The biological logic begins with the Sertoli cell, the somatic nurse cell of the seminiferous epithelium. Sertoli cells provide the structural scaffold, metabolic substrates, and paracrine signals that developing germ cells require, and they orchestrate the apoptotic elimination and phagocytic clearance of defective cells before sperm release. During spermiogenesis, the final phase of sperm construction, histones are replaced first by transition proteins and then by protamines, a chromatin remodeling process accompanied by transient physiological DNA breaks that are normally repaired before final condensation. Experimental studies show that Sertoli cells suppress apoptotic DNA fragmentation in pachytene spermatocytes and round spermatids through paracrine and cell-contact-dependent mechanisms. If Sertoli-cell support weakens, under-protaminated chromatin, incomplete DNA repair, and the persistence of damaged germ cells could theoretically follow, allowing sperm with abnormal packaging or unresolved breaks to reach the ejaculate.

FSH is the key endocrine regulator of this support system. It acts through the FSH receptor, a seven-transmembrane G protein-coupled receptor expressed exclusively on Sertoli cells, triggering the canonical cAMP/PKA pathway alongside context-dependent ERK/MAPK and PI3K/Akt/mTOR cascades. These coordinated pathways regulate Sertoli-cell metabolic activity, junctional dynamics, glucose uptake, glycolysis, and lactate production, the last being critical because developing spermatids depend substantially on Sertoli-cell-derived lactate. Strikingly, experimental work shows that conditional deletion of the lactate dehydrogenase gene Ldha in Sertoli cells altered more than 2,400 metabolites in sperm and produced profound defects in spermiogenesis. FSH withdrawal, meanwhile, increased DNA fragmentation in primary spermatocytes and spermatids in cultured human seminiferous tubules, providing direct mechanistic support for the idea that FSH-dependent signaling helps maintain germ-cell DNA integrity.

The central insight of the review, however, is that circulating FSH concentrations may not accurately reflect effective intratesticular FSH action. Inter-individual variation in FSH receptor expression, receptor polymorphisms, ligand-receptor interactions, receptor trafficking, and downstream signaling efficiency may all influence the biological response to an equivalent serum FSH level. Clinical data indicate that some idiopathic infertile men have reduced testicular volume and sperm counts despite subnormal to normal serum FSH, suggesting that the hormone measured in blood is a marker of endocrine stimulation rather than a direct measure of biological action at the Sertoli-cell level. The review therefore defines relative Sertoli-cell FSH hyporesponsiveness as a functional phenotype of reduced effective FSH signaling, irrespective of whether the defect resides in ligand bioactivity, receptor biology, or downstream intracellular competence. Some men with normal or near-normal FSH may nevertheless exhibit this state.

The strongest direct clinical evidence comes from pharmacogenetic trials of recombinant FSH therapy. In a multicenter prospective study, Simoni and colleagues demonstrated that recombinant FSH reduced the DNA fragmentation index in idiopathic infertile men depending on the FSHR p.N680S genotype, with a significant reduction seen only in homozygous N carriers. Other trials have reported mean DFI reductions of roughly 20 to 50 percent after three months of treatment, although these studies differ markedly in patient selection, baseline gonadotropin levels, FSH preparation, dose, duration, and SDF assay. A pooled analysis of individual patient data found that higher post-treatment testosterone and younger age were associated with greater DFI improvement. Collectively, these findings support the biological plausibility of a relationship between FSH signaling and sperm DNA integrity, but they do not establish that relative hyporesponsiveness is the underlying cause of elevated SDF.

Associative human evidence adds indirect support. Common variants in the FSHB and FSHR genes, including the FSHB promoter −211G>T variant and FSHR variants such as −29G>A, Thr307Ala, and Asn680Ser, have been associated with modest differences in serum FSH, inhibin B, and testicular volume, with less consistent associations for sperm concentration. These polymorphisms appear to modify testicular responsiveness to FSH and may explain why some men with low-normal FSH levels exhibit impaired spermatogenesis. Endocrine biomarkers such as inhibin B and anti-Müllerian hormone correlate with spermatogenic output and provide indirect information about Sertoli-cell function, but they are neither specific indicators of SDF nor direct measures of effective FSH responsiveness. The genotype-phenotype associations remain modest, not consistently replicated across populations, and do not establish causality.

To translate this hypothesis into testable research, the review proposes the FERTILE framework, a seven-domain conceptual model integrating FSH and effective intratesticular signaling, endocrine markers including inhibin B, AMH, and testosterone, receptor and ligand genetics, testicular structure, inflammation and oxidative stress, lifestyle and environmental factors, and evaluation of DNA integrity using standardized assays. The framework is explicitly qualitative, intended for biological stratification and hypothesis generation rather than clinical decision-making. It acknowledges that SDF assays, including TUNEL, SCSA, SCD, and the comet assay, measure overlapping but non-identical aspects of DNA damage and generate non-comparable numerical values, a methodological obstacle that remains one of the major barriers to standardization in both research and clinical practice.

The review is careful to situate the hypothesis within the broader multifactorial pathophysiology of SDF. Varicocele, characterized by dilated veins of the pampiniform plexus, promotes testicular hyperthermia, oxidative stress, hypoxia, and impaired Sertoli-cell function, and meta-analyses of varicocelectomy consistently demonstrate significant postoperative reductions in SDF, with weighted mean differences of roughly −6 percent at three months and greater reductions at six months. Oxidative stress from smoking, obesity, infection, and environmental toxicants induces DNA strand breaks, oxidative base modifications, and chromatin cross-linking, and a prospective study of 105 obese men found that a 12-week lifestyle intervention reduced mean DFI from 20.2 to 17.5 percent. The Global Andrology Forum 2026 guidelines on antioxidant use emphasize that a complete clinical and andrological evaluation should precede therapy and warn against indiscriminate or prolonged antioxidant use. Established causes should be identified and managed before considering additional hypothesis-driven mechanisms.

The review also outlines how the hypothesis could be falsified. It would be considered unsupported if prospectively stratified randomized trials demonstrate that recombinant FSH does not improve SDF or chromatin packaging in predefined pharmacogenetic subgroups, if in vitro models show that blocking downstream FSHR signaling cascades does not affect protamine incorporation or DNA integrity, or if in vivo studies demonstrate that variation in FSHR signaling efficiency does not correlate with markers of Sertoli-cell support or germ-cell survival. Validation would require assessment of FSH receptor abundance, localization, ligand-induced signaling activity, and downstream phospho-signaling responses in Sertoli cells from men with and without elevated SDF, correlated with standardized SDF assays, chromatin-packaging markers, endocrine profiles, genotype, and reproductive outcomes. Such comprehensive datasets are currently unavailable.

The proposed model may ultimately explain why some men with apparently preserved endocrine profiles and conventional semen parameters nevertheless exhibit elevated SDF and impaired reproductive outcomes. A recent meta-analysis including more than 12,000 IVF and ICSI cycles reported that elevated SDF was associated with reduced implantation and pregnancy rates, particularly in conventional IVF, and showed a detrimental trend for live birth. If future studies demonstrate that relative Sertoli-cell FSH hyporesponsiveness contributes to persistent sperm DNA damage, biologically targeted interventions could potentially improve semen quality and reproductive outcomes in appropriately selected patients. Until such evidence becomes available, the FERTILE framework and the concept of relative Sertoli-cell FSH hyporesponsiveness should be regarded as hypothesis-generating research tools intended to facilitate biological stratification and future translational investigation rather than as a basis for changing routine evidence-based clinical practice.

Subject of Research: Reproductive Biology

Article Title: Relative Sertoli-cell FSH hyporesponsiveness as a potential contributor to sperm DNA fragmentation: a hypothesis-driven narrative review and proposal of the FERTILE framework

Article References: Kandil, H. (2026). Relative Sertoli-cell FSH hyporesponsiveness as a potential contributor to sperm DNA fragmentation: a hypothesis-driven narrative review and proposal of the FERTILE framework. Frontiers in Urology, 6, Article 1915445. https://doi.org/10.3389/fruro.2026.1915445

Image Credits: AI Generated

DOI: 10.3389/fruro.2026.1915445

Keywords: sperm DNA fragmentation, FSH, Sertoli cells, male infertility, FERTILE framework, pharmacogenetics, reproductive endocrinology, Relative, Sertoli-cell, hyporesponsiveness, potential, contributor