FSH Receptor Polymorphism p.N680S and Efficacy of FSH Therapy
Condition: Male Infertility
MeSH terms: Infertility; Infertility, Male
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Detailed 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.
    

Intervention name(s): follitropin alpha
Intervention type(s): Drug
Intervention description(s): All subjects included in the study will receive recombinant FSH therapy (follitropin alpha: Gonal-f 150 I.U. s.c. every other day for 12 weeks). Follow up: 12 further weeks after end of treatment.
Previous studies included in the Cochrane meta-analysis used: hMG/hCG, 150 IU three times a week for 13 weeks; purified FSH, 150 IU/day for 12 weeks; rec hFSH, 150 IU/day for 12 weeks; rec hFSH, 100 IU on alternate days for 3 months. Therefore any dosage > 100 IU on alternate days is eligible. The duration of treatment is based on the duration of one spermatogenetic cycle.
Other intervention name(s): Gonal f
Intervention MeSH terms: Follicle Stimulating Hormone
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: Single (Care Provider)
Primary purpose: Treatment