Pharmacogenetics of Follicle-Stimulating Hormone Action in the Male

Genetic variants in FSH and its receptor affect sperm production, but current evidence is too small and contradictory for clinical use

Journal: Andrology | Published: 2025-04-30 | Type: Narrative Review | PMID: 40304702 Authors: Graziani A, Grande G, Scafa R, Selice R, Garolla A, Rocca MS, Vinanzi C, Ferlin A (University of Padova and University Hospital of Rome/Tor Vergata, Italy) Funding/COI: Funding not disclosed; authors declare no conflicts of interest

Summary

FSH therapy for idiopathic male factor infertility — which contributes to roughly half of all couple infertility — produces wildly variable results, and clinicians currently have no reliable way to predict who will respond. This review asks whether genetic variants in the FSH beta-subunit gene (FSHB) and the FSH receptor gene (FSHR) could fill that gap. The answer, after surveying the available pharmacogenetics literature, is: not yet.

Claims

• Male factor infertility is implicated in approximately 50% of couple infertility cases
• FSH therapy effects in idiopathic MFI are described by the authors as "variable and unpredictable," unlike the well-established FSH + hCG protocol for hypogonadotropic hypogonadism
• Two genetic loci dominate the literature: FSHB c.-211 G>T (affecting FSH production) and FSHR p.N680S and p.T307A (affecting receptor sensitivity/expression)
• Proposed physiological framework: reduced FSHR sensitivity → compensatory FSH rise → normal testicular volume and sperm count; reduced FSHB transcription → low FSH → smaller testes, lower sperm count; both reduced → severely impaired testicular function
• One multicentric prospective study found FSHR p.N680S N/N homozygotes had decreased sperm DNA fragmentation index response to rh-FSH — a potential negative predictor
• Authors explicitly state: "genetic evaluation of FSHB and FSHR is recommended only for research purposes, since the data are not conclusive and even contrasting"
• No pooled effect sizes are reported; underlying studies are too heterogeneous

Study Quality

This is a narrative review, not a systematic review or meta-analysis, which means the authors chose which studies to include without a registered protocol or formal quality assessment framework. That introduces selection bias by design. The underlying clinical studies it synthesizes are almost uniformly small and monocentric — the table of pharmacogenetics studies lists samples in the tens to low hundreds, with varying entry criteria (some require FSH <8 IU/L plus oligozoospermia, others define inclusion differently) and varying endpoints (sperm concentration, total sperm count, DNA fragmentation index, pregnancy rate). One prospective RCT is listed, but it is single-center. Heterogeneity across studies makes pooling impossible and renders the "contrasting" results unsurprising — they may be comparing different patient populations rather than detecting true genetic signal.

The authors do acknowledge these limitations directly, which is more intellectual honesty than many reviews in this space offer.

Red Flags

• Narrative review format is inherently susceptible to cherry-picking; no PRISMA flow or search strategy documented
• Underlying studies are small and mostly monocentric — inadequate statistical power to detect modest pharmacogenetic effects
• No quantified effect sizes or confidence intervals provided for the genetic associations described
• Funding source not disclosed — a transparency gap for an academic review from a group that consults in reproductive medicine
• "Contrasting" results across studies are presented without attempting formal meta-analytic reconciliation
• The framework diagram (Figure 1) is mechanistically plausible but not directly validated in the cited clinical data

Strengths

• Authors are unusually blunt about the field's limitations and resist overselling the genetic approach
• Physiological framework for FSHB/FSHR polymorphism interactions is coherent and useful for understanding why clinical results diverge
• University of Padova group has genuine depth in male reproductive endocrinology
• Correctly distinguishes idiopathic MFI (where FSH therapy is uncertain) from hypogonadotropic hypogonadism (where it is established)
• Calls explicitly for studies combining genetic, clinical, biochemical, seminal, and testicular cytology data — a reasonable roadmap

Verdict

This review is worth reading as an honest accounting of an underdeveloped field. The pharmacogenetics of FSH therapy is biologically credible — receptor polymorphisms do affect testicular function, and the physiological logic for personalized dosing is sound. But the clinical studies are too small, too heterogeneous, and too contradictory to support genetic testing for FSH therapy decisions today. The authors say so plainly, which distinguishes this from the genre of reviews that hype preliminary findings into clinical guidelines. The practical takeaway for the field: larger multicenter RCTs stratified by FSHB and FSHR genotype are needed before pharmacogenetics can move from the research bench into the fertility clinic.