Polymorphism of gonadotropin action; molecular mechanisms and clinical implications

Various structural alterations of gonadotropins and their receptors (R) contribute to the polymorphism of gonadotropin action. One reason is the microheterogeneity of gonadotropins due to variations in the degree of their glycosylation. This alters the intrinsic bioactivity of gonadotropins, as reflected by changes in their bioactivity to immunoreactivity ratios in various physiological and clinical conditions. We have reassesses this phenomenon by improved in vitro bioassay and immunoassay methods, and it appears that the intrinsic bioactivity of gonadotropins, in particular of LH, is more constant than previously demonstrated. The second part of this chapter deals with a common polymorphism that was recently discovered in the gene of the LH beta-subunit. The variant LH beta allele contains two point mutations, both altering the amino acid sequence (Trp8Arg and Ile 15Thr), the latter one in addition introduces a new glycosylation signal to the LH beta peptide. The variant seems to represent an evolutionary early form of LH, being structurally closer to hCG than wild-type LH. The LH variant is common world-wide, with the carrier frequency varying from 28% in Finland to 7.5% in North American Hispanics. The LH variant differs functionally from wild-type LH, and it seems to predispose the carriers to mild aberrations of reproductive function. The third section summarizes our findings on the first mutation of the FSHR gene. This inactivating missense mutation is located in the gene sequence encoding the extracellular domain of the FSHR (Ala 189Val). The mutated receptor protein is apparently incorrectly folded and devoid of biological activity. The mutation explains about 50% of the hereditary form of hypergonadotropic ovarian dysgenesis in the Finnish population.