Hormonal Regulation of Sertoli and Leydig Cell States in Non-Obstructive Azoospermia: A Critical Narrative Review

Non-obstructive azoospermia (NOA) includes diverse disorders whose somatic-cell abnormalities depend on developmental history, endocrine exposure, genotype, and tissue injury. This critical narrative review examines hormonal regulation of Sertoli and Leydig cell states and the interpretation of maturity-associated findings in human NOA. PubMed searching and reference tracing informed a purposive synthesis of developmental, histological, molecular, and interventional evidence. Human studies describe heterogeneous immature-like programs, spatially restricted mature features, and injury-associated dysfunction. Fetal Klinefelter findings indicate early somatic abnormalities, whereas adult tissue studies reveal local differences in chromosome constitution and germ-cell support. These observations address distinct biological questions and should be interpreted within their original designs. The proposed framework records maturity-associated evidence, injury, and chronology separately within each somatic compartment. Convergence across molecular and non-transcriptomic domains can strengthen maturity characterization, but the suggested reporting criterion remains unvalidated. Serial-biopsy evidence in severe congenital hypogonadotropic hypogonadism supports hormone-dependent forward Sertoli maturation. Its applicability to primary testicular NOA remains uncertain. Cross-sectional and ex vivo findings identify candidate mechanisms but do not establish within-person reversal or validated sperm-retrieval prediction.