Estrogenic induction of spermatogenesis in the hypogonadal (hpg) mouse: role of androgens

Abstract

Testicular development is arrested in the hypogonadal (hpg) mouse due to a congenital deficiency of hypothalamic gonadotropin-releasing hormone synthesis. Previous studies have demonstrated that chronic treatment of these mice with estradiol induces testicular maturation and qualitatively normal spermatogenesis, but it is not known whether these are direct effects via estrogen receptors expressed in the testis, or indirect actions via the pituitary gland. The aim of the current studies was to determine whether the actions of estradiol require the presence of androgens. Sensitive assays revealed that chronic estradiol treatment produced time-dependent increases in pituitary FSH production but no increases in pituitary LH or testicular testosterone content could be detected. As a functional test of androgen dependence, hpg mice were treated for 70 days with estradiol plus Casodex (bicalutamide), an androgen receptor antagonist. Casodex treatment markedly attenuated both the estradiol-induced increase in testicular weight and the proliferation of the seminiferous epithelium, as revealed by morphometric analysis. However, it did not affect the estradiol-induced increase in pituitary FSH content, nor did it affect estradiolinduced increases in the weight of the seminal vesicles and epididymides. We conclude that increased FSH production is not sufficient to explain the increase in testicular development induced by estradiol in hpg mice; there is a requirement for functional androgen receptors for induction of testicular growth.

Estradiol Induction of Spermatogenesis Is Mediated via an Estrogen Receptor-α Mechanism Involving Neuroendocrine Activation of Follicle-Stimulating Hormone Secretion

“…It is unlikely that Leydig cells are directly involved in the ER␣-mediated E2 induction of spermatogenesis because intratesticular steroid levels decline in E2-treated hpg males (18), and concurrent induction of circulating FSH is consistent with elevated Sertoli cell markers and limited postmeiotic germ cell development, typical of known FSH activity in androgen-deficient testes (3,44). The present findings confirm that E2 administration does not increase serum (16) or testicular (17,18) levels in hpg mice so that the E2-induced increase in seminal vesicle weight must be a direct E2 effect on seminal vesicles as reported previously (45). Therefore, the stimulatory effect of E2 for spermatogenesis in hpg mice most likely involves extratesticular ER␣ actions leading to increased circulating FSH and enhanced Sertoli cell maturation/function.…”

“…However, later studies demonstrated that comparable spermatogenesis in hpg mice is induced after similar treatment with estradiol (E2) (16). Interestingly, this E 2 effect is dependent on a functional AR (17,18) and coincides with increased circulating FSH levels. Prompted by the disparities in the available evidence on the mechanism and site of action by which E2 induces spermatogenesis in hpg mice, the present study set out to segregate the spermatogenic actions of E2 by two complementary pharmacogenetic experiments using: 1) selective estrogen receptor (ER)␣ or ER␤ agonists in gonadotropin-deficient hpg mice, and 2) pure androgen (DHT) and estrogen (E2) treatments in novel compound hpg/ER knockout lines selectively lacking ER␣ or ER␤ (hpg/␣ERKO or hpg/␤ERKO mice) on the hpg genetic background.…”

Gpr54−/− mice show more pronounced defects in spermatogenesis than Kiss1−/− mice and improved spermatogenesis with age when exposed to dietary phytoestrogens

“…Neonatal administration of weak environmental estrogens stimulates the first wave of spermatogenesis at puberty in rats (Atanassova et al 2000). Chronic treatment of the GNRH-deficient (Hpg) mice with estradiol implants can increase the size of the testis and stimulate complete spermatogenesis qualitatively (Ebling et al 2000, Baines et al 2005, Ebling et al 2006. We hypothesized that estrogenic compounds found in normal mouse food may contribute to the increase in spermatogenesis found in Gpr54 K/K and Kiss1 K/K mice as they age.…”

“…It has been proposed that estrogen stimulates spermatogenesis by increasing FSH secretion from the pituitary, which acts synergistically with testosterone (Baines et al 2005). E 2 -induced spermatogenesis in Hpg mice is prevented by an androgen receptor antagonist (Baines et al 2005) and requires ESR1 but not ESR2 signaling (Allan et al 2010).…”

“…E 2 -induced spermatogenesis in Hpg mice is prevented by an androgen receptor antagonist (Baines et al 2005) and requires ESR1 but not ESR2 signaling (Allan et al 2010). It is not clear whether phytoestrogens stimulate spermatogenesis by a similar mechanism.…”