Hormonal Therapy Before Sperm Retrieval in Men With Non-Obstructive Azoospermia: From Controversy to Precision Using the APHRODITE Criteria.

Purpose: To review the biological rationale, clinical evidence, limitations, and future directions for hormonal therapy before sperm retrieval in men with non-obstructive azoospermia (NOA), with emphasis on phenotype-based selection using the APHRODITE criteria. Methods: A narrative review was conducted, integrating evidence on hypothalamic-pituitary-gonadal axis regulation, Leydig- and Sertoli-cell function, intratesticular testosterone, gonadotropin-based stimulation, sperm retrieval outcomes, and endocrine phenotyping in NOA. Particular attention was given to mechanistic studies and controlled cohorts evaluating hCG, FSH, or combined gonadotropin therapy before microdissection testicular sperm extraction. Results: Hormonal therapy in NOA remains controversial because available studies are heterogeneous and largely observational. However, mechanistic data show that hormonal therapy using hCG can increase intratesticular testosterone and stimulate spermatogonial activity, while exogenous FSH may support Sertoli-cell function. Clinical evidence suggests that benefit is most likely in selected men with biochemical hypogonadism, especially those with normal or moderately elevated FSH, whereas men with advanced hypergonadotropic testicular failure appear less likely to respond. Conclusions: Hormonal therapy before sperm retrieval in testicular NOA should be considered a selective, off-label strategy rather than a universal intervention. APHRODITE-based stratification may help identify candidates for endocrine optimization and guide future randomized trials.