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

Abstract

SummaryLuteinizing hormone (LH) is a pituitary heterodimeric glycoprotein essential in male and female reproduction. Its functional polymorphic variant (V‐LH) is determined by two missense mutations (rs1800447, A/G, Trp8Arg; rs34349826, A/G, Ile15Thr) in the LH β‐subunit encoding gene (LHB; 19q13.3; 1111 bp; 3 exons). Among women, V‐LH has been associated with higher circulating LH and reduced fertility, but the knowledge of its effect on male reproductive parameters has been inconclusive. The objective of this study was to assess the effect of V‐LH on hormonal, seminal and testicular parameters in the Baltic young men cohort (n = 986; age: 20.1 ± 2.1 years) and Estonian idiopathic infertility patients (n = 607; 35.1 ± 5.9 years). V‐LH was detected by genotyping of the underlying DNA polymorphisms using PCR‐RFLP combined with resequencing of a random subset of subjects. Genetic associations were tested using linear regression under additive model and results were combined in meta‐analysis. No significant difference was detected between young men and infertility patients for the V‐LH allele frequency (11.0 vs. 9.3%, respectively). V‐LH was associated with higher serum LH in both, the young men cohort (p = 0.022, allelic effect = 0.26 IU/L) and the idiopathic infertility group (p = 0.008, effect = 0.59 IU/L). In meta‐analysis, the statistical significance was enhanced (p = 0.0007, resistant to Bonferroni correction for multiple testing; effect = 0.33 IU/L). The detected significant association of V‐LH with increased serum LH remained unchanged after additional adjustment for the SNPs previously demonstrated to affect LH levels (FSHB ‐211G/T, FSHR Asn680Ser, FSHR ‐29A/G). Additionally, a suggestive trend for association with reduced testicular volume was observed among young men, and with lower serum FSH among infertility patients. The V‐LH carrier status did not affect sperm parameters and other circulating reproductive hormones. For the first time, we show a conclusive contribution of V‐LH to the natural variance in male serum LH levels. Its downstream clinical consequences are still to be learned.

Association of novel SNPs in gonadotropin genes with sperm quality traits of Boer goats and Boer crosses

“…It was reported that mutations in the LH gene may influence the level of LH serum in men (Punab et al 2015); LH affects Leydig cells, induces testosterone production, and indirectly controls spermatogenesis (McLachlan et al 1996;França et al 2005). Therefore, varying LH levels or function may influence semen quality.…”

Homozygous nonsense mutation Trp28X in the LHB gene causes male hypogonadism

“…The Trp28Arg and Ile35Thr mutations in exon 2 are the most common LHB allele variant, and the carrier frequency ranges from 0 to 53% in various populations [15], including 11% in Chinese women [16]. The Trp28Arg and Ile35Thr carrier status does not affect T levels and the sperm parameters in adult males, but LH levels increase [17].…”

Genetics of Sex Hormone-Binding Globulin and Testosterone Levels in Fertile and Infertile Men of Reproductive Age

“…Young men (n = 578) were recruited by the AC-TUH between May 2003 and June 2004 in the framework of a prospective study Environment and Reproductive Health (EU sixth FP project QLRT-2001-02911). The study group has been used previously in a number of genetic association studies of male reproductive parameters [ 1 , 9 ]. The current study excluded subjects with severe genital pathologies (cryptorchidism, n = 9) or missing data (no DNA, n = 27; incomplete clinical records, n = 3).…”

“…Oligozoospermia was diagnosed according to the World Health Organization criteria valid at the time of recruitment (sperm concentration <20 mln/mL) [ 25 ]. Patients with causal factors for male infertility were excluded from the genetic analysis ( ) [ 2 , 7 , 9 ]. The final number of genotyped patients was 641 (aged 31.6 ± 6.0 years).…”

“…Other examples of extensively analyzed variants in andrology settings have smaller genetic effects on male reproductive parameters, e.g. FSH receptor (p.Asn680Ser/p.Thr307Ala) [ 4 , 5 ], FSHR −29 G>A (rs1394205) [ 6 , 7 ], and luteinizing hormone (LH) isoforms (V-LH, Trp8Arg/ Ile15Thr) [ 8 , 9 ].…”