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

Abstract

Estetrol (E 4 ) 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 (E 2 ), E 4 has 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 E 4 exhibits an activity profile distinct from that of E 2 on mammary gland. Compared with E 2 , E 4 acted as a low-affinity estrogen in both human in vitro and murine in vivo models. E 4 was 100 times less potent than E 2 to stimulate the proliferation of human breast epithelial (HBE) cells and murine mammary gland in vitro and in vivo respectively. This effect was prevented by fulvestrant and tamoxifen, supporting the notion that ERa (ESR1) is the main mediator of the estrogenic effect of E 4 on the breast. Interestingly, when E 4 was administered along with E 2 , it significantly antagonized the strong stimulatory effect of E 2 on HBE cell proliferation and on the growth of mammary ducts. This study characterizes for the first time the impact of E 4 on mammary gland. Our results highlight that E 4 is less potent than E 2 and exhibits antagonistic properties toward the proliferative effect of E 2 on breast epithelial cells. These data support E 4 as a potential new estrogen for clinical use with a reduced impact on breast proliferation.

Effects of drospirenone and norethisterone acetate combined with estradiol on mammographic density and proliferation of breast epithelial cells—A prospective randomized trial

“…Hirschberg, et al Maturitas 126 (2019) [18][19][20][21][22][23][24] proliferation [29]. Additionally, estretol, as an alternative to estradiol or conjugated equine estrogen, in combination with a progestogen has been suggested to be the next generation of safe MHT [30]. Although DRSP as a derivative of spironolactone is qualitatively different from classic progestogens, the present data indicate that it will not be the final solution for future breast safe MHT.…”

Use of estetrol with other steroids for attenuation of neonatal hypoxic-Ischemic brain injury: to combine or not to combine?

“…However, the presence of E2 abolished these effects mediated by E4 [34]. Our previous studies demonstrated that the concomitant exposure to E2 and E4 in vitro and in vivo resulted in a partially antagonized effect of E4 on the proliferation induced by E2 on HBE cells and on mammary gland growth [88]. These observations are in concert with our present results connected to the concomitant use of E4 and E2: neither in vitro nor in vivo combinations of E4 and E2 (except the combination of the highest dose of E4 with E2 in vitro ) showed any significant positive result compared to the vehicle group suggesting that E4 and E2 possibly antagonize each other effects.…”

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

“…Altogether, these powerful pharmacological tools allow us to uncouple nuclear and membrane actions of ERα with a selective activation of MISS using PaPE‐1 or EDC and of nuclear ERα using estetrol. The novel understanding of action of this new class of selective ER modulator–like molecules led to the idea that they would decrease the proliferative action of estrogens23, 29 and, thereby, lower the risk of breast and/or uterine cancer induced by sex hormones 30, 31…”