Endocrine Abstracts

Determinants of male reproductive system are highly complex. The palette of genetic variants modulating testicular function and fertility potential, are expected to be heterogenous. Our team has exploited complimentary study designs to provide novel insights and robust data on the contribution of genetic variation to testicular physiology and risk to impaired fertility in men. Firstly, I discuss our discovery studies utilizing the candidate gene approach and focusing on gonadotropin FSH and LH beta encoding genes FSHB and LHB. The discovered FSHB –211G/T (rs10835638) represents so far the only identified genetic variant with direct major effect on male serum FSH levels. Our and other groups have suggested its pharmacogenetic potential to identify the best responders to male FSH treatment. Our resequencing data of the LHB gene enables to assess the impact of previously suggested and novel variants on male reproductive physiology. Secondly, I address the robustness of genetic associations from published GWA studies for circulating testosterone and SHBG, and their contribution to testicular and sperm parameters. Thirdly, I talk about our ongoing screen for genomic structural variants (copy number variants, CNVs) in male idiopathic infertility. CNVs involving genes critical for the regulation of spermatogenesis are promising candidates responsible for strong or causative genetic effects. The majority of studies investigating the role of CNVs in male infertility have been focused on sex chromosomes. Our team aimed at characterisation of the genome-wide load and profile of CNVs among men with idiopathic infertility. Based on the study data, we propose an overall altered autosomal CNV profile as a considerable risk factor leading to male infertility and report novel genomic hotspots and recurrent CNVs as potential causes of impaired spermatogenesis. In perspective, uncovering the genetic contribution to testicular (mal)function is expected to lead to improved diagnostics, optimal treatment and perspective pharmacogenetic approaches in andrology clinics.