Pharmacogenetics of FSH Action in the Male

Abstract

Male infertility is a major contributor to couple infertility, however in most cases it remains "idiopathic" and putative treatment regimens are lacking. This leads to a scenario in which intra-cytoplasmic spermatozoa injection (ICSI) is widely used in idiopathic male infertility, though the treatment burden is high for the couple and it entails considerable costs and risks. Given the crucial role of the Follicle-stimulating hormone (FSH) for spermatogenesis, FSH has been used empirically to improve semen parameters, but the response to FSH varied strongly among treated infertile men. Single nucleotide polymorphisms (SNPs) within FSH ligand/receptor genes (FSHB/FSHR), significantly influencing reproductive parameters in men, represent promising candidates to serve as pharmacogenetic markers to improve prediction of response to FSH. Consequently, several FSH-based pharmacogenetic studies have been conducted within the last years with unfortunately wide divergence concerning selection criteria, treatment and primary endpoints. In this review we therefore outline the current knowledge on single nucleotide polymorphisms (SNPs) in the FSH and FSH receptor genes and their putative functional effects. We compile and critically assess the previously performed pharmacogenetic studies in the male and propose a putative strategy that might allow identifying patients who could benefit from FSH treatment.

Keywords: FSH; genetics; idiopathic male infertility; pharmacogenetic studies; single nucleotide polymorphism (SNP); spermatogenesis.

Figure 1

(A) Descriptive diagnoses according to semen analyses of 26,091 men in infertile couples who attended the Center of Reproductive Medicine and Andrology (CeRA), Münster over the last 30 years. (B) Clinical diagnoses in the same men. Data from Androbase^©, the clinical patient database. Adopted from Tüttelmann et al. (2).

Figure 2

FSHB and FSHR: Gene, promotor and protein structure. (A) Structure of the FSHB gene and promotor. The FSHB gene consists of three exons. The transcription factor LHX3 binds to the FSHB promotor as well as FOXL2 (binding sites are bold) and SMAD (binding sites are underlined) (28). The transcription start site is located on exon 1. The SNP rs10835638 (c.-211G>T) is located in the promotor region of the FSHB gene. (B) Structure of the FSHR gene and promotor. The gene consists of 10 exons. The transcription factors USF bind to the E-box and the transcription starts. The SNP rs1294205 is located in the promotor region (c.-29G>A) of the FSHR gene. The SNPs rs6165 (c.919A>G) and rs616 (c.2039A>G) are located in exon 10. (C) Protein structure of FSH and FSHR. A three-dimensional homology model of the FSH/FSHR complex is shown. The 7 TMD, constituted by transmembrane helices connected by intracellular (IL) and extracellular (EL) loops, was modeled based on the determined active structure-conformation of the β2-adrenergic receptor (29). The (monomeric) extracellular complex between the hinge region, the leucine-rich repeat domain, and FSH were taken as suggested by a structure determined for a fragment (24). The hinge region structurally links the leucine-rich repeat domain with the 7 TMD. The FSHR (backbone white-7 TMD, light blue-hinge, light gray leucine-rich repeat domain) binds the hormone [FSHβ (dark gray) and FSHα (blue), surface representation] at the extracellular side between the leucine-rich repeat domain and the hinge region. The exact orientation between the different components to each other is still unclear. The p.Thr307Al variant is located in the hinge region, where a derived structure is not known yet. The intracellular coiled loop (light green), where also not structural motifs are known yet, harbors the second amino acid variant p.Asn680Ser. The 3-D model of the FSH/FSHR-complex was kindly provided by Gunnar Kleinau (Charité Berlin, Germany).

Figure 3

Impact of rs10835638 (FSHB c.-211G>T) and rs6166 (FSHR c.2039 A>G) on serum FSH, transcriptional activity of FSHB and receptor sensitivity of FSHR. Decreasing receptor sensitivity and transcriptional activity of FSHB lead to reduced testicular volume shown by circle diameter. The red color indicates unfavorable genotype, the green color a favorable genotype for reproductive fitness. The numbers show the percentage of carriers of combined genotypes in a German population group. The least favorable genotypes are marked with a black line. Men with TT/GG are predicted to show lowest testicular volume. Adopted from Tüttelmann et al. (56).

Figure 4

Current study outline and proposal for upcoming study outline. The current study outlines for pharmacogenetic studies are very heterogeneous and vary in many components. With the proposal for upcoming study outline we suggest to focus on the selected parameters to generate a substantial clinical study. The colored circles indicate the major critical components of a clinical study. The circles are complemented by the respective subgroups that contribute to this parameter. In the selected parameters for proposing upcoming study outlines, the colors of the artificial pie-chart correspond to the respective parameters like study design, selection criteria, FSH treatment, and endpoints on the left side.