TY - JOUR
T1 - Infertility with defective spermatogenesis and steroidogenesis in male mice lacking androgen receptor in Leydig cells
AU - Xu, Qingquan
AU - Lin, Hung Yun
AU - Yeh, Shauh Der
AU - Yu, I. Chen
AU - Wang, Ruey Shen
AU - Chen, Yen Ta
AU - Zhang, Caixia
AU - Altuwaijri, Saleh
AU - Chen, Lu Min
AU - Chuang, Kuang Hsiang
AU - Chiang, Han-Sun
AU - Yeh, Shuyuan
AU - Chang, Chawnshang
N1 - Funding Information:
Acknowledgements We thank Drs. Richard R. Behringer and Keith L. Parker at M.D. Anderson Cancer Center and University of Texas Southwestern Medical Center for providing Amhr2-Cre mice. This work was supported by NIH grant DK60948 and George Whipple Professor Endowment.
PY - 2007/8
Y1 - 2007/8
N2 - 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 17β-HSD3, 3β-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.
AB - 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 17β-HSD3, 3β-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.
KW - Androgen receptor
KW - Leydig cell
KW - Spermatogenesis
KW - Steroidogenesis
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U2 - 10.1007/s12020-007-9015-0
DO - 10.1007/s12020-007-9015-0
M3 - Article
C2 - 17955388
AN - SCOPUS:36949033156
SN - 1355-008X
VL - 32
SP - 96
EP - 106
JO - Endocrine
JF - Endocrine
IS - 1
ER -
