FSH Receptor Polymorphism p.N680S and Efficacy of FSH Therapy

Male Infertility Clinical Trial

Official title: Significance of the FSH Receptor Polymorphism p.N680S for the Efficacy of FSH Therapy of Idiopathic Male Infertility: a Pharmacogenetic Approach

Status Completed

Clinical Trial Summary

CONDITION: Idiopathic male infertility In men with idiopathic infertility, the sperm DNA fragmentation index (DFI) within 12 weeks of FSH therapy and 12 weeks follow-up improves depending on the FSHR genotype as assessed by the non-synonymous SNP rs6166 (wild type or p.N680S).

This is a phase II b, multicenter, prospective, open label, one arm, clinical trial stratified according to the patient's genotype.

INTERVENTION: FSH therapy (150 I.U. sc every other day for 12 weeks) in infertile men who are homozygous for the wild-type FSHR or the p.N680S allele of the FSHR. Duration of intervention per patient: 12 weeks

Primary efficacy endpoint: Sperm DFI. Number of patients with an improvement in DFI > 60% Key secondary endpoint(s): pregnancy, semen parameters, serum levels of inhibin B and AMH.

Clinical Trial Description

Male factor infertility is responsible for about 50% of cases of involuntary couple infertility and remains idiopathic in about half of the cases. At present, there are no consistently effective treatments for male idiopathic infertility. Since follicle-stimulating hormone (FSH) is fundamental for spermatogenesis, recombinant hFSH is empirically used for male infertility treatment. The response to FSH, however, is highly variable and while sperm parameters improve in some patients, about 50% of the subjects do not clearly respond to FSH. Several studies were performed in the past and a recent Cochrane meta-analysis showed that FSH treatment of male idiopathic infertility overall significantly improves pregnancy rate. Nevertheless, no predictive marker of response to FSH, allowing a stratified therapeutic approach, was identified so far.

The sperm DNA fragmentation index (DFI) provides an estimation of genetic integrity of spermatozoa and was shown to improve significantly after FSH treatment. Therefore, DFI could be used as a pharmacodynamic marker of FSH in the male.

In women, the response to FSH varies depending on the FSH receptor (FSHR) genotype, as determined by the non-synonymous SNP rs6166, which exchanges the amino acid Asn to Ser in codon 680. This SNP is very common, with a minor allele frequency of 0.4. Women homozygous for Ser at amino acid position 680 of the FSHR are less sensitive to endogenous and exogenous FSH compared to those homozygous for Asn and require more FSH for multiple follicular growth and maturation in assisted reproduction. The investigators hypothesize that the variable response to FSH in unselected infertile men is due to a different individual sensitivity to FSH as determined by the common FSHR polymorphism rs6166. In particular the investigators will test the hypothesis that men homozygous for Asn at 680 (wild type) will respond better to exogenous FSH treatment in terms of sperm DFI compared to men homozygous for Ser, assessing sperm DFI as pharmacodynamic parameter of FSH.

Men with idiopathic infertility and normal serum FSH levels, candidate for treatment with FSH, will be recruited. Men with a sperm DFI > 15% will be included in the trial if carriers of the homozygous Asn/Asn or Ser/Ser at aminoacid position 680. The FSHR genotype will be assessed centrally and the physician will only receive the information whether the patient is eligible for entering the trial (i.e. homozygous) but both the physician and the patient will remain blind to the genotype. Human recombinant FSH (Gonal-f, Merck Serono) will be self-administered sc at the dose of 150 IU every other day for 12 weeks, followed by 12 weeks of observation (follow up). Changes in sperm DFI will be the primary end point and compared between the two arms. In addition, the effects on pregnancy rate and other clinical and hormonal parameters will be evaluated.

Should this pilot, proof-of-principle trial demonstrate that the response to FSH in male idiopathic infertility depends on FSHR genotype, larger interventional trials aiming at assessing the effects on pregnancy rate will be justified. ;

Study Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Caregiver), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Infertility
• Infertility, Male
• Male Infertility

• NCT number: NCT02349945
• Study type: Interventional
• Source: Azienda USL Modena
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: January 2011
• Completion date: December 2015