Disparate response of wild-type and variant forms of LH to GnRH stimulation in individuals heterozygous for the LHbeta variant allele.

Abstract

There is a common genetic variant of LH due to two amino acid changes in the LHbeta subunit, Trp(8)Arg and Ile(15)Thr. In order to compare the relative activities of wild type (wt-LH) and variant LHbeta (v-LHbeta) genes in LH production and secretion, we performed gonadotrophin-releasing hormone (GnRH) stimulation tests for healthy females (n = 7) and males (n = 10) heterozygous for the v-LHbeta allele. Blood samples were drawn up to 180 min after injection of GnRH. The serum samples were subjected to two immunofluorometric assays, one detecting wt hormone, the other detecting equally both LH types. The wt/total ratio increased significantly (P < or = 0.016) after GnRH injection in males. This indicates that the proportion of wt-LH increases in the circulation in men but not in women, and that women consequently secrete relatively more v-LH. An in-vitro bioassay was performed on 0 and 60 min samples, and the bio/immunoreactivity (B/I) ratio decreased in both sexes (P = 0.010-0.012). This supports the previously reported lower B/I ratio of wt. than v-LH, since wt-LH is expected to accumulate in circulation because of its longer half-life. In conclusion, these findings demonstrate that wt.- and v-LH respond differently to GnRH stimulation in men and women heterozygous for v-LHbeta. These results are in agreement with previously documented differences of the two forms in circulation, as well as with different promoter activities of the two LHbeta alleles.