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

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/alpha ERKO) or ER beta (hpg/beta ERKO) knockout or wild-type ER (hpg/WT) background treated with subdermal E2 or DHT implants for 6 wk. In hpg/WT and hpg/beta ERKO, but not hpg/alpha ERKO mice, E2 increased testis and epididymal weight, whereas DHT-induced increases were unaffected by ER alpha or ER beta inactivation. E2 but not DHT treatment increased serum FSH (but not LH) in hpg/WT and hpg/beta ERKO but not hpg/alpha ERKO 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 ER alpha-dependent E2 postmeiotic responses. An ER alpha-mediated effect was confirmed by treating hpg mice for 6 wk by subdermal selective ER-alpha (16 alpha-LE2) or ER beta (8 beta-VE2) agonist implants. ER alpha (but not ER beta) agonist increased testis and epididymal weight, Sertoli cell, spermatogonia, meiotic, and postmeiotic germ cell numbers. Only ER alpha agonist markedly increased serum FSH, whereas either agonist induced small rises in serum LH. Administration of ER alpha agonist or E2 in the presence of functional ER alpha 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 ER alpha-dependent neuroendocrine mechanism increasing blood FSH and Sertoli cell function. (Endocrinology 151: 2800-2810, 2010)