Estrogen Regulation of Testicular Function

Evidence supporting a role for estrogen in male reproductive tract development and function has been collected from rodents and humans. These studies fall into three categories: i) localization of aromatase and the target proteinTable 1. ARKO mice have enlarged sex accessory organ weights presumably as a result of elevated serum testosterone levels and enhanced androgen action, and show disturbances of spermatogenesis, which is associated with increased apoptosis of developing germ cells [6,7]. However, the results of fertility assessment in ARKO mice have been rather inconsistent, sexual function being impaired in one line of mice and not in the other; these differences are thought to be due to the amounts of residual aromatase gene products in mutant mice [7,57]. In contrast to the lack of E2, overexpression of the aromatase gene and enhanced E2 production in mice induced cryptorchidism or undescended testis, spermatogenic arrest, Leydig cell hyperplasia, and decreased serum FSH and testosterone levels. Disruption of spermatogenesis was associated with decreased FSH levels while increased exposures to E2 induce Leydig cell hyperplasia [58]. Progressive degeneration of testicular tissue, dilation of the seminiferous tubules, and sexual behavioral problems are typical findings in αERKO mice [5]. Disruption of spermatogenesis has been attributed to fluid retention, which causes pressure atrophy of the seminiferous epithelium [59]. The obvious differences in the phenotypes of ARKO and αERKO mice, as were determined in early studies, implied that ERα is not the sole mediator of estrogen action and that another ER protein may be present in testicular cells. These speculations were confirmed by cloning of ERβ in the rat prostate and ovary [60]. Subsequently, the bulk of experimental evidence shows that ERβ regulates germ cell development. For example, ERα inactivation had no effect on the number of Sertoli cells and spermatogonia whereas ERβ inactivation increased the number of spermatogonia by more than 50% in neonatal mice [61]. However, it is surprising that in spite of the evidence for ERβ regulation of mitosis in spermatogonia, which serve as stem cells for the process of spermatogenesis, disturbances of sperm production were not evident in βERKO mice. On the other hand, the presence of ERα in Sertoli cells has not been demonstrated. Paradoxically, spermatogenic arrest occurs in α ERKO mice, which have ERβ protein. These observations suggest that testicular cells regulate Sertoli cell support of germ cell development through unidentified ERα-mediated mechanisms. This line of thinking is supported by data from experiments in which germ cells were transplanted from donor males homozygous for the mutation ERα-/to testes of wild-type ERα+/+ recipient mice depleted of germ cells. When mated to wild-type females, the recipients sired offspring heterozygous for the mutation ERα+/but retained the coat-color marker of the ERα-/donor mice. This finding confirmed that somatic cells in the testis, but not germ cells, have a requirement for ERα in order to support the process of spermatogenesis [62,63]. In contrast to the αERKO, βERKO males retain full fertility but tend to show increased incidence of prostate hyperplasia with advancing age[64]. Perhaps not unexpectedly, male αβERKO mice are infertile, which is likely due to ERα deficiency because these effects are absent in βERKO mice [65,66].