title: Estradiol induction of spermatogenesis is mediated via an estrogen receptor-{alpha} 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.
authors.affiliation: ANZAC Research Institute, Sydney, New South Wales 2139, Australia.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Allan
authors.forename: John F
authors.initials: JF
authors.lastname: Couse
authors.forename: Ulla
authors.initials: U
authors.lastname: Simanainen
authors.forename: Jenny
authors.initials: J
authors.lastname: Spaliviero
authors.forename: Mark
authors.initials: M
authors.lastname: Jimenez
authors.forename: Karina
authors.initials: K
authors.lastname: Rodriguez
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Korach
authors.forename: David J
authors.initials: DJ
authors.lastname: Handelsman
mesh_terms: D000818:Animals; D013196:Dihydrotestosterone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood*; D006062:Gonadotropins / Q000172:deficiency / Q000235:genetics; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009490:Neurosecretory Systems / Q000187:drug effects* / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D012669:Seminal Vesicles / Q000187:drug effects / Q000378:metabolism; D013091:Spermatogenesis / Q000187:drug effects* / Q000235:genetics; D013737:Testis / Q000187:drug effects / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D006062:Gonadotropins; D013196:Dihydrotestosterone; D004958:Estradiol; D005640:Follicle Stimulating Hormone
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