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 17beta-estradiol (E(2)). 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 - E(2) 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 E(2) production, may be a useful strategy for breast cancer therapy. 4 - Secretion of alpha-fetoprotein (AFP), rather than only levels of E(2) 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 - ERbeta may be sufficient for the trophic effects of estrogen in the brain, and ERalpha may be the primary target of trophic effects in the body. 8 - ERbeta may play a role in the trophic effects of androgens, and may also be relevant in the periphery. 9 - Downstream of E(2)'s effects at ERbeta, there may be consequences for biosynthesis of progestogens and/or androgens. 10 - Changes in histones and/or other factors, which may be downstream of ERbeta, potentially underlie the divergent effects of E(2) in the brain and peripheral tissues.