Infertility with defective spermatogenesis and hypotestosteronemia in male mice lacking the androgen receptor in Sertoli cells

TLDR

Androgens and the androgen receptor are essential for male fertility, yet how AR signaling in specific testicular cell types regulates spermatogenesis remains poorly understood. A Cre‑Lox strategy was used to delete the AR gene exclusively in Sertoli cells, generating S‑AR‑/y mice. S‑AR‑/y mice exhibited testicular atrophy, infertility with diplotene arrest, almost no epididymal sperm, reduced serum testosterone, elevated LH, and down‑regulation of AMH, ABP, cyclin A1, and sperm‑1, demonstrating that Sertoli‑cell AR is required for normal spermatogenesis and testosterone production.

Abstract

Androgens and the androgen receptor (AR) play important roles in male fertility, although the detailed mechanisms, particularly how androgen/AR influences spermatogenesis in particular cell types, remain unclear. Using a Cre-Lox conditional knockout strategy, we generated a tissue-specific knockout mouse with the AR gene deleted only in Sertoli cells (S-AR -/y ). Phenotype analyses show the S-AR -/y mice were indistinguishable from WT AR mice (B6 AR +/y ) with the exception of testes, which were significantly atrophied. S-AR -/y mice were infertile, with spermatogenic arrest predominately at the diplotene premeiotic stage and almost no sperm detected in the epididymides. S-AR -/y mice also have lower serum testosterone concentrations and higher serum leuteinizing hormone concentrations than B6 AR +/y mice. Further mechanistic studies demonstrated that S-AR -/y mice have defects in the expression of anti-Müllerian hormone, androgen-binding protein, cyclin A1, and sperm-1, which play important roles in the control of spermatogenesis and/or steroidogenesis. Together, our Sertoli cell-specific AR knockout mice provide in vivo evidence of the need for functional AR in Sertoli cells to maintain normal spermatogenesis and testosterone production, and ensure normal male fertility.