Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility

Abstract

Gonadal function is controlled by the two pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). While LH mainly regulates gonadal steroidogenesis, FSH is considered essential for folliculogenesis in the female and spermatogenesis in the male. We recently discovered that an inactivating point mutation in the FSH receptor (R) gene causes a recessively inherited form of hypergonadotropic ovarian failure in homozygous females. This 566C-->T mutation, predicting an alanine to valine substitution, is located in exon 7 of the FSHR gene, in the region encoding the extracellular domain of the receptor molecule. Functional testing showed a clear-cut reduction in ligand binding and signal transduction by the mutated receptor. Hence, lack of FSH function is incompatible with ovarian follicular maturation and female fertility. In the male, FSH is generally considered essential for the pubertal initiation of spermatogenesis and maintenance of quantitatively normal sperm production in adults. We report here the first characterization of males homozygous for an inactivating FSHR mutation. They have variable degrees of spermatogenic failure, but, surprisingly, do not show azoospermia or absolute infertility. These results question the essential role of FSH for the initiation of spermatogenesis, and demonstrate that FSH is more important for female than for male fertility.

Regulation of testicular function in men: implications for male hormonal contraceptive development

“…The contrast with LH-␤ mutations [12] implies that either the LH receptor itself or constitutively produced T has a role in male fetal sexual differentiation. Inactivating mutations in the FSH receptor result only in oligozoospermia with reduced testicular size and normal fertility [16], similar to the phenotypes observed in FSH-␤ and FSH-receptor knockout mice [17,18]. This finding implies that the presence of FSH is not an absolute requirement for the pubertal initiation and maintenance of spermatogenesis or fertility, a conclusion identical to that ascertained in the FSH and LH depletion experiments in man described above.…”

Mechanisms involved in the homologous down-regulation of transcription of the follicle-stimulating hormone receptor gene in Sertoli cells

“…One of the most important biochemical signaling networks involved in controlling normal spermatogenesis in mammals exists between the anterior lobe of the pituitary gland and Sertoli cells in the testis (Griswold et al, 1975(Griswold et al, , 1976(Griswold et al, , 1977Orth, 1984;Singh and Handelsman, 1996;Kumar et al, 1997;Tapanainen et al, 1997;Dierich et al, 1998). The biological events controlled by this endocrine mechanism result from the interaction of follicle-stimulating hormone (FSH) with the FSH receptor and the subsequent transduction of molecular information across the membrane leading to the production of second messengers such as cAMP (Means et al, 1980) and Ca 2 + (Chaudhary et al, 1996;Lalevee et al, 1999) and changes in gene expression.…”

Role of androgen and gonadotrophins in the development and function of the Sertoli cells and Leydig cells: Data from mutant and genetically modified mice

“…As discussed above, mouse FSHβ (Kumar et al, 1997) and FSHR (Abel et al, 2000;Dierich et al, 1998) knockout phenotypes are both fertile with slight reduction of sperm quality. Inactivating mutations of FSHβ in humans cause azoospermia (Layman et al, 2002;Lindstedt et al, 1998;Phillip et al, 1998), but individuals with FSHR inactivation are oliozoospermic, and some have even sired children (Tapanainen et al, 1997). The exact human phenotype of FSH inactivation therefore remains unclear.…”