INCB28060 The estrogenic activity of steroids with a
The estrogenic activity of steroids with a C19 methyl group may provide a selective advantage in estrogen physiology that is not provided by E2. In this regard, 5α-androstanediol has been proposed to be a second physiological estrogen in fetal mouse INCB28060 based on the timing of ERβ synthesis in mouse brain, which begins at embryonic day 10.5 [32,102,103], well before embryonic day 18.5 when aromatase (which catalyzes the synthesis of E2) is first expressed. Thus, there are at least two physiological estrogens in mouse brain. Moreover, other studies find that ERβ mediates the actions of 5α-androstanediol in human brain cells [33,67].
In addition, Δ5-androstenediol is synthesized in the brain [56,57], providing a third endogenous estrogen in mouse brain. Finally, 27-hydroxycholesterol also is present in the brain . Thus, there may be four physiological neuro-estrogens. The unique anti-inflammatory response in brain microglia due to binding of Δ5-androstenediol to ERβ may be the first of a series of specialized physiological activities for Δ5-androstenediol, 5α-androstanediol, and 27-hydroxycholesterol in the brain and other organs. It is interesting that E2 and Δ5-androstenediol regulate different physiological responses through ERβ in microglia.
We propose that some activities of the ER in different regions of the mammalian brain [32,34,35,105] were important in amphioxus or in lamprey. Although the head and brain are poorly developed in amphioxus [, , , ], many genes conserved between amphioxus and vertebrates are expressed in lamprey brain [107,109,110]. It appears that these genes were important in the evolution of the brain during the transition from amphioxus to lamprey [107,107,108,109]. It is tempting to speculate that transcriptional regulation of the SR in an ancestral amphioxus by Δ5-androstenediol, 5α-androstanediol, 27-hydroxycholesterol, or 27-OH paraestrol, as well as by E2, was important in brain evolution [85,86], which would place the origins of responses to estrogens in the brain as contemporary with its reproductive actions.
The physiological effects of Δ5-androstenediol, 5α-androstanediol, and 27-hydroxycholesterol and other alternative ligands, such as phytochemicals [13,14,16,47] in transcriptional activation of the ER in other organs such as liver , kidney and lung [, , ] also merit investigation.
Also relevant for the evolution of estrogen physiology is the presence in lamprey of an ancestor of AR and PR as well as, a corticoid receptor (CR) [4,20,96], which is the ancestor of the GR and MR [4,96]. These steroid receptors have transcriptional properties that are similar to their mammalian orthologs [40,112]. Crosstalk between the ER and the PR, GR, and MR may have contributed to the evolution of the brain [, , ] and other organs during the transition from amphioxus to lamprey.
Future research There is a need to verify the presence of Δ5-androstenediol, 5α-androstanediol, and 27-hydroxycholesterol in amphioxus and lamprey to provide evidence for the physiological activity of these alternative ligands early in the evolution of the ER. Synthesis of Δ5-androstenediol, 5α-androstanediol, and 27-hydroxycholesterol in amphioxus and lamprey can be studied through metabolism of radioactive cholesterol in tissue extracts from amphioxus and lamprey. Of course, transcriptional activation of amphioxus SR and lamprey ER by Δ5-androstenediol, 5α-androstanediol, and 27-hydroxycholesterol will be necessary to determine their biological activity in relation to E2. The functions of these alternative ligands in mammals merit further study in view of the evidence that 5α-androstanediol and Δ5-androstenediol are important in prostate  and brain microglia [49,55], respectively. Investigation of Δ5-androstenediol, 5α-androstanediol, and 27-hydroxycholesterol actions in tissues with ERα and ERβ during different stages in development may uncover additional physiological responses mediated by these ‘alternative’ estrogens. In this regard, the slow continuous increase in DHEA synthesis from birth, which is coupled with increased synthesis of Δ5-androstenediol , merits further study, as does the role of Δ5-androstenediol during fetal development , when DHEA levels are high [118,119].