Infertility with defective spermatogenesis and steroidogenesis in male mice lacking androgen receptor in Leydig cells.
Androgen and the androgen receptor (AR) have been shown to play critical roles in male fertility. Our previous data demonstrated that mice lacking AR (AR(-/y)) revealed incomplete germ cell development and lowered serum testosterone levels, which resulted in azoospermia and infertility. However, the consequences of AR loss in Leydig cells remain largely unknown. Using a Cre-LoxP conditional knockout strategy, we generated a tissue-specific knockout mouse (L-AR(-/y)) with the AR gene deleted by the anti-Müllerian hormone receptor-2 (Amhr2) promoter driven Cre expressed in Leydig cells. Phenotype analyses show that the outside appearance of L-AR(-/y) mice was indistinguishable from wild type mice (AR(+/y)), but with atrophied testes and epididymis. L-AR(-/y) mice were infertile, with spermatogenic arrest predominately at the round spermatid stage and no sperm could be detected in the epididymis. L-AR(-/y) mice also have lower serum testosterone concentrations and higher serum leuteinizing hormone and follicle-stimulating hormone concentrations than AR(+/y) mice. Further mechanistic studies demonstrated that hypotestosteronemia in L-AR(-/y) mice is not caused by reducing numbers of Leydig cells, but instead by the alterations of several key steroidogenic enzymes, including 17beta-HSD3, 3beta-HSD6, and P450c17. Together, L-AR(-/y) mice provide in vivo evidence that functional AR in Leydig cells is essential to maintain normal spermatogenesis, testosterone production, and required for normal male fertility.
Xu
Qingquan
Q
Department of Pathology, the Cancer Center, University of Rochester, 601 Elmwood Ave, Box 626, Rochester, NY 14642, USA.
Lin
Hung-Yun
HY
Yeh
Shauh-Der
SD
Yu
I-Chen
IC
Wang
Ruey-Shen
RS
Chen
Yen-Ta
YT
Zhang
Caixia
C
Altuwaijri
Saleh
S
Chen
Lu-Min
LM
Chuang
Kuang-Hsiang
KH
Chiang
Han-Sun
HS
Yeh
Shuyuan
S
Chang
Chawnshang
C
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053713:Azoospermia / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D004822:Epididymis / Q000473:pathology; D005260:Female; D015870:Gene Expression; D007985:Leydig Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D011944:Receptors, Androgen / Q000378:metabolism*; D013087:Spermatids / Q000254:growth & development; D013091:Spermatogenesis / Q000502:physiology*; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D013737:Testis / Q000473:pathology; D013739:Testosterone / Q000097:blood*
D011944:Receptors, Androgen; D013739:Testosterone; D015067:17-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D013254:Steroid 17-alpha-Hydroxylase