Characterization of the oestrogenic activity of non‐aromatic steroids: are there male‐specific endogenous oestrogen receptor modulators?

Background and purpose:  The endogenous oestrogens have important biological functions in men as well as in women. Because 17β‐oestradiol and oestrone are also formed in the male body, these aromatic oestrogens are generally thought to be responsible for exerting the required oestrogenic functions in the male. In the present study, we tested the hypothesis that some of the non‐aromatic steroids that are androgen precursors or metabolites with hydroxyl groups at C‐3 and/or C‐17 positions may also be able to serve as ligands for the oestrogen receptors (ER) in the male. Experimental approach:  A total of sixty non‐aromatic steroids (selected from families of androstens, androstans, androstadiens, oestrens and oestrans) were analysed for their ability to bind and activate the human ERα and ERβ in vitro and in cultured cells. Key results:  Six of the non‐aromatic steroids, that is, 5‐androsten‐3β,17β‐diol, 5α‐androstan‐3β,17β‐diol, 5(10)‐oestren‐3α,17β‐diol, 5(10)‐oestren‐3β,17β‐diol, 4‐oestren‐3β,17β‐diol and 5α‐oestran‐3β,17β‐diol, were found to have physiologically relevant high binding affinity (∼50% of that of oestrone) for human ERα and ERβ. These non‐aromatic steroids also activated the transcriptional activity of human ERs and elicited biological responses (such as growth stimulation) in two representative ER‐positive human cancer cell lines (MCF‐7 and LNCaP) with physiologically relevant potency and efficacy. Molecular docking analysis of these six active compounds showed that they could bind to ERα and ERβ in a manner similar to that of 17β‐oestradiol. Conclusions and implications:  These results provide evidence for the possibility that some of the endogenous androgen precursors or metabolites could serve as male‐specific ER ligands.