Characterization of the oestrogenic activity of non-aromatic steroids: are there male-specific endogenous oestrogen receptor modulators?
OBJECTIVE
The endogenous oestrogens have important biological functions in men as well as in women. Because 17beta-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.


METHODS
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 ERalpha and ERbetain vitro and in cultured cells.


RESULTS
Six of the non-aromatic steroids, that is, 5-androsten-3beta,17beta-diol, 5alpha-androstan-3beta,17beta-diol, 5(10)-oestren-3alpha,17beta-diol, 5(10)-oestren-3beta,17beta-diol, 4-oestren-3beta,17beta-diol and 5alpha-oestran-3beta,17beta-diol, were found to have physiologically relevant high binding affinity ( approximately 50% of that of oestrone) for human ERalpha and ERbeta. 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 ERalpha and ERbeta in a manner similar to that of 17beta-oestradiol.


CONCLUSIONS
These results provide evidence for the possibility that some of the endogenous androgen precursors or metabolites could serve as male-specific ER ligands.
Wang
Pan
P
Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Wen
Yujing
Y
Han
Gui-Zhen
GZ
Sidhu
Pritam Kaur
PK
Zhu
Bao Ting
BT
D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D012727:Sex Characteristics; D013256:Steroids / Q000378:metabolism*; D014158:Transcription, Genetic
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D013256:Steroids