Estrogen action: A historic perspective on the implications of considering alternative approaches

In the 50 years since the initial reports of a cognate estrogen receptor (ER), much has been learned about the diverse effects and mechanisms of estrogens, such as 17β-estradiol (E2). This expert narrative review briefly summarizes perspectives and/or recent work of the authors, who have been addressing different aspects of estrogen action, but take a common approach of using alternative considerations to gain insight into mechanisms with clinical relevance, and inform future studies, regarding estrogen action. Their “Top Ten” favorite alternatives that are discussed herein are as follows. 1 — E2 has actions by binding to a receptor that do not require its enzymatic conversion. 2 — Using a different strategy for antibody binding could make the estrogen receptor (ER) more discernible. 3 — Blocking ERs, rather than E2 production, may be a useful strategy for breast cancer therapy. 4 — Secretion of α-fetoprotein (AFP), rather than only levels of E2 and/or progesterone, may influence breast cancer risk. 5 — A peptide derived from the active site of AFP can produce the same benefits of the entire endogenous protein in endocrine cancers. 6 — Differential distribution of ER subtypes in the body and brain may underlie specific effects of estrogens. 7 — ERβ may be sufficient for the trophic effects of estrogen in the brain, and ERα may be the primary target of trophic effects in the body. 8 — ERβ may play a role in the trophic effects of androgens, and may also be relevant in the periphery. 9 — Downstream of E2's effects at ERβ, there may be consequences for biosynthesis of progestogens and/or androgens. 10 — Changes in histones and/or other factors, which may be downstream of ERβ, potentially underlie the divergent effects of E2 in the brain and peripheral tissues.