Sertoli Cell-Androgen Receptor DNA-Binding Domain Is Essential for Estradiol-Induction of Spermatogenesis.

Androgen receptor (AR) actions are vital for spermatogenesis. Paradoxically, estradiol (E2) induces spermatogenesis and increases circulating FSH levels in androgen-deficient hypogonadal (Gnrh1-/−) but not global AR−/Y mice. We have determined the role of Sertoli cell AR in E2-induced spermatogenic development using our transgenic model with Sertoli cell-specific disruption (in frame Ar exon 3 deletion) of a crucial zinc finger in the AR DNA binding domain; denoted SARΔZF. Mature (10 week old) SARΔZF males were infertile and displayed testes 30% of normal size, which were found to have cytoplasmic Sertoli cell ARΔZF localisation (confocal microscopy). Detailed stereological (optical disector) analysis showed normal total Sertoli and spermatogonial cell numbers, but 50% of normal spermatocyte numbers and limited spermatid development in SARΔZF versus wildtype testes. Serum LH and FSH levels were significantly elevated in SARΔZF males, and total intratesticular testosterone (T), DHT, 3a-diol and 3β-diol levels (ng/ testis) were all significantly elevated in SARΔZF relative to wildtype testes, whereas E2 remained undetectable (LC-MS). Disruption of Sertoli cell AR function had differential effects on expression of steroidogenic factors (qPCR), with elevated Hsb3b6, Hsd17b3 and Lhr mRNA levels contrasting with normal Cyp11a1 and reduced Cyp17a1 and Star mRNA expression in SARΔZF compared to wildtype testes. To determine Sertoli cell AR requirement for E2-induced spermatogenesis, SARΔZF males were treated with E2 (1 cm sc implants) for 6 weeks. Circulating FSH levels were reduced to normal levels in E2-treated SARΔZF males. Total intratesticular T remained elevated, whereas total DHT, 3a-diol and 3β-diol were all reduced to normal levels in E2-treated versus untreated SARΔZF testes. E2 had no effect on Sertoli cell numbers and spermatogenic development in SARΔZF males, indicating that Sertoli AR DNA binding is indispensable for E2-induced meiotic competence and postmeiotic development. Our SARΔZF paradigm represents a valuable model to differentiate Sertoli cell AR-regulation of Leydig cell steroidogenesis and the steroidal induction of spermatogenesis.