To characterize the clinical features of a female patient with isolated follicle-stimulating hormone (FSH) deficiency and to investigate the underlying mechanisms of FSH inactivation. The proband was a 29-year-old woman with primary amenorrhea, impaired pubertal development, and infertility. Subsequently, reproductive endocrine was screened. DNA sequencing was conducted for the identification of FSHβ mutation. RT-PCR, western blots, in vitro immunometric assay, and bioassay were performed to confirm the impact of the mutation on FSH expression and biological activity. Molecular model consisting of FSHα and mutant FSHβ subunit was built for the structural analysis of FSH protein. The evaluation of reproductive endocrine revealed undetectable basal and GnRH-stimulated serum FSH. Sequencing of the FSHβ gene identified a homozygous nonsense mutation at codon 97 (Arg97X). RT-PCR and western blot analysis revealed the mutation Arg97X did not affect FSHβ mRNA and protein expression. But in vitro immunometric assay and bioassay demonstrated the production of normal bioactive FSH protein was disturbed by the mutation Arg97X. Structural analysis showed the surface structure of the resulting mutant FSH presented with lock-and-key, mosaic binding pattern, while the native structure was an encircling binding mode. The mutation Arg97X could disturb structural stability of the resulting FSH protein consisting of FSHα and mutant FSHβ subunit, which may lead to FSH deficiency.

Recent rapid advances in assisted reproductive health technologies enables couples with subfertility to conceive through various intervention. Majority of treatment modalities target the female partner. However it is important to identify and treat male factor subfertility right at the outset. We report a case of isolated follicle stimulating hormone deficiency resulting in azoospermia and primary subfertility. A 28 year otherwise healthy male presented with primary subfertility with a healthy female counterpart. He was found to have non obstructive azoospermia with low seminal fluid volume. He had normal external genitalia and potency with increased libido. Further evaluation revealed an isolated deficiency of follicle stimulating hormone with elevated testosterone levels. His luteinizing hormone and prolactin levels were normal. Contrast enhanced CT scan of chest, abdomen and pelvis and MRI scan of the pituitary fossa were normal too. In the era of modern reproductive technology it is important to further evaluate males with non-obstructive azoospermia to detect underlying gonadotropin deficiency.

Our aim was to describe the clinical and genetic findings in an adolescent male with isolated follicle-stimulating hormone (FSH) deficiency and demonstrate the efficacy of recombinant human FSH (rhFSH) replacement in this case. A 14.5-year-old adolescent male was referred with normal pubertal development and small testes. Serum testosterone, FSH, and luteinising hormone (LH) were measured at baseline and after gonadotropin-releasing hormone (GnRH) stimulation. Testicular biopsy was performed, and rhFSH replacement was administered for 6 months. The patient's FSHβ gene was amplified and sequenced. Basal and GnRH-stimulated FSH levels were undetectable, in contrast with increased LH levels under both conditions. Histopathological investigation of a testicular biopsy specimen revealed a reduced number of Sertoli cells, the absence of germ cells, Leydig cell hyperplasia, and a thickened basement membrane in seminiferous tubules. The testicular size changed from 1 ml at baseline to 6 ml after 6 months of rhFSH replacement. Sequencing of the FSHβ gene exon 3 revealed a new missense mutation (c.364T>C, resulting in p.Cys122Arg) in a homozygous state in the patient; both parents and a sister carried the same mutation in a heterozygous state. We also compared our case with all similar cases published previously. We herein described an adolescent male with isolated FSH deficiency due to a novel FSHβ gene mutation associated with a prepubertal testes size and normal virilisation.