DES exerts its anti-androgen effects mainly through classical ER signaling, particularly via ERα
2005 Study Abstract
It is now accepted that estrogens play a role in male fertility and that exposure to exogenous estrogens during fetal/neonatal life can lead to reproductive disorders in the male.
However, the estrogen receptor (ER)-mediated processes involved in the regulation of male reproduction during fetal and neonatal development are still largely unclear.
We previously reported that ER beta deficiency affects gametogenesis in mice but changes neither the number nor the differentiated functions of fetal Leydig cells.
We recently showed, in an organotypic culture model, that estradiol and diethylstilbestrol decrease the number and differentiated functions of Leydig cells in rat testes explanted at 14.5 dpc. Furthermore, the exposure of laboratory animals to high doses of exogenous estrogenic compounds during fetal or neonatal life leads to an increase in the frequency of hypospadias and cryptorchidism. Lastly, the male offspring of women treated with DES during pregnancy have a higher incidence of cryptorchidism and hypospadias.
We show here that ER alpha-deficient mice (ER alpha-/-) display higher levels of testicular testosterone secretion than wild-type mice from fetal d 13.5 onwards.
This results from higher levels of steroidogenic activity per fetal Leydig cell, as indicated by the hypertrophy of these cells and the higher levels of mRNA for StAR, P450c17 and P450scc in the testis, for a similar number of Leydig cells. Because LH is not produced on fetal d 13.5 and because no change in plasma LH concentration was observed in 2-d-old ER alpha-deficient mice, LH is probably not involved in the effects of estrogens on testicular steroidogenesis in fetal and early neonatal Leydig cells. Furthermore, inactivation of ER beta did not change the effect of ER alpha inactivation on steroidogenesis. Lastly, in an organ culture system, 1 mum diethylstilbestrol (DES) decreased the testosterone secretion of wild-type fetal and neonatal testes but not of ER alpha-/- testes.
Thus, this study shows that endogenous estrogens physiologically inhibit steroidogenesis via ER alpha by acting directly on the testis early in fetal and neonatal development.
Sources and more information
- Full text (free access) : Endogenous Estrogens Inhibit Mouse Fetal Leydig Cell Development via Estrogen Receptor α, Endocrinology, NCBI PubMed PMID: 15661855, 2005 May.
- Identification of fetal Leydig cells featured image credit academic.oup.