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

Abstract

Both testosterone and its nonaromatizable metabolite dihydrotestosterone (DHT) induce spermatogenesis in gonadotropin-deficient hpg mice. Surprisingly, because aromatization is not required, estradiol (E2) also induces spermatogenesis and increases circulating FSH in hpg mice, but the mechanism remains unclear. We studied E2-induced spermatogenesis in hpg mice on an estrogen receptor (ER)-alpha (hpg/alphaERKO) or ERbeta (hpg/betaERKO) knockout or wild-type ER (hpg/WT) background treated with subdermal E2 or DHT implants for 6 wk. In hpg/WT and hpg/betaERKO, but not hpg/alphaERKO mice, E2 increased testis and epididymal weight, whereas DHT-induced increases were unaffected by ERalpha or ERbeta inactivation. E2 but not DHT treatment increased serum FSH (but not LH) in hpg/WT and hpg/betaERKO but not hpg/alphaERKO hpg mice. DHT or E2 alone increased (premeiotic) spermatogonia and (meiotic) spermatocytes without significant change in Sertoli cell numbers. DHT alone increased postmeiotic spermatids, regardless of ER presence, compared with variable ERalpha-dependent E2 postmeiotic responses. An ERalpha-mediated effect was confirmed by treating hpg mice for 6 wk by subdermal selective ER-alpha (16alpha-LE(2)) or ERbeta (8beta-VE(2)) agonist implants. ERalpha (but not ERbeta) agonist increased testis and epididymal weight, Sertoli cell, spermatogonia, meiotic, and postmeiotic germ cell numbers. Only ERalpha agonist markedly increased serum FSH, whereas either agonist induced small rises in serum LH. Administration of ERalpha agonist or E2 in the presence of functional ERalpha induced prominent gene expression of specific Sertoli (Eppin, Rhox5) and Leydig cell (Cyp11a1, Hsd3b1) markers. We conclude that E2-induced spermatogenesis in hpg mice involves an ERalpha-dependent neuroendocrine mechanism increasing blood FSH and Sertoli cell function.

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

“…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.…”

Identification of Increased Amounts of Eppin Protein Complex Components in Sperm Cells of Diabetic and Obese Individuals by Difference Gel Electrophoresis

“…This protein contributes to the control of free radical formation and lipid peroxidation (63,64), exerts antibacterial activity (which interestingly is abolished by the binding of advanced glycation end products formed as a consequence of hyperglycemia) (64 -66) and modulates immune and inflammatory responses (67). Interestingly, expression of lactotransferrin and also of clusterin (69) and eppin (70) at least in rodents is dependent on estrogens (70). Comparison of calculated and experimentally observed molecular masses and isoelectric points of the lactotransferrin forms being present in protein spots 244 and 247 reveals minor deviations (Tables II-IV).…”

The Blood-Testis Barrier and Its Implications for Male Contraception

“…These ER␣-KO mice were infertile largely because of a defect in fluid reabsorption by efferent ductules of the epididymis, thereby disrupting spermatogenesis in the seminiferous epithelium (Hess et al, 1997). However, it is noteworthy that despite the loss of 1) ER␣ alone (Eddy et al, 1996;Hess et al, 1997) or ER␣ alone in somatic cells (Mahato et al, 2000, 2) ER␤ alone (Krege et al, 1998;Antal et al, 2008), or 3) both ER␣ and ER␤ (Dupont et al, 2000) in mice, or in rats treated with ER␣ agonist (16␣-lactone-estradiol 2) or ER␤ agonist (8␤-vinyl-estradiol 2) (Allan et al, 2010), spermatogenesis developed normally. Even though ER␣(Ϫ/Ϫ) adult mice were infertile [but not ER␤-null mice, because ER␤(Ϫ/Ϫ) mice exhibited no compromised fertility (Couse et al, 2001)].…”