Testosterone Replacement Therapy Induces Spermatogenesis and Partially Restores Fertility in Luteinizing Hormone Receptor Knockout Mice

Abstract

Testosterone (T) is essential for spermatogenesis, fertility, and maintenance of the male phenotype. We analyzed in hypogonadal LH receptor knockout (LuRKO) male mice whether T treatment can restore their phenotype, spermatogenesis, and fertility. In LuRKO mice, spermatogenesis is arrested at round spermatids, adult-type Leydig cells are absent, T production is dramatically decreased, the animals are cryptorchid, and their accessory sex organs are atrophic. T replacement therapy from 21 d of life for 60 or 120 d in LuRKO mice induced a male phenotype macroscopically indistinguishable from that of wild-type littermates as well as full spermatogenesis and testicular descent. Thus, the absence of LH-dependent prepubertal androgen priming is not necessary for subsequent maturation of the male phenotype. Conspicuously, some abnormalities remained in epididymal histology after T treatment despite normal expression of several epididymis-specific genes in caput epididymis. The mice displayed normal mating behavior, although at lower frequency than wild-type controls. The spermatozoa were able to fertilize oocytes, but their impaired passage from epididymis to uterus was apparent. The mice remained subfertile, because only 9% of all breedings resulted in pregnancy, and only two of 13 mice (15%) were fertile. Moreover, inflammation in epididymides and prostate was found in many T-treated LuRKO mice, which probably impaired sperm transport and contributed to their high rate of subfertility. In conclusion, T replacement initiated prepubertally only partially restores the fertility of LuRKO mice, even though most features of the male phenotype recover. Full fertility may require higher and/or earlier postnatal T exposure or production of other Leydig cell factors lacking in this model.

Experimental rodent models of prostatitis: limitations and potential

“…Recently Pakarainen et al 162 reported that four of six (67%) testosterone-treated LH receptor knockout (LuR-KO) mice exhibited marked inflammation in the prostate, characterized by the abundant presence of lymphocytes in stromal tissue and between tissue layers in prostate glands. The 8 week long testosterone replacement regimen started at the prepubertal age of 21 days to restore both anatomical abnormalities and accessory sex organ function in these hypogonadal LuRKO male mice.…”

“…[163][164][165] Additionally, in some LuRKO mice testosterone replacement also induced severe inflammation in the coagulating glands, vasa deferentia, and epididymis. 162 Long-term administration of testosterone in Lobund-Wistar and Noble rat strains has been shown to induce invasive prostate adenocarcinomas. 61,166 It has been demonstrated that testosterone alone blocks 17b-estradiol-induced prostate inflammation, but prostatitis has not been reported to occur in animals treated with testosterone alone.…”

“…It seems likely that this pathology is related to the disturbance of sperm transport to ejaculated semen in the testosterone-treated LuRKO males. 162 This mouse transgenic model may hold some promise for future studies. Both hormone-induced and immunologically induced prostatitis may potentially be at work in this model.…”

Extragonadal LH/hCG action—Not yet time to rewrite textbooks

“…In conclusion, poorly developed secondary sex characteristics and infertility are observed in both sexes. Further detail about the phenotype of this model are in our previous reports (Zhang et al, 2001a;Zhang et al, 2003;Zhang et al, 2004;Pakarainen et al, 2005c;Pakarainen et al, 2005b;Pakarainen et al, 2005a).…”

Ovarian wedge resection restores fertility in estrogen receptor β knockout (ERβ −/− ) mice

“…Ovarian transplantation has been used to investigate the mechanism of reproductive failure in transgenic mice (13,16,17), and ovarian wedge resection is often used very successfully to restore fertility to anovulatory women. In the present study, we have used ovarian transplantation and wedge resection as tools to study subfertility in ER␤ Ϫ/Ϫ mice.…”