An activating mutation of the follicle-stimulating hormone receptor autonomously sustains spermatogenesis in a hypophysectomized man

J Clin Endocrinol Metab. 1996 Apr;81(4):1367-70. doi: 10.1210/jcem.81.4.8636335.


As both gonadotropins, LH and FSH, are required for normal spermatogenesis, patients with pituitary insufficiency need hCG plus human menopausal gonadotropin therapy to induce spermatogenesis and establish fertility. In a patient hypophysectomized because of a pituitary tumor, who, despite undetectable serum gonadotropin levels, had normal testis volume and semen parameters and fathered three children under testosterone substitution alone, we hypothesized an activating mutation of the FSH receptor. Exon 10 of the FSH receptor gene was amplified from genomic 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 transition 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, indicating that this mutation leads to ligand-independent constitutive activation of the FSH receptor. We conclude that this activating mutation of the FSH receptor, the first ever described, autonomously sustains spermatogenesis in the absence of gonadotropins.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / radiotherapy
  • Adenoma / surgery
  • Adult
  • Amino Acid Sequence
  • Animals
  • Aspartic Acid
  • Base Sequence
  • Chlorocebus aethiops
  • Cyclic AMP / metabolism
  • DNA Primers
  • Exons
  • Fertility*
  • Follicle Stimulating Hormone / blood
  • Follicle Stimulating Hormone / pharmacology
  • Glycine
  • Humans
  • Hypophysectomy*
  • Kinetics
  • Luteinizing Hormone / blood
  • Male
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Pituitary Neoplasms / radiotherapy
  • Pituitary Neoplasms / surgery
  • Point Mutation*
  • Polymerase Chain Reaction
  • Polymorphism, Single-Stranded Conformational
  • Receptors, FSH / biosynthesis
  • Receptors, FSH / genetics*
  • Receptors, FSH / physiology
  • Recombinant Proteins / metabolism
  • Spermatogenesis*
  • Testosterone / therapeutic use
  • Transfection


  • DNA Primers
  • Receptors, FSH
  • Recombinant Proteins
  • Aspartic Acid
  • Testosterone
  • Luteinizing Hormone
  • Follicle Stimulating Hormone
  • Cyclic AMP
  • Glycine