We recently succeeded in creating mice with the luteinizing hormone receptor gene knockout (LHRKO) by a homologous DNA recombination technology. Targeting deletion of the LHR gene at the promoter to exon one region completely inactivated the gene, which resulted in no detectable LHR in the gonads of homozygous animals. The LHR null males are not lethal but sterile, while their heterozygous littermates appear to be normal. The external and internal genitalia of homozygous males were grossly underdeveloped and spermatogenesis was arrested at the spermatocytes. The phenotype is believed to be caused by decreased androgen influence in the absence of LH stimulation of testicular Leydig cells. Testosterone replacement therapy, in spite of improvement in testicular morphology and spermatogenesis, did not restore male fertility, as homozygous males have very low sperm numbers and motility. In view of the fact that LH has pervasive actions, mediated by its receptors in gonadal and nongonadal tissues such as functional LHR in sperm and epididymis and with preliminary results obtained from LHRKO males, we hypothesize that the contribution of LH to spermatogenesis may be more than just acts on Leydig cells for androgen production. Having this unique LHRKO mouse model enables us to selectively investigate the crucial roles of LH in reproductive biology. This proposed research is aimed at searching for potential causes of infertility in LHRKO males even after androgen replacement therapy. Therefore, this small grant application will only focus on two aspects that are known to be critical in spermatogenesis and sperm maturation, listed as two specific aims: 1) investigating the effect of LHRKO on spermatogenic cells. 2) determining the effect of LHRKO on sperm maturation. These functional data are essential for us to further investigate the vital role of LH in male reproduction at biochemical and molecular levels. Infertility in human due to genetic defects in LHR or LH-p subunit are increasingly recognized, but there are no naturally occurring animal models with the corresponding mutations available for study. Thus, the data obtained from these LHRKO mice will not only advance our understanding on how important the actions of LH are for normal male reproductive physiology but will also facilitate developing better diagnostic and therapeutic options for male infertility and, conversely, developing more effective and safer male contraceptive reagents.
| Yuan, F P; Lin, D X; Rao, C V et al. (2006) Cryptorchidism in LhrKO animals and the effect of testosterone-replacement therapy. Hum Reprod 21:936-42 |
| Lo, Kirk C; Lei, Zhenmin; Rao, Ch Venkateswara et al. (2004) De novo testosterone production in luteinizing hormone receptor knockout mice after transplantation of leydig stem cells. Endocrinology 145:4011-5 |
| Lei, Z M; Mishra, S; Ponnuru, P et al. (2004) Testicular phenotype in luteinizing hormone receptor knockout animals and the effect of testosterone replacement therapy. Biol Reprod 71:1605-13 |
| Lei, Z M; Zou, W; Mishra, S et al. (2003) Epididymal phenotype in luteinizing hormone receptor knockout animals and its response to testosterone replacement therapy. Biol Reprod 68:888-95 |
