Follicle‐Stimulating Hormone to Inhibin B Ratio Among Primary Infertile Men With Low Testosterone—A Biochemical Marker of Testicular Reserve

INTRODUCTION: In adult males, Inhibin B (InhB) production depends on follicle-stimulating hormone (FSH)-which stimulates InhB as part of a negative feedback loop on the pituitary gland-and on spermatogenic activity, which reflects the functional state of the seminiferous epithelium. We aimed to (i) investigate the role of the FSH/InhB ratio in a homogeneous cohort of primary infertile men with low testosterone levels and (ii) evaluate its reliability as a marker of impairment severity. METHODS: Data from 1568 consecutive primary infertile men, defined according to World Health Organization (WHO) criteria, were analyzed. Patients underwent thorough assessments comprising complete demographic, clinical, genetic, and laboratory investigations, including semen analysis and sperm DNA fragmentation index (SDF) testing. Low testosterone was defined as serum total testosterone (tT) < 3.5 ng/mL, according to the EAU threshold. Patients with any chromosomal alteration and history of cryptorchidism were excluded from the analysis. The final cohort was stratified into two groups based on the median FSH/InhB ratio (≤ 0.23 vs. > 0.23). Descriptive statistics were used to summarize baseline characteristics, and linear regression analysis was performed to evaluate the associations between the FSH/InhB ratio and sperm concentration. RESULTS: Overall, 360 men (23%) reported tT < 3.5 ng/mL. Of these, men with higher FSH/InhB ratio levels displayed lower mean testicular volume (TV) [13.5 (10, 20) vs. 17.5 (15, 22.5) mL, p < 0.001], anti-Müllerian hormone (AMH) [0.2 (0.16, 2.7) vs. 6 (3.5, 7.2) ng/mL, p = 0.01] and total motile sperm count (TMSC) [4.4 (0.4, 21.6) vs. 15.7 (2, 55), p < 0.001], along with higher rates of non-obstructive azoospermia (NOA) (31.7% vs. 12.8%, p < 0.001). No additional significant differences were observed between the groups. At multivariable linear regression analysis, smaller TV [β = 2.42 (95% CI 1.41, 2.86); p`0.01], higher BMI [β = -1.24 (95% CI -2.25, -0.23); p = 0.02] and higher FSH/InhB ratio [β = -0.53 (95% CI -1.04, -0.03); p = 0.04] were identified as independent predictors of lower sperm concentration, after adjusting for age and tT. CONCLUSIONS: Among primary infertile men with low tT levels, those with a higher FSH/InhB ratio exhibited a more severe phenotype, characterized by reduced TV, lower TMSC, and higher rates of NOA as compared with those with a lower ratio. These findings identify a distinct endocrine phenotype characterized by reduced InhB production at comparable FSH levels, which is associated with impaired gonadal function. The FSH/InhB ratio emerges as a useful biomarker to stratify gonadal dysfunction severity in men with primary infertility and hypogonadism.