THE ROLE OF LUTEINIZING HORMONE-BETA GENE POLYMORPHISM IN THE ONSET AND PROGRESSION OF PUBERTY IN HEALTHY BOYS

An immunologically anomalous LH with two point mutations in its beta-s ubunit gene (Trp(8)Arg and Ile(15)Thr) has recently been described. Th is polymorphism is common in Finland; 28% of the population are home- or heterozygous for the variant allele. To assess the effect of the LH variant on LH action, we correlated its presence in a group of 49 hea lthy boys with the onset and progression of puberty. This group was fo llowed-up longitudinally from a mean age of 11.7 +/-. 0.1 yr for 3 yr at 3-month intervals. In addition, we studied the prevalence of the va riant LR in boys with constitutional pubertal delay (testicular volume less than or equal to 4 mL after 13.5 yr of age). The LH beta gene st atus of each subject in this study was judged from a single venous blo od sample using two immunofluorometric LH assays-with different combin ations of monoclonal antibodies: one detecting both the variant and wi ld-type LH, and the other detecting only wild-type hormone. Of the boy s with pubertal onset at a normal age, 36 (74%) were homozygous for th e wild-type LH beta allele, 12 (24%) were heterozygous, and 1 (2%) was homozygous for the variant LH beta allele. Clear differences in puber tal parameters were found between the boys with normal and mutated (ho me- or heterozygous) LH genotypes. During the follow-up, the boys with the mutated genotype had smaller testicular volumes (P < 0.03), were shorter (P < 0.02), had slower growth rates (P < 0.04), and had lower serum insulin-like growth factor I-binding protein-3 levels (P < 0.03) than the boys with the normal LH genotype. In the boys with delayed o nset of puberty, the frequency of the variant LH beta allele did not d iffer from that in the reference population, indicating that the varia nt LH is not associated with conditions due to disturbed control of th e reactivation of GnRH secretion. We conclude that during the progress ion of puberty, the variant LH may be less active in stimulating testi cular growth than wild-type LH. Thus, the gene may affect tempo, contr ibuting to the wide normal variation in pubertal progression in health y boys. Our results also suggest that the variant LH not only affects the course of puberty, but is already involved in the regulation of th e GH-insulin-like growth factor I axis during childhood.