The rediscovery of estetrol and its implications for estrogen treatment.

In 2001, the lead author of this paper, Herjan J.T. Coelingh Bennink at Pantarhei Bioscience (PRB; Zeist, The Netherlands), started a new research program on E4 with the aim to investigate whether E4 could be used as an estrogen for human therapeutic use. Historically crucial for the rediscovery of E4 was the first study on the bioavailability of E4 in rats, demonstrating a remarkable and much higher oral bioavailability than that of other natural estrogens. This finding was confirmed in humans, where E4 demonstrated an oral bioavailability of 70%-80%, a long elimination half-life of about 20-28 hours, and minimal binding to sex hormone-binding globulin. These characteristics made E4 notably more suitable for once-a-day oral dosing than other natural estrogens. 14 15 16 These findings were confirmed in 2002 by Johnson & Johnson (J&J; New Brunswick, NJ). This company was planning to develop E4 for menopausal hormone therapy (MHT), but after the publication of the Woman’s Health Initiative study in 2002, 17 J&J decided not to embark on MHT anymore. PRB then decided to discontinue efforts to develop E4 for MHT and shifted to the development of E4 for combined oral contraception (COC). The first presentation on “a new natural human estrogen” took place at the 10th World Congress on Menopause in Berlin (Germany) in 2002.

The rediscovery of E4 and the new research and development data stimulated many other researchers to evaluate the clinical potential of E4 for a range of new applications. Estetrol research is presently ongoing in dysmenorrhea, 35 endometriosis, 36 female sexual function, 37 wound healing, 38 neonatal hypoxic-ischemic encephalopathy, 39 and hair loss. 40 In addition, E4 has been proposed as a component of an oral male contraceptive. 41

A century after the discovery of the natural estrogens estrone, estradiol, and estriol, the human fetal estrogen estetrol has been rediscovered and investigated extensively. The journey of estetrol from its identification in 1965 and its rediscovery and successful clinical development since 2001 confirms its potential as a unique and most likely safer estrogen for human use.