Also important in binding of E to the
Also important in binding of E2 to the ER is the hydroxyl on the D ring, which has a stabilizing contact with His-524 in ERα (Fig. 7) and with His-475 in ERβ (Fig. S1) [8,9,36,37].
The spatial relationship of the functional groups on the A and D rings on E2 has been used to develop chemicals containing properly spaced A and D rings that are either estrogens, such as diethylstilbestrol (DES) or anti-estrogens such as 4-OH-tamoxifen (4-OH-TAM) and raloxifene [7,8,36,38,42] (Fig. 3).
Many synthetic chemicals in the environment contain a phenolic group corresponding to the A ring on E2 and often contain a D ring with some similarity to the D ring on E2, which together promotes binding to the ER, disrupting normal 7ACC1 physiology (Fig. 4) [10,11,43]. For example, the phenolic hydroxyls on bisphenol A (BPA) contact Arg-394, Glu-353 and His-524 in human ERα (Fig. 8) [16,44].
Similarly, many chemicals in plants contain an aromatic A ring corresponding to the A ring and a second six-carbon ring that can mimic the D ring on E2 (Fig. 5), and this promotes binding with nM Kd and transcriptional activation of ERα and ERβ [11,43,45]. For example, genistein (Figs. 9, Supplement Fig. S2)  and E2 (Figs. 7, Supplement Fig. S1) have similar contacts between their A rings and Arg-394 and Glu-353 in human ERα, and Arg-346 and Glu-305 in ERβ, as well as with their D rings and His-524 in ERα, and His-475 in ERβ [16,46].
Activities of estrogens with novel structures In the past decade the concept that a steroid must have an aromatic A ring with a C3-phenolic group to be a physiological estrogen has undergone revision because steroids with a different A ring have been shown to be transcriptional activators of ERα and ERβ, and thus act as physiological estrogens [32,, , , ]. Δ5-Androstenediol, 5α-androstanediol, and 27-hydroxycholesterol (Fig. 1) are examples of physiological estrogens that do not contain an aromatic A ring with a C3 phenolic group, and thus expand the potential structures of physiological ligands for the ER. Phytochemicals and synthetic industrial chemicals also have structures that differ from that of E2. Below we briefly review some physiological activities of these estrogens with novel structures.
An evolutionary perspective. What is the ancestral estrogen and what were its ancestral physiological activities – that is, why is E2 more than a reproductive hormone? The traditional model is that E2 and its metabolites are the main physiological estrogens in mammals, and thus the estrogenic actions of Δ5-androstenediol, 5α-androstanediol, and 27-hydroxycholesterol which lack an aromatic A ring are perplexing. The physiological actions of ERα and ERβ in non-reproductive tissues, such as the brain, also deserve elucidation. To begin to provide a perspective on these phenomena, we draw on Dobzhansky  with a modified paradigm ‘Nothing in estrogen physiology makes sense except in the light of evolution’. We use this evolutionary perspective [9,85,86] to investigate various inter-related questions including when did the ER arise, what were the ligand(s) that activate the ancestral ER receptor, and what were the physiological actions of the ER in basal chordates and vertebrates?
ERα and ERβ are expressed in the brain: transcriptional activation by 5α-androstanediol and Δ5-androstenediol The presence of an ER and SR in ovaries and testis in amphioxus indicates that some reproductive functions of estrogens in males and females evolved in a basal chordate [21,22,97], although transcriptional activation of the ER in uterus or prostate evolved hundreds of millions of years after the evolution of amphioxus, lamprey, and coelacanth. As mentioned above, the ER has physiological actions in the brain. ERα and ERβ are reported to be expressed in different regions in the brain during development in males and females [30,32,, , , ]. Thus, E2 is a neurosteroid, as well as a reproductive steroid. Moreover, Δ5-androstenediol and 5α-androstanediol, which have a different A ring than E2, have been found to be transcriptional activators of the brain ER [32,49].