The role of luteinizing hormone-beta gene polymorphism in the onset and progression of puberty in healthy boys.

Abstract

An immunologically anomalous LH with two point mutations in its beta-subunit gene (Trp8Arg and Ile15Thr) has recently been described. This polymorphism is common in Finland; 28% of the population are homo- 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 healthy boys with the onset and progression of puberty. This group was followed-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 variant LH in boys with constitutional pubertal delay (testicular volume < or = 4 mL after 13.5 yr of age). The LH beta gene status of each subject in this study was judged from a single venous blood sample using two immunofluorometric LH assays with different combinations of monoclonal antibodies: one detecting both the variant and wild-type LH, and the other detecting only wild-type hormone. Of the boys with pubertal onset at a normal age, 36 (74%) were homozygous for the wild-type LH beta allele, 12 (24%) were heterozygous, and 1 (2%) was homozygous for the variant LH beta allele. Clear differences in pubertal parameters were found between the boys with normal and mutated (homo- 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 onset of puberty, the frequency of the variant LH beta allele did not differ from that in the reference population, indicating that the variant LH is not associated with conditions due to disturbed control of the reactivation of GnRH secretion. We conclude that during the progression of puberty, the variant LH may be less active in stimulating testicular growth than wild-type LH. Thus, the gene may affect tempo, contributing to the wide normal variation in pubertal progression in healthy boys. Our results also suggest that the variant LH not only affects the course of puberty, but is already involved in the regulation of the GH-insulin-like growth factor I axis during childhood.

Mutations and polymorphisms in the gonadotrophin genes; clinical relevance

“…Tapanainen, K. Pettersson, & I. Huhtaniemi, unpublished observation). We have also found that boys with v-LH have slower overall progression, gain of height and gain of testis weight at puberty (Raivio et al, 1996). These findings suggest that the bioactivity of v-LH may be lower than that of the wt hormone.…”

Determination of a common genetic variant of luteinizing hormone using DNA hybridization and immunoassays

“…The hybridization assay may prove clinically useful in the differential diagnostics of delayed puberty. Raivio et al (1996) found that the V-LHb allele was associated with slow tempo of pubertal progression in boys, although the time of onset of puberty was not affected. In addition, pubertal boys homo-or heterozygous for the V-LH form were reported to have smaller testicular volumes, shorter stature and slower growth rates than boys with WT LH.…”

‘Carriers of V‐LH among 1593 Baltic men have significantly higher serum LH’

“…The association between V‐LH and reduced testes volume has been previously reported in a small study (49 boys) on pubertal onset and progression, where V‐LH carriers additionally exhibited slower pubertal progression and growth rate (Raivio et al ., 1996). Another study reported increased prevalence of V‐LH among cryptorchid boys born with gestational age > 40 weeks and suggested that the lower hormonal efficacy of V‐LH predisposes for improper testicular descent in late pregnancy (Kaleva et al ., 2005).…”

“…Case–control association studies in male patients have suggested V‐LH as a risk factor for cryptorchidism (Kaleva et al ., 2005) and testicular cancer (Elkins et al ., 2003). A small‐scale study ( n  = 49) investigating the onset and progression of puberty in healthy boys reported slower progression of puberty and lower testes volume in V‐LH carriers (Raivio et al ., 1996). In a European cohort of middle‐aged and elderly men (EMAS study: n  = 2748 men, eight European countries), V‐LH was associated with reduced levels of serum LH (Huhtaniemi et al ., 2010).…”