Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation

Estetrol (E4) is a natural estrogen produced exclusively by the human fetal liver during pregnancy. Its physiological activity remains unknown. In contrast to ethinyl estradiol and estradiol (E2), E4has a minimal impact on liver cell activity and could provide a better safety profile in contraception or hormone therapy. The aim of this study was to delineate if E4exhibits an activity profile distinct from that of E2on mammary gland. Compared with E2, E4acted as a low-affinity estrogen in both humanin vitroand murinein vivomodels. E4was 100 times less potent than E2to stimulate the proliferation of human breast epithelial (HBE) cells and murine mammary glandin vitroandin vivorespectively. This effect was prevented by fulvestrant and tamoxifen, supporting the notion that ERα (ESR1) is the main mediator of the estrogenic effect of E4on the breast. Interestingly, when E4was administered along with E2, it significantly antagonized the strong stimulatory effect of E2on HBE cell proliferation and on the growth of mammary ducts. This study characterizes for the first time the impact of E4on mammary gland. Our results highlight that E4is less potent than E2and exhibits antagonistic properties toward the proliferative effect of E2on breast epithelial cells. These data support E4as a potential new estrogen for clinical use with a reduced impact on breast proliferation.