Oestradiol-induced spermatogenesis requires a functional androgen receptor

Abstract

Spermatogenesis requires androgen but, paradoxically, oestradiol (E2) treatment stimulates spermatogenic development in gonadotrophin- and androgen-deficient hypogonadal (hpg) mice. The mechanisms of E2-induced spermatogenesis were investigated by determining intratesticular E2 levels and testis cell populations in E2-treated hpg male mice, and E2 spermatogenic actions were determined in androgen receptor-knockout (ARKO) mice. Despite increased serum E2 concentrations (150-300 pmol L(-1)), intratesticular E2 concentrations declined fivefold (P < 0.001) in E2-treated v. untreated hpg male mice. Serum FSH reached 40% of normal and total testicular numbers of known FSH-responsive Sertoli, spermatogonia and meiotic spermatocyte populations were significantly (P < 0.001) elevated 1.7-, 4- and 13-fold, respectively. However, E2 administration also increased androgen-dependent pachytene spermatocytes and post-meiotic spermatids to levels comparable with testosterone-treated hpg testes. Selective investigation of androgen receptor involvement used E2-treated ARKO mice, which were found to exhibit increased (1.6-fold; P < 0.05) intratesticular E2 concentrations and suppression of the elevated serum gonadotrophins, although FSH remained twofold higher than normal. However, testis size and total Sertoli, spermatogonia and spermatocyte numbers were not increased in E2-treated ARKO male mice. Therefore, E2-stimulated murine spermatogenic development occurs with markedly suppressed and not elevated intratesticular E2 levels and displays an absolute requirement for functional androgen receptors. We propose that this paradoxical E2 spermatogenic response is explained by predominantly extratesticular E2 actions, increasing FSH to combine with residual androgen activity in hpg testes to stimulate pre- to post-meiotic development.

Di(n-butyl) phthalate has no effect on the rat prepubertal testis despite its estrogenic activity in vitro

“…Although the high doses of estrogenic substances have a negative impact on testis development and initiation of spermatogenesis [8][9][10], lower doses have a stimulatory effect [10][11][12]. The stimulatory effect of estradiol on spermatogonia number/ /proliferation has been confirmed by recent studies [13,14]. According to studies performed by Jobling et al [15], DEHP is slightly estrogenic, which may explain its stimulatory effect on spermatogonia.…”

DNA-binding-dependent androgen receptor signaling contributes to gender differences and has physiological actions in males and females

“…We previously showed that our genomic ARKO mice have a modest reduction in serum testosterone levels (Notini et al 2005); therefore, their phenotype arises through a combination of loss of genomic AR signaling and testosterone deficiency. However, treatment of genomic ARKO males with supraphysiological levels of testosterone for 6 weeks has no effect on any phenotypic parameter examined ( (Lim et al 2008), and H E MacLean & R A Davey, unpublished data), supporting the hypothesis that the ARKO male phenotype is caused by the loss of DNA-binding-dependent AR actions. Therefore, our study is strongly suggestive that androgens act through the genomic AR signaling pathway to play a physiological role in a number of tissues in both sexes.…”

Xenoestrogens diethylstilbestrol and zearalenone negatively influence pubertal rat's testis.

“…The mutual action of FSH and estrogen was also reported in our previous study when concomitant administration of estradiol benzoate and FSH to immature rats resulted in the enhancement of FSH stimulatory effect on the initiation of spermatogenesis by estrogen [21]. Lim et al [40] reported recently that Estimulated spermatogenic development in hpg mice occurred with markedly suppressed intratesticular E levels. Authors suggested that this inducing effect of E on spermatogenesis is caused by extratesticular E actions, predominantly increase in FSH level, what was also suggested before by Ebling et al [41].…”