Monge's disease at 100 years: Revisiting the origins and endocrine mechanisms of chronic mountain sickness

Abstract

Chronic mountain sickness (CMS), first described by Carlos Monge Medrano in 1925, is characterized by excessive erythrocytosis (EE), hypoxemia, and neurocognitive disturbances in long-term high-altitude residents. This narrative review revisits Monge's contribution in the light of modern research. CMS is now recognized worldwide, where genetic predisposition and environmental stressors jointly shape susceptibility to high-altitude life. Although hypoxia-driven erythropoietin (EPO) stimulation has long been considered the primary mechanism, recent evidence highlights the critical role of sex hormones in modulating erythropoiesis. EE, once the defining feature, is now complemented by symptom-based scoring systems that better capture the syndrome. Testosterone promotes erythroid expansion by stimulating progenitors, enhancing EPO sensitivity, and suppressing hepcidin, whereas estrogens counteract these effects by downregulating GATA1 and modulating hypoxia-inducible pathways. Elevated testosterone or high testosterone-to-estradiol ratios correlate with hemoglobin, hematocrit, and EE in CMS, explaining its greater prevalence and severity in men. Advances in molecular biology have identified the hypoxia–testosterone–EPO axis, with regulators such as SENP1 and GATA1, as central to disease susceptibility. Excessive androgenic signaling also worsens sleep-disordered breathing and cognitive dysfunction, while estrogenic modulation appears protective, opening avenues for prevention and therapy. In conclusion, CMS should be regarded as a multifactorial disorder shaped by hypoxia, hormones, gene–environment interactions, and cellular stress. Despite progress, underdiagnosis and limited healthcare attention in South American highlands remain major challenges, underscoring the relevance of Monge's seminal description. © The Author(s) 2025. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).