The molecular basis of impaired follicle-stimulating hormone action: evidence from human mutations and mouse models

Abstract

The pituitary gonadotropin follicle-stimulating hormone (FSH) interacts with its membrane-bound receptor to produce biologic effects. Traditional functions of FSH include follicular development and estradiol production in females, and the regulation of Sertoli cell action and spermatogenesis in males. Knockout mice for both the ligand (Fshb) and the receptor (Fshr) serve as models for FSH deficiency, while Fshb and Fshr transgenic mice manifest FSH excess. In addition, inactivating mutations of both human orthologs (FSHB and FSHR) have been characterized in a small number of patients, with phenotypic effects of the ligand disruption being more profound than those of its receptor. Activating human FSHR mutants have also been described in both sexes, leading to a phenotype of normal testis function (male) or spontaneous ovarian hyperstimulation syndrome (females). As determined from human and mouse models, FSH is essential for normal puberty and fertility in females, particularly for ovarian follicular development beyond the antral stage. In males, FSH is necessary for normal spermatogenesis, but there are differences in human and mouse models. The FSHB mutations in humans result in azoospermia; while FSHR mutations in humans and knockouts of both the ligand and the receptor in mice affect testicular function but do not result in absolute infertility. Available evidence also indicates that FSH may also be necessary for normal androgen synthesis in males and females.

Figure 1.

The structure of the human FSHB gene is shown with all known mutations, all of which reside within exon 3. The 3 exons are indicated as to whether they are translated or untranslated. The blue circles beside each mutation indicate the number of times the allele has been reported in a family with isolated FSH deficiency (note: there may be more than 1 affected member within the family). FSH indicates follicle-stimulating hormone. See online version for color reference.

Figure 2.

The structure of the human FSHR protein is shown with the large extracellular domain (ECD) and the serpentine domain, which consists of 7 transmembrane domains (TMDs), 3 extracellular loops (ECLs); 3 intracellular loops (ICLs); and an intracytoplasmic tail carboxy-terminal (COOH) tail. Not all amino acids in the ECD are shown (including Tyr 335 in the hinge region) as no human mutations have been identified to affect it. Inactivating missense mutations are indicated by a black circle and white letter, corresponding to the location of the affected amino acid and mutant. Activating mutations are indicated by gray-shaded circles and a black letter, corresponding to the mutant amino acid residue. In both cases, the amino acid letter shown is the wild type. See online version for color reference.

Figure 3.

The LH pulses are shown for a female with an FSHB mutation (patient #2 in Table 3) who had serum LH levels drawn every 10 minutes overnight. Note the LH pulses indicated by arrowheads, which are similar to women with PCOS. Modified from Barnes et al. LH indicates luteinizing hormone; PCOS, polycystic ovary syndrome.