Endocrine Abstracts

Estetrol (E4) is a natural human steroid, produced exclusively during pregnancy by the fetal liver. Estetrol has been discovered in 1965 by Diczfalusy at the Karolinska Institute in Stockholm.

The role of E4 in embryonic physiology and/or human pregnancy is not known. During human pregnancy E4 is detectable from 9 weeks pregnancy onwards. Estetrol reaches the maternal blood circulation via the placenta. Maternal and fetal E4 concentrations increase exponentially during pregnancy and peak at high levels at term with fetal levels about 10–20 times higher than maternal levels as confirmed by data obtained by Pantarhei Bioscience. Based on low receptor binding compared to estradiol (E2), E4 was thought to be a weak estrogen. Since the early eighties the molecule has been neglected.

The pharmacological properties of oral E4 as investigated by Pantarhei Bioscience can be summarised as follows. Estetrol is orally bioavailable in the rat and acts as an estrogen on bone, brain, vagina and endometrium. Estetrol suppresses hot flushes and inhibits ovulation. Surprisingly, E4 acts as an estrogen antagonist on the breast since it was shown to prevent development of breast tumors and to remove pre-existing breast tumors in the DMBA rat model.

In phase I studies in early postmenopausal women E4 showed high oral absorption, full dose linearity, high bioavailability, low inter-subject variability and a long elimination half-life with a mean of 28 hours. Estetrol appeared to be efficacious, safe and without side-effects up to a dose of 20 mg per day for 28 days.

Estetrol will be developed further for the treatment of breast cancer, prostate cancer, osteoporosis and for those Th2-mediated auto-immune diseases, that are known to improve during pregnancy.