Follicle stimulating hormone beta in reproductive dysfunction

Follicle stimulating hormone (FSH) is a pituitary glycoprotein that is essential for pubertal development, the aromatization of testosterone to estradiol, the maturation of the follicle in females, and spermatogenesis in males. It may also be involved in androgen production in men and women. With the critical role of FSH in normal reproductive function, it is conceivable that inactivating mutations in FSHβ might result in spermatogenic, ovulatory, and pubertal disorders in humans. The purpose of this research study was to determine the prevalence of FSHβ mutations among three patient populations with reproductive dysfunction: oligo- and azoospermia, 46, XX ovarian failure, and idiopathic hypogonadotropic hypogonadism (IHH). In addition, the construction of an improved, more usable dual expression vector was necessary to analyze FSHβ mutations in vitro. When transfected into Chinese hamster ovary (CHO) cells, the newly constructed expression vector, pαFSHβ resulted in the production of immunoreactive and bioactive FSH in vitro. To validate this construct, transfection of a previously described inactivating human FSHβ mutation, Cys82Arg, failed to produce immunoreactive and bioactive FSH, confirming its importance in normal FSH synthesis and function and its role in the phenotype of hypogonadism. Among the three patient populations studied, two different missense mutations were identified. A single patient with 46, XX ovarian failure was heterozygous for an Ala43Pro missense mutation in FSHβ exon three. In vitro analysis of the Ala43Pro demonstrated no loss of bioactivity or immunoreactivity suggesting that Ala43Pro is most likely a polymorphism. Among patients with IHH, two were heterozygous for a Ser20Ile missense mutation. Since affected individuals demonstrated heterozygosity for this missense mutation and because a sibling with hypergonadotropic hypogonadism was also heterozygous for Ser20Ile, it is unlikely that Ser20Ile is the sole cause of IHH in these patients. Men with oligospermia and azoospermia did not demonstrate any FSHβ mutations. In conclusion, we have described a new dual expression vector, which was validated for the functional analysis of human FSHβ mutations in vitro. We demonstrate that the Cys82Arg mutation causes impaired function in vitro. Although FSH assumes paramount importance in normal reproduction, mutations in humans with reproductive disorders studied are extremely rare.