Isolated follicle-stimulating hormone (FSH) deficiency in a young man with normal virilization who did not have mutations in the FSHbeta gene

Objective: To determine the cause of isolated FSH deficiency in a young infertile man. Design: Case report. Setting: Clinical and genetic studies in an academic research environment. Patient(s): A 19-year-old man with normal virilization, azoospermia, and isolated FSH deficiency. Intervention(s): Pituitary and gonadal functions were evaluated at baseline and after repeated GnRH stimulation. FSH was tested with both immunological and biological methods. The FSHbeta gene was sequenced in the patient and in a series of 50 controls. Main Outcome Measure(s): Clinical, endocrine, and genetic characterization of an infertile patient with isolated FSH deficiency. Result(s): LH and T secretions were normal. No interference in FSH measurement was detected, and serum FSH concentrations were very low and completely unresponsive to repeated GnRH stimulation. No circulating FSH-like bioactivity was detected by means of rat Sertoli cell bioassay. Other pituitary functions were unaffected, and no lesions were seen at pituitary nuclear magnetic resonance (NMR). Inhibin B and activin levels were normal, but a progressive decrease of activin concentrations was seen during GnRH stimulation. The coding sequence of the FSH gene was normal, but the patient was homozygous for a novel G/T substitution in the promoter region within a P response element. This substitution was present in heterozygosity in eight out of 50 controls and in homozygosity in one man with normal FSH levels. Conclusion(s): We report an infertile male with isolated FSH deficiency but no evidence of mutations in the FSH gene. The G/T substitution in the FSH promoter represents a novel silent polymorphism, indicating that other defects in factors involved in FSH-specific expression should be taken into account.