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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.

Keywords

Testosterone chronic mountain sickness hypoxia SENP1 erythropoiesis GATA-1

Introduction

Human responses to hypoxia occur along a continuum. Acute reactions include hyperventilation, tachycardia, and sympathetic activation; acclimatization over days to weeks involves erythropoiesis, renal bicarbonate excretion, and ventilatory adjustments; while developmental adaptation during growth produces permanent traits, such as larger lung volumes and chest dimensions in highland natives.^1,2 Genetic adaptation, in contrast, emerges over generations through selection of alleles such as EPAS1 and EGLN1 in Tibetans. This distinction separates reversible physiological adjustments (acclimatization) from irreversible transgenerational changes (developmental and genetic adaptation).³

Highland populations have lived for millennia under chronic hypobaric hypoxia, developing distinct physiological and genetic strategies for survival. Early fossil evidence from Jebel Irhoud (Morocco, ∼300,000 years ago, 1000 m) and Kibish Omo (Ethiopia, ∼200,000 years ago, 1300 m) indicates occupation of moderate altitudes.^4,5 Archaeological sites on the Tibetan Plateau (∼4600 m, 40,000–30,000 years ago)⁶ and in the Peruvian Andes (∼4480 m, ∼14,000 years ago)⁷ document the earliest permanent settlements at extreme altitudes. These migratory and settlement patterns shaped the physiological and genetic responses to chronic hypoxia that contribute to variability in high-altitude tolerance and the risk of chronic mountain sickness (CMS).

The physiological burden of hypoxia was first described by Jesuit priest José de Acosta in 1590, who reported severe headaches, vomiting, and distress while crossing the Pariacaca mountains at 4500 m in Peru, symptoms now recognized as acute mountain sickness (AMS).⁸ AMS affects sedentary individuals and athletes after rapid ascents, manifesting as headache, dizziness, gastrointestinal discomfort, fatigue, and sleep disturbances.⁹ By contrast, CMS develops only after prolonged residence at high altitude, characterized by excessive erythrocytosis (EE) and multi-organ involvement. It is now understood as a maladaptive response to sustained hypoxia, with prevalence reaching up to 30% in parts of Latin America compared with ∼10% in Asia.¹⁰

Dr Carlos Monge Medrano provided the first clinical description of CMS in 1925 in a man from Cerro de Pasco (4340 m, Peru).¹¹ Current diagnostic criteria require sustained EE (Hb ≥21 g/dL in men, ≥ 19 g/dL in women) along with dyspnea, headache, cyanosis, sleep disturbance, and tinnitus.^12,13 Recent studies at extreme altitudes, such as La Rinconada (Peru, > 4500 m), show that EE can occur even without overt symptoms, highlighting heterogeneity in clinical expression.¹⁴ While Monge Medrano initially emphasized hematologic abnormalities, he also noted neurovascular symptoms, including insomnia, persistent headache, confusion, dizziness, visual disturbances, and paresthesia in high-altitude residents.¹¹

This review will address: (1) the history and symptoms of CMS; (2) Monge Medrano's 1925 description compared with current definitions; (3) the pathophysiology of CMS; (4) recent insights emphasizing the role of testosterone; and (5) the clinical and andrological implications of chronic hypoxia and erythrocytosis. The review follows the Scale for the Assessment of Narrative Review Articles (SANRA)¹⁵ (Supplementary Table 1).

Carlos Monge Medrano's original 1925 clinical description compared with the current definition

In 1925, Peruvian physician Carlos Monge Medrano published the first formal clinical description of chronic mountain sickness (CMS), later termed Monge's disease, based on the case of a 38-year-old engineer residing in Cerro de Pasco, Peru (4338 m).¹¹ Monge identified a constellation of symptoms related to life at high altitude that were initially misattributed to rheumatologic or hematologic disorders such as primary polycythemia (formerly Vaquez's disease).

He emphasized “hyperglobulia” (polycythemia) as the hallmark of the condition, accompanied by facial redness, fatigue, dizziness, and musculoskeletal pain, all of which improved after descent to sea level. The striking reddish or vinous facial discoloration, characteristic of high-altitude residents, reflects a physiological response to excessive erythrocytosis (EE), whereby elevated hemoglobin enhances oxygen transport under hypoxic conditions.¹⁶

Although not all manifestations described by Monge are recognized today, his distinction of CMS from acute altitude illnesses was pivotal. The Lake Louise criteria diagnose AMS when headache is accompanied by gastrointestinal discomfort, fatigue, or dizziness after recent ascent (≥6 h). High-altitude cerebral edema (HACE) represents severe AMS progression with ataxia and altered mental status, while high-altitude pulmonary edema (HAPE) is a non-cardiogenic pulmonary edema due to hypoxic vasoconstriction and elevated capillary pressure, presenting with dyspnea, cough, cyanosis, and crackles.¹⁷

When contrasted with current diagnostic criteria, Monge's description shows both overlap and divergence (Table 1). Polycythemia and facial cyanosis remain central features, whereas bone pain or episodic dizziness is now considered nonspecific. Some of these nonspecific findings may reflect sequelae of past infections such as typhoid, or exposure to pathogens like Brucella in the central Andes, known to cause chronic osteoarticular complications in the region.^18–24

Table 1.

Clinical history, signs, and symptoms described by Carlos Monge-Medrano (1925) and their association with the current definition of chronic mountain sickness (CMS).

Category	Description (Monge-Medrano, 1925)	Present in current CMS definition
Clinical history	Childhood/adolescent illnesses: measles, mumps, bronchitis, typhoid, malaria	No
	Sharp lower extremity pains after traveling to 2378 m (in 1906)	No
Signs	High-altitude polycythemia*	Yes
	Reddish and congestive face	Yes
	Change in skin/face color	Yes
Symptoms	Osteocopic pain	No
	Dizziness	No

*Note: “Polyglobulia” was the term used by Monge-Medrano for high-altitude polycythemia (HAPC), now defined as excessive erythrocytosis (EE) (hemoglobin ≥21 g/dL in males or ≥19 g/dL in females with multi-organ complications.^12,13 Source: Monge-Medrano, 2025.¹¹

The patient's narrative detailed progressive congestion, insomnia, mental confusion, and visual disturbances, corroborated by Monge's examination. Many systemic complaints, including fatigue, insomnia, and pain, were reversible with descent (Table 2), highlighting the dynamic nature of CMS. Table 3 summarizes Monge's original clinical features alongside current diagnostic criteria, underscoring both continuity and evolution in its characterization. Through careful observation and patient testimony, Monge laid the foundation for modern recognition of CMS as a distinct syndrome with occupational health implications.

Table 2.

Signs and symptoms at high altitude (HA) and low altitude (LA), and their association with CMS.

Signs and symptoms at HA	Signs and symptoms at LA	CMS criterion met
Insomnia	Disappeared	Yes
Loss of cognitive clarity / work errors	Not described	Yes
Generalized bone pain	Persistent	No
Weight loss	Not described	Yes
Wine-colored stain on palate	Disappeared	No
Congested lips, eyes, throat	Disappeared	Yes
Episodic dizziness and transient visual loss	Disappeared	No
Polycythemia*	Disappeared	Yes

* Studies in non-CMS individuals living at 5100 m develop excessive erythrocytosis like that of CMS patients, excessive erythrocytosis would no longer be a hallmark of CMS at this extreme altitude.¹⁴

Table 3.

Symptoms observed in Monge-Medrano’s patient: Physician’s summary and relation to CMS.

Symptom or Clinical feature	Related to CMS definition
Persistent facial cyanosis	Yes
Epistaxis and fainting upon straining	Yes
Osteoscopic pain and generalized arthralgia	No
Cyclical periods of complete remission followed by relapse	Yes
Functional incapacity during flare-ups	Yes

Source: Monge Medrano, 1925.¹¹

A notable observation was his patient's reduced occupational performance, manifested as impaired concentration and frequent errors at altitude, which he attributed to chronic hypoxia.¹¹ Modern polygraphy studies in residents of La Rinconada (>5000 m) corroborate this insight, showing pronounced nocturnal hypoxemia (median SpO₂ = 79%) and elevated desaturation indices, particularly in CMS patients.²⁵ These findings provide physiological support for Monge's early interpretation.

Today, CMS is recognized as encompassing hematologic, cardiopulmonary, and neurovascular manifestations.²⁶ In addition to polycythemia and cyanosis, symptoms include chronic headache, sleep disturbances, impaired concentration, and, in severe cases, cognitive decline or mood alterations. Such features reflect the impact of sustained hypoxemia and increased blood viscosity on cerebral perfusion and microvascular function.²⁷

Monge also noted that CMS affected both highland natives and newcomers after two to three years of residence, with highest incidence in the fourth and fifth decades.²⁸ Importantly, he emphasized its reversibility: symptoms typically resolved after descent to lower altitudes, underscoring CMS as a maladaptive acclimatization to chronic hypoxia rather than permanent adaptation. Relocation provides a natural setting to examine reversibility, with rapid hematocrit and red cell mass decline explained by neocytolysis triggered by falling erythropoietin (EPO).²⁹ Most clinical manifestations: headache, fatigue, cyanosis, and sleep disturbances improve substantially, though recovery is heterogeneous. Hematological changes are largely reversible, but long-standing cases may retain residual complications such as pulmonary hypertension or neurocognitive deficits.^12,30

Further evidence comes from Tibetan refugees born at altitude but living at sea level, who display lower hemoglobin, hematocrit, and red cell counts compared with their high-altitude counterparts. Tibetans at low altitude also exhibit blunted ventilatory and vascular responses to hypoxia, as well as reduced hypoxic induction of HIF-regulated genes and attenuated EPO responses, linked to EPAS1 and EGLN1 variants.³¹ These findings suggest that descent reverses most hematological alterations of CMS while revealing new physiological adjustments to relatively hyperoxic environments.

Laboratory tests in Monge's index case (Supplementary Table 2) revealed EE, the hallmark of CMS. Additional results included prolonged coagulation time (11 min), indicating a hypocoagulable state with bleeding tendency, rather than thrombosis. In contrast, blood viscosity was markedly elevated, approximately twice normal (3–4 centipoise, cP) impairing microcirculation and predisposing to pulmonary hypertension and paradoxical thrombosis. Red cell morphology showed basophilic stippling and mild anisocytosis, indicating disordered erythropoiesis, changes not specific to CMS and also seen in lead poisoning, sideroblastic anemia, megaloblastic anemia, hemolysis, or chronic disease.³²

Because permanent relocation is often limited by socioeconomic constraints, management of CMS commonly relies on palliative measures. Interventions such as phlebotomy or pharmacological therapy may relieve symptoms and help prevent complications, including pulmonary hypertension and heart failure.³³

Finally, Monge stressed the socioeconomic burden of CMS, noting that his patient became unable to work at altitude. His call for systematic research and labor protections remains highly relevant, particularly as both mining and industrial activity expand in high-altitude regions.

Through meticulous clinical observation, Monge anticipated modern concepts in high-altitude medicine, recognizing CMS as a disorder of maladaptation to chronic hypoxia, with excessive erythropoietic drive and systemic consequences. His 1925 report endures as both a clinical milestone and a pioneering contribution to environmental medicine.

Pathophysiology of chronic mountain sickness

Hypoxia occurs under both physiological and pathological conditions, and erythrocyte adaptation is central to understanding hypoxia-related diseases.³⁴ At high altitude, reduced barometric pressure causes sustained hypoxemia, which stimulates renal EPO production and promotes erythropoiesis to improve oxygen transport.³⁵ However, in EE, serum EPO levels plateau rather than rise further, suggesting that androgen excess characterized by elevated testosterone and reduced dehydroepiandrosterone sulphate (DHEAS) plays a pivotal role in the pathogenesis of chronic mountain sickness (CMS) and EE.³⁵ This deviation from the classic hypoxia–EPO–erythropoiesis paradigm underscores the role of hormonal mechanisms and suggests new avenues for therapeutic intervention.

In CMS, this compensatory mechanism becomes maladaptive, resulting in EE, defined as hemoglobin >21 g/dL in men or >19 g/dL in women.³⁶ Although elevated hemoglobin improves oxygen delivery potential, EE markedly increases blood viscosity, impairing microcirculatory flow and paradoxically reducing tissue oxygenation. Both high viscosity and EE are linked to pulmonary hypertension, right ventricular hypertrophy, and thrombotic risk, in part due to hypoxia-driven pulmonary vasoconstriction.^25,26,37

Erythropoiesis is tightly regulated through the kidney–bone marrow axis. Under normoxia, peritubular interstitial cells produce basal EPO, while prolyl hydroxylase domain (PHD) enzymes hydroxylate hypoxia-inducible factor (HIF)-α, targeting it for degradation.³⁸ Hypoxia reduces PHD activity, stabilizing HIF-α, which dimerizes with HIF-β and activates transcription of EPO.³⁸

The Janus kinase 2 (JAK2) gene is a key regulator of erythropoietin receptor (EPOR) signaling. Under hypoxic conditions, secreted EPO binds to EPOR on bone marrow progenitors, activating downstream JAK2/signal transducer and activator of transcription 5 (STAT5), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) pathways.³⁹ This signaling cascade enhances erythroid survival, proliferation, and differentiation, leading to reticulocyte and red blood cell expansion, increased hemoglobin concentration, and improved oxygen-carrying capacity, thereby restoring tissue oxygen delivery.⁴⁰

EPO-induced erythroferrone, secreted by erythroblasts, suppresses hepatic hepcidin, thereby increasing iron release from storage organs and intestinal absorption to meet the demand for red blood cell production.⁴¹ At high altitude, hypoxia activates this EPO–erythropoiesis cascade, promoting sustained red cell production as an adaptive response. However, in individuals who develop EE and CMS, serum EPO levels plateau rather than continue rising, and EE appears to be driven predominantly by androgen excess rather than persistent EPO stimulation.³⁵

Beyond erythrocytosis, CMS involves additional maladaptive mechanisms: a blunted ventilatory response to hypoxia,⁴² vascular endothelial growth factor (VEGF)-mediated vascular remodeling and mucosal congestion,⁴³ as well as systemic inflammation and oxidative stress, which impair endothelial function and hematopoietic regulation.⁴⁴ Together, these pathways underscore CMS as a multisystem disorder of hypoxia maladaptation.

Molecular mechanisms further expand this complexity. High-altitude polycythemia (HAPC) involves increased erythropoiesis, reduced erythrocyte apoptosis, and accumulation of abnormal, fragile red cells. Activated CD73/adenosine/S1P/2,3-BPG and eENT1/adenosine/BPGM pathways enhance oxygen release, but at the cost of impaired hemolysis resistance, highlighting maladaptive erythrocyte metabolic remodeling under chronic hypoxia.⁴⁵

Finally, recent evidence implicates altered microRNA expressions. Plasma exosomal microRNAs are differentially expressed in CMS patients: hsa-miR-122-5p, hsa-miR-423-5p, hsa-miR-4433b-3p, hsa-miR-1291, and hsa-miR-106b-5p are upregulated, whereas hsa-miR-200c-3p is downregulated in Tibetan CMS patients compared to healthy high-altitude controls. These findings suggest that microRNAs contribute to CMS pathogenesis and may serve as biomarkers or therapeutic targets.⁴⁶

A modern analysis of CMS pathophysiology, with emphasis on the role of testosterone

While Carlos Monge Medrano's early descriptions emphasized hematologic and neurovascular manifestations, modern insights reveal that CMS arises from complex endocrine, vascular, and inflammatory mechanisms, with sex hormones playing a pivotal role in its pathogenesis.

High-altitude exposure leads to elevated hemoglobin concentration and, more importantly, increased total hemoglobin mass, the primary determinant of oxygen-carrying capacity.⁴⁷ Beyond hypoxia-driven responses, sex hormones critically modulate erythropoietic regulation. Epidemiological studies consistently report higher hemoglobin and hematocrit levels in men than in women, an effect not explained by EPO concentrations but by hormonal influences that alter renal hemodynamics and reset erythropoietic thresholds.⁴⁸ Testosterone therapy significantly increases serum EPO in healthy men and shifts the EPO–hemoglobin relationship upward, suggesting recalibration of the erythropoietic set point.⁴⁹

Testosterone thus plays a central role in acclimatization and maladaptation at high altitude, particularly in regulating erythropoiesis and vascular homeostasis.^50,51 It enhances red blood cell mass both directly, by stimulating erythroid progenitors, and indirectly, by potentiating EPO signaling.⁵² At sea level, testosterone supplementation raises hemoglobin and hematocrit in hypogonadal men,⁵³ whereas at high altitude, endogenous testosterone may exacerbate EE in susceptible individuals.⁵⁴ By contrast, estrogens exert protective effects, suppressing erythroid progenitor survival under chronic hypoxia by downregulating GATA-binding factor 1 (GATA-1) and inducing apoptosis.⁵⁵ This sexual dimorphism highlights the integration of endocrine and hypoxia-responsive mechanisms.

Andean studies show that men with CMS exhibit significantly higher serum testosterone compared with healthy highlanders.⁵⁴ Testosterone correlates positively with hemoglobin and hematocrit,⁵⁰ reinforcing its mechanistic role in EE. Estradiol levels, by contrast, may be reduced in CMS, disturbing the testosterone-to-estradiol ratio and favoring a pro-erythropoietic state.⁵⁵ This imbalance has been documented in both men³⁵ and women.⁵⁶

Several symptoms originally described by Monge Medrano as insomnia, fatigue, poor concentration, and cognitive impairment are now recognized as neurobehavioral manifestations of CMS.²⁶ Emerging evidence suggests that testosterone contributes to these disturbances through effects on sleep architecture, cerebral oxygenation, and neurovascular regulation.⁵⁷ Excess testosterone has been associated with sleep-disordered breathing and central sleep apnea, both of which exacerbate nocturnal hypoxemia,^57,58 as well as mood instability and reduced cognitive flexibility.⁵⁹ Impaired working memory, frequently reported at extreme altitudes, may be further aggravated by testosterone-driven neurovascular dysregulation, compounding the detrimental effects of hypoxia on cerebral perfusion.^60,61 These mechanisms are particularly relevant in aging men permanently residing at altitude or in workers chronically exposed to hypoxia.^62,63

A key integrative model proposes the existence of a hypoxia–testosterone–EPO axis: chronic hypoxia stimulates hypothalamic–pituitary activation of testosterone, which enhances EPO sensitivity and erythropoiesis. When this axis becomes dysregulated due to genetic predisposition, age-related decline in oxygen sensing, or excessive androgenic drive, CMS may develop.^54,64,65 Animal studies support this model, showing that chronic hypoxia increases testicular steroidogenesis,⁶⁶ while in humans, healthy highlanders maintain a more balanced hormonal profile.^54,55 These insights have opened therapeutic perspectives, such as moderate suppression of testosterone⁵³ or modulation of EPO signaling⁶⁷ to control EE in CMS.

GATA transcription factors further shape hematopoiesis. GATA-1 promotes erythrocyte maturation by activating erythroid genes, GATA-2 maintains hematopoietic stem cell expansion, and GATA-3, although central in T-cell differentiation, indirectly influences erythropoiesis through progenitor balance.⁶⁸ Among these, GATA-1 is the master erythroid transcription factor, regulating red cell differentiation, hemoglobin synthesis, and progenitor survival.⁶⁹ Dysregulation of GATA-1 has been linked to maladaptive erythropoiesis under hypoxia, as observed in CMS.⁷⁰

Testosterone, via androgen receptor (AR) signaling, promotes erythropoiesis and is associated with increased expression of erythroid transcription factors such as GATA-1, though a direct AR–GATA-1 regulatory mechanism remains to be fully elucidated.⁷¹ SENP1 (sentrin-specific protease 1), a key deSUMOylating enzyme, reinforces erythroid expansion by stabilizing HIF-1α, enhancing AR signaling, and potentiating GATA-1 activity.^72–78 Genetic studies in Andean highlanders show that SENP1 polymorphisms, as well as variants in VEGFA and CARD14, increase susceptibility to CMS.^74,75,79,80

Sex differences further modulate these mechanisms. Estrogens inhibit GATA-1, which may explain the lower prevalence of CMS in women.^55,81,83Conversely, impaired GATA-1 activity has been linked to reduced Leydig cell function and diminished steroidogenesis, creating a feedback loop between erythropoiesis and androgen production.⁷⁹ Comparative studies show that a lower testosterone-to-estradiol ratio, as observed in Ladakhis compared with Andeans, favors vascular adaptation and limits erythropoiesis.⁸⁴

Environmental and age-related factors also influence this axis. Melatonin suppresses AR activity by reducing SENP1 protein levels and increasing HDAC1 SUMOylation.⁸⁵ In older adults, circadian disruption may prevent SENP1 degradation, amplifying androgenic activity and contributing to age-related risk of CMS.⁸⁶

Finally, genetic and sex-related factors converge in shaping CMS susceptibility. Estrogens may confer protection by modulating the HIF pathway and attenuating EPO signaling,^87,88 while variants affecting HIF regulation, EPO production, and AR activity further support the multifactorial basis of CMS.^{74,75,89–91}

An integrated discussion of the clinical and andrological implications of chronic hypoxia and erythrocytosis in high-altitude residents

One hundred years ago, Carlos Monge Medrano described altitude-induced erythrocytosis in a resident of Cerro de Pasco (>4000 m).^11,28 In 1929, G.H. Roger named the condition “Monge's disease”.⁹² CMS affects both native and migrant high-altitude populations.⁹³ Monge also noted its higher prevalence in older men and genetically predisposed individuals, observations later confirmed.^94,95

CMS has since become a well-recognized model of human maladaptation to chronic hypoxia. From Monge's pioneering clinical work¹¹ to twenty-first-century molecular and genetic studies,⁹⁶ our understanding has advanced considerably. CMS is no longer viewed solely as a disorder of EE but rather as a multifactorial syndrome involving hormonal, ventilatory, cardiovascular, and genetic mechanisms.^64,91,97

Although Monge emphasized the association between EE and CMS, current evidence indicates that CMS is not invariably linked to EE. In a Peruvian study, clinical CMS scores correlated with impaired health status regardless of hemoglobin levels, showing that symptom burden more accurately reflects disease severity.⁹⁸ This dissociation reframes diagnostic criteria and informs the study of other hematologic disorders.

Clinically, the Qinghai CMS scoring system has standardized diagnosis worldwide.¹² This semi-quantitative tool integrates hemoglobin concentration with symptom severity, with a score ≥6 indicating CMS and further stratification into mild, moderate, or severe categories. It emphasizes both erythrocytosis and functional impairment as key markers of maladaptation (Supplementary Table 3).

A growing body of evidence highlights testosterone as a key modulator in CMS pathophysiology. Elevated testosterone contributes to the higher prevalence of CMS in men.^{50,52–54,64,99} Animal studies further show that testosterone replacement restores resting ventilation and augments hypoxic ventilatory responses.¹⁰⁰ These hormonal effects may exacerbate hypoxemia and clinical symptoms, while β-estradiol exerts opposite actions.¹⁰¹

In contrast, estrogen and progesterone appear protective in women, attenuating EPO signaling and modulating the HIF pathway.^55,102,103 Genetic studies also support sex-linked differences, with polymorphisms in EPAS1, EGLN1, and the androgen receptor influencing CMS susceptibility.^{55,91,104,105} Women of reproductive age generally display lower hemoglobin levels and CMS scores than men, despite similar oxygen saturation,¹⁰⁶ and nocturnal periodic breathing is more common in males.¹⁰⁷

Several mechanisms underlie these sex differences. Menstruation acts as a natural phlebotomy, reducing iron stores and hematocrit, and thereby protecting against EE. This advantage is lost after menopause, when hemoglobin and hematocrit rise and CMS prevalence in women approaches or even surpasses that of men.^102,108 Estrogen and progesterone also enhance ventilatory drive, improve oxygenation, and modulate erythropoiesis.¹⁰³

After menopause, the loss of these protective factors and a relative increase in androgenic influence raise CMS risk, a pattern supported by findings of low oxygen saturation associated with high testosterone/estradiol ratios in postmenopausal women.¹⁰⁹ Notably, testosterone stimulates erythropoiesis by enhancing EPO production and suppressing hepcidin,⁷¹ without directly upregulating HIF isoforms.

Taken together, these observations indicate that sex hormones and menstrual physiology are central to explaining sex-related differences in CMS. Premenopausal women benefit from both menstrual blood loss and estrogenic regulation of erythropoiesis, whereas the loss of these protections after menopause converges with, or even surpasses, male prevalence rates.

Management strategies for CMS include descent (when feasible), phlebotomy, oxygen therapy, and oral acetazolamide.^33,110–112 While these provide symptomatic relief, they do not address the underlying mechanisms, underscoring the need for targeted molecular interventions, particularly those involving the HIF pathway or hormonal modulation. Additionally, CMS significantly impacts cardiovascular and pulmonary function, making the study of ventricular remodeling and pulmonary arterial pressure in chronic hypoxia essential.¹¹³

CMS also illustrates the broader spectrum of human adaptation and maladaptation to chronic environmental stress, linking altitude medicine with research on oxygen homeostasis and acclimatization.¹¹⁴ An integrated approach that combines endocrinology, cardiology, genetics, and high-altitude physiology is therefore essential.

A centenary analysis of Monge's contribution to the recognition of CMS in the Andes has recently been published,¹¹⁵ providing a complementary historical account to the present narrative review. A century after Monge's original description, his insight remains crucial: excessive erythropoiesis represents an adaptive response that, once it surpasses compensatory capacity, becomes pathological. Yet, despite its significance, Monge's contribution has been underrepresented in international narratives; with recent historical reviews of hypoxia omitting his role.³¹ Such omission diminishes the legacy of Latin American science in shaping global understanding of high-altitude adaptation and disease, an oversight this review seeks to correct.

Strengths

A major strength of this narrative review is its integration of historical and contemporary perspectives on CMS. By anchoring the discussion in Carlos Monge Medrano's seminal 1925 description of altitude-induced erythrocytosis, the review underscores how his clinical observations in Cerro de Pasco provided the conceptual foundation for recognizing CMS as a distinct maladaptive response to chronic hypoxia. Revisiting this historical context highlights the continuity between past and present, situating advances in endocrinology, genetics, and physiology within Monge's original framework, thereby ensuring that his pioneering contribution remains visible while guiding modern research in high-altitude medicine.

Another strength is the global perspective. Although first described in Andean populations, CMS is now recognized in any population residing above 2500 m. Today, nearly 500 million people live above 1500 m, including 81.6 million above 2500 m and 14.4 million above 3500 m.¹¹⁶ These populations are concentrated in the Andes, Himalayas, and Ethiopian Highlands, where chronic hypobaric hypoxia has shaped diverse physiological and genetic adaptations. Importantly, 1.2–33% of these individuals may develop CMS, depending on altitude, age, sex, and ancestry, placing nearly 82 million people worldwide at risk.^10,117,118

Conclusion

In conclusion, Monge's disease, now recognized as CMS, reflects a complex interplay of hypoxia, hormones, and genetics. Honoring Monge's legacy requires renewed recognition of his foundational contributions to this evolving field. CMS exemplifies the delicate balance between adaptation and maladaptation. Continued interdisciplinary research is essential to refine diagnostic criteria, develop preventive strategies, and design therapies tailored to the sex-specific and genetic profiles of high-altitude populations.

Supplemental Material

sj-docx-1-sci-10.1177_00368504251387827 - Supplemental material for Monge's disease at 100 years: Revisiting the origins and endocrine mechanisms of chronic mountain sickness

Supplemental material, sj-docx-1-sci-10.1177_00368504251387827 for Monge's disease at 100 years: Revisiting the origins and endocrine mechanisms of chronic mountain sickness by Gustavo F Gonzales in Science Progress

Footnotes

Acknowledgements

AI tools for language improvement were used.

ORCID iD

Gustavo F Gonzales

Ethical considerations

This research did not involve any human participants. Thus, ethical approval or informed patient consent was not required and is not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Author contributions

Gustavo F. Gonzales: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Validation; Visualization; Writing – original draft; Writing – review & editing.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

Available under request

Supplemental material

Supplemental material for this article is available online.

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