E4 in Stockholm, another group was instrumental in increasing our knowledge of the biosynthesis of the new estrogen. The research group, led by Samuel Solomon at McGill University in Montreal proved that some androgens, and especially dehydroepiandrosterone sulfate (DHEAS), were converted into E4 by the fetoplacental unit (neutral pathway). Today, we know that although the fetal liver plays a key role in E4 production, the placenta is also involved through both the phenolic and neutral pathways. In the early days attempts were made to use conversion of neutral steroids into E4 for clinical purposes. A few investigations seemed to provide positive results, but it was soon realized that its evaluation during pregnancy was controversial due to differing results, making elevated E4 levels in cases of significant pregnancy complications difficult to interpret. However, years later studies on the biochemical and pharmacologic properties of E4, as well as data on its clinical efficacy and safety, led to its current use in hormonal contraception and menopausal hormone therapy (HT), and it is expected to play a major role in future estrogen therapies.