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Endocrinol."],"abstract":"<jats:p>High-altitude hypoxia is a sustained environmental stressor that reduces inspired oxygen pressure and challenges tissue oxygen delivery. The male reproductive system is sensitive to oxygen availability, vascular perfusion, testosterone support, Sertoli-cell metabolic function and blood-testis barrier integrity. Human high-altitude exposure studies, mountaineering observations and animal hypobaric hypoxia models indicate that exposure to high altitude or hypobaric hypoxia is associated with reductions in sperm concentration, total sperm count, motility, viability and normal morphology, accompanied in experimental models by testicular structural injury, oxidative stress and reproductive endocrine alterations. However, the magnitude and reversibility of these changes vary substantially across studies. This variability suggests that altitude-related reproductive dysfunction is not a single linear consequence of hypoxia, but a dynamic process governed by exposure intensity, duration, acclimatization, systemic stressors and local testicular compensatory capacity. Building on the classical hypoxia-oxidative stress-germ-cell injury paradigm, this review proposes an integrated framework centered on testicular oxygen homeostasis, dual microenvironmental injury and spermatogonial niche vulnerability. In this model, high-altitude hypoxia first challenges the balance among oxygen delivery, microvascular blood flow, temperature and metabolism. When compensation fails, injury is propagated through two interconnected compartments: the interstitial vascular endothelial niche-Leydig-cell-immune axis and the seminiferous Sertoli-cell-blood-testis barrier-germ-cell support system. Peritubular myoid cells, the basement membrane and extracellular matrix form a boundary layer that links these compartments and participates in the spermatogonial stem-cell niche. The rete testis\/efferent ductules, epididymal segmental microenvironment, blood-epididymis barrier and seminal extracellular vesicles are best interpreted as downstream or modifying layers rather than primary mechanisms. Whether injury reaches spermatogonia or the spermatogonial stem-cell niche may determine whether recovery is rapid and complete or delayed and incomplete. The review also identifies evidence gaps, including direct measurement of local testicular oxygen tension, compartment-specific experimental designs, niche-targeted endpoints and longitudinal high-altitude\/lowland return cohorts.<\/jats:p>","DOI":"10.3389\/fendo.2026.1939784","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:23:24Z","timestamp":1788413004000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["High-altitude hypoxia and male reproductive dysfunction: testicular oxygen homeostasis, microenvironmental injury and spermatogonial niche vulnerability"],"prefix":"10.3389","volume":"17","author":[{"given":"Jiahao","family":"Li","sequence":"first","affiliation":[{"name":"School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine","place":["Lanzhou, China"]},{"name":"Department of Urology, The 940th Hospital of Joint Logistic Support Force of 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