AN ACTIVATING MUTATION OF THE FOLLICLE-STIMULATING-HORMONE RECEPTOR AUTONOMOUSLY SUSTAINS SPERMATOGENESIS IN A HYPOPHYSECTOMIZED MAN

As both gonadotropins, LH and FSH, are required for normal spermatogen esis, patients with pituitary insufficiency need hCG plus human menopa usal gonadotropin therapy to induce spermatogenesis and establish fert ility. In a patient hypophysectomized because of a pituitary tumor, wh o, despite undetectable serum gonadotropin levels, had normal testis v olume and semen parameters and fathered three children under testoster one substitution alone, we hypothesized an activating mutation of the FSH receptor. Exon 10 of the FSH receptor gene was amplified from geno mic DNA by PCR, screened by single stranded conformation polymorphism gel electrophoresis, and sequenced. We identified a heterozygous A-->G base change at nucleotide position 1700, leading to an Asp-->Gly tran sition in codon 567 in the third intracytoplasmatic loop. COS-7 cells transiently transfected with the mutated receptor displayed a 1.5-fold increase in basal cAMP production compared to wild-type receptor, ind icating that this mutation leads to ligand-independent constitutive ac tivation of the FSH receptor. We conclude that this activating mutatio n of the FSH receptor, the first ever described, autonomously sustains spermatogenesis in the absence of gonadotropins.