Localization patterns of the ganglioside G(M1) in human sperm are indicative of male fertility and independent of traditional semen measures

Semen analysis lacks a functional component and best identifies extreme cases of infertility. The ganglioside G(M1) is known to have functional roles during capacitation and acrosome exocytosis. Here, we assessed whether G(M1) localization patterns (Cap‐Score™) correspond with male fertility in different settings: Study 1 involved couples pursuing assisted reproduction in a tertiary care fertility clinic, while Study 2 involved men with known fertility versus those questioning their fertility at a local urology center. In Study 1, we examined various thresholds versus clinical history for 42 patients; 13 had Cap‐Scores ≥39.5%, with 12 of these (92.3%) achieving clinical pregnancy by natural conception or ≤3 intrauterine insemination cycles. Of the 29 patients scoring <39.5%, only six (20.7%) attained clinical pregnancy by natural conception or ≤3 intrauterine insemination cycles. In Study 2, Cap‐Scores were obtained from 76 fertile men (Cohort 1, pregnant partner or recent father) and compared to 122 men seeking fertility assessment (Cohort 2). Cap‐Score values were normally distributed in Cohort 1, with 13.2% having Cap‐Scores more than one standard deviation below the mean (35.3 ± 7.7%). Significantly, more men in Cohort 2 had Cap‐Scores greater than one standard deviation below the normal mean (33.6%; p = 0.001). Minimal/no relationship was found between Cap‐Score and sperm concentration, morphology, or motility. Together, these data demonstrate that Cap‐Score provides novel, clinically relevant insights into sperm function and male fertility that complement traditional semen analysis. Furthermore, the data provide normal reference ranges for fertile men that can help clinicians counsel couples toward the most appropriate fertility treatment.