Role of FSH in male gonadal function

The production of male gametes depends on the concerted action of the two g onadotropins FSH and LH on the testis. The action of LH is mediated through the production of testosterone by the Leydig cells. Since male germ cells possess neither FSH nor androgen receptors, the action of FSH and testoster one occurs through the Sertoli cells. Although the precise function of thes e two hormones remains elusive, the existing evidence suggest that both FSH and testosterone are able to stimulate all phases of spermatogenesis. In the male FSH is required for the determination of Sertoli cell number, a nd for induction and maintenance of normal sperm production. The crucial ro le of FSH in male gonadal function has been clearly illustrated by the disc overy of a patient with an activating mutation of the FSH receptor. This pa tient had been hypophysectomized because of a pituitary tumor and, under te stosterone substitution was unexpectedly fertile in spite of undetectable s erum gonadotropin levels and had fathered three children. In this patient w e could demonstrate a heterozygous activating mutation of the FSH receptor which resulted in cAMP production independent of FSH stimulation. This find ing represents the first description of an activating mutation of the FSH r eceptor and demonstrates that FSH alone maintains spermatogenesis in man. On the other hand, the effects of the lack of FSH action are unclear. Among five men with a homozygous inactivating mutation of the FSH receptor only one was infertile and spermatogenesis was variably affected in the others. However, serum inhibin B values in these men were not completely suppressed and serum FSH levels were only moderately elevated, indicating the possibi lity that FSH receptor function was not completely abolished by the mutatio n. Elimination of FSH action is a prerequisite to suppress completely sperm atogenesis for contraceptive purposes, while administration of both LH and FSH is necessary to induce sperm production in patients with hypogonadotrop ic hypogonadism. Experimental immunization of male monkeys against FSH mark edly reduced germ cell proliferation and even induced infertility. At the cellular level, FSH stimulates the cAMP-dependent activation of prot ein kinase A in Sertoli cells, but the molecular mechanism of FSH action is poorly understood. In the primate, the gonadotropin withdrawal achieved by administration of a GnRH antagonist leads to a premeiotic arrest of germ c ell proliferation, probably due to inhibition of the mitotic division of A- pale spermatogonia. Therefore, FSH might be the prime inducer of spermatogo nial proliferation, while the successive maturation process could proceed i ndependently of FSH. In summary, clinical and experimental evidence support the concept of an ir replaceble role of FSH in the primate. Only the combination of FSH and test osterone, however, supports a qualitatively and quantitatively fully normal spermatogenesis.