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

• Published in: Endocrinology (Philadelphia) 2010-06, Vol.151 (6), p.2800-2810
• Main Authors: Allan, Charles M, Couse, John F, Simanainen, Ulla, Spaliviero, Jenny, Jimenez, Mark, Rodriguez, Karina, Korach, Kenneth S, Handelsman, David J
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Agonists; Biological and medical sciences; Dihydrotestosterone; Estrogen receptors; Estrogens; Follicle-stimulating hormone; Fundamental and applied biological sciences. Psychology; Gametocytes; Gene expression; Gonadotropins; Implants; Inactivation; Luteinizing hormone; Meiosis; Metabolites; Pituitary (anterior); Receptors; Sex hormones; Spermatids; Spermatocytes; Spermatogenesis; Spermatogonia; Testes; Testosterone; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2009-1477

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)-α (hpg/αERKO) or ERβ (hpg/βERKO) knockout or wild-type ER (hpg/WT) background treated with subdermal E2 or DHT implants for 6 wk. In hpg/WT and hpg/βERKO, but not hpg/αERKO mice, E2 increased testis and epididymal weight, whereas DHT-induced increases were unaffected by ERα or ERβ inactivation. E2 but not DHT treatment increased serum FSH (but not LH) in hpg/WT and hpg/βERKO but not hpg/αERKO 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 ERα-dependent E2 postmeiotic responses. An ERα-mediated effect was confirmed by treating hpg mice for 6 wk by subdermal selective ER-α (16α-LE2) or ERβ (8β-VE2) agonist implants. ERα (but not ERβ) agonist increased testis and epididymal weight, Sertoli cell, spermatogonia, meiotic, and postmeiotic germ cell numbers. Only ERα agonist markedly increased serum FSH, whereas either agonist induced small rises in serum LH. Administration of ERα agonist or E2 in the presence of functional ERα 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 ERα-dependent neuroendocrine mechanism increasing blood FSH and Sertoli cell function. Although not necessary, estradiol is sufficient to induce spermatogenesis in the gonadotropin-deficient hpg mouse by an ERα-dependent mechanism that increases blood FSH and activates Sertoli cell function.