title: Infertility with defective spermatogenesis and steroidogenesis in male mice lacking androgen receptor in Leydig cells.
abstract: 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.
authors.affiliation: Department of Pathology, the Cancer Center, University of Rochester, 601 Elmwood Ave, Box 626, Rochester, NY 14642, USA.
authors.forename: Qingquan
authors.initials: Q
authors.lastname: Xu
authors.forename: Hung-Yun
authors.initials: HY
authors.lastname: Lin
authors.forename: Shauh-Der
authors.initials: SD
authors.lastname: Yeh
authors.forename: I-Chen
authors.initials: IC
authors.lastname: Yu
authors.forename: Ruey-Shen
authors.initials: RS
authors.lastname: Wang
authors.forename: Yen-Ta
authors.initials: YT
authors.lastname: Chen
authors.forename: Caixia
authors.initials: C
authors.lastname: Zhang
authors.forename: Saleh
authors.initials: S
authors.lastname: Altuwaijri
authors.forename: Lu-Min
authors.initials: LM
authors.lastname: Chen
authors.forename: Kuang-Hsiang
authors.initials: KH
authors.lastname: Chuang
authors.forename: Han-Sun
authors.initials: HS
authors.lastname: Chiang
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: 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*
chemical_list: 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