Endocrine Abstracts

The gonadotropic hormones, LH and FSH are critical regulators of normal sexual functions including steroidogenesis and gametogenesis. Their essential role is underscored by the development of various hypogonadal phenotypes arising from genetic mutations. Constitutive activation of their cognate receptors also disturbs their function. We earlier showed that transgenic expression of an activating mouse Fshr mutant (mFSHR^D580H) in granulosa cells, under the anti-Müllerian hormone promoter, distorts ovarian function. Contrarily, transgenic males expressing this mutant in Sertoli cells were largely normal. To study further whether amplified FSH action affects spermatogenesis, we crossed the transgenic Fshr mutant males with Lhr deficient knockout (Lhr^−/−) mice, the homozygotes of which present with hypogonadism and infertility. The phenotype of the female litters from the crossbreeds largely mimicked those of Lhr^−/− females. However, the double-mutant males presented with rescue of fertility, with normal testes size and spermatogenesis, and partially recovered seminal vesicles, but with delayed puberty, reflecting incomplete rescue of testosterone production. On attainment of full sexual maturity these mice sired litters similar to the wild-type (WT) littermates. Histologically, the testes of the adult mice partly mimicked those of Lhr^−/− male mice with total absence of discernible Leydig cells in the interstitial space. In contrast, the seminiferous tubuli had normal diameter with full spermatogenesis. As expected, the Fshr, a Sertoli cell marker was upregulated in these mice, while the Leydig cell-specific genes, including Lhr and some key steroidogenic enzymes, were downregulated. Interestingly, treatment of these mice with the antiandrogen, flutamide had no effect on spermatogenesis, whereas it completely blocked spermatogenesis in the WT controls. Our findings demonstrate that excessive Fshr activation, in the absence of LH-stimulated Leydig cell function, and even without testosterone action, is able to restore and maintain spermatogenesis.

Disclosure: This work was supported by the Wellcome Trust Programme, grant 082101/Z/07/Z, the MRC, grant 060002 and the ESE short-term fellowship.