Inherited disorders of the gonadotropin hormones.

Inherited disorders of the pituitary gonadotropins, LH and FSH, are rare. No mutations of the common alpha-subunit gene have been described. A single case of an FSH beta gene mutation has been reported. This mutation consisted of a two nucleotide deletion that caused a frameshift of codons 61-86 followed by premature termination. A homozygous patient with this mutation presented with primary amenorrhea and infertility. Serum FSH levels were low and LH levels were elevated. A postmenopausal heterozygous relative had subnormal FSH and LH and it was postulated that the mutant FSH beta subunit may have impaired gonadotrope function. Only a single example of an LH beta gene mutation has been described. This case was reported in a male who failed to undergo puberty, had elevated immunoreactive LH, but low bioactive LH and low testosterone. The LH beta gene is a member of the CG beta/LH beta gene cluster that resides on chromosome 19q. No rearrangements or deletions were observed and there was a homozygous substitutions of Gln 54 with Arg. The substituted Gln residue is conserved in each of the glycoprotein hormone beta-subunits. Recombinant mutant LH was expressed in CHO cells and was shown to be immunologically active, but it did not bind to the LH receptor, explaining the absence of bioactivity. This finding suggests that Gln 54 is either a contact site for the receptor or that the mutation alters the conformation of LH to prevent binding to the receptor. The serum LH bio/immuno (B/I) ratio in heterozygotes was 50% of control samples, consistent with normal production and stability of the mutant hormone in vivo. Male heterozygotes exhibited slightly reduced testosterone and only one of four was fertile. Female heterozygotes had regular menses and were fertile. A polymorphic variant of LH has been reported. The variant is prevalent in Finland (24% heterozygotes) and several cases have been reported in Japan. The LH variant consists of two amino acid substitutions (W8R; I15T) that correspond to residues normally found in CG beta. The I15T substitution may introduce a glycosylation site. The variant LH has increased bioactivity, but a reduced serum half-life. It is unclear whether the LH variant is of clinical significance aside from altering immunoactivity in some assays. In addition to gonadotropin mutations, defects in gonadotrope viability (SF-1; DAX-1 mutations) and in GnRH secretion (Kallmann syndrome; SF-1; DAX-1) can also lead to hypogonadotropic hypogonadism (Fig. 1). As noted in other talks, the LH-R and FSH-R are also targets for mutations. Thus, genetic defects have now been identified at each level of the H-P-G axis.