Elevated Hematocrit from Testosterone Therapy vs High-Altitude Adaptation: A Comparative Analysis

Nelson Vergel · 2025-06-15T22:22:33-0500

From this thread: WARNING: Do not believe Internet "gurus" proclaiming no need to manage hematocrit on TRT - Excel Male TRT Forum

Underlying Physiological Mechanisms

Testosterone Replacement Therapy (TRT) and Erythrocytosis: Exogenous testosterone stimulates red blood cell (RBC) production through multiple mechanisms. It induces an increase in erythropoietin (EPO) levels and establishes a new higher EPO/hemoglobin “set point,” signaling the bone marrow to produce more RBCs. Testosterone also suppresses hepcidin, the master iron-regulator hormone, thereby increasing iron availability for hemoglobin synthesis. Additionally, testosterone (and its metabolite estradiol) directly promotes hematopoietic stem cell proliferation and survival. Historically, androgens were even used as treatments for anemia due to these erythropoietic effects. Besides raising RBC count (and thus hematocrit, Hct), TRT has ancillary effects such as increasing plasma volume via sodium and water retention. In summary, TRT-induced erythrocytosis arises from hormone-driven marrow stimulation (via EPO and other pathways) coupled with expanded blood volume.

High-Altitude Hypoxia and Polycythemia: At high altitudes, the lower oxygen pressure (hypoxia) is the primary trigger for increased RBC production. Hypoxia is sensed by kidneys, which upregulate HIF-1/HIF-2 (hypoxia-inducible factors) and markedly increase EPO secretion, driving the bone marrow to produce more RBCs. In contrast to TRT, this is a compensatory response to improve oxygen delivery. Initial adaptation to altitude also includes a reduction in plasma volume (via diuresis), which concentrates hemoglobin and raises hematocrit even before new RBCs are made. Over longer exposure, RBC mass increases significantly. Importantly, high-altitude natives and acclimatized individuals exhibit additional adaptations: hypoxia triggers vasodilation in systemic vessels (mediated in part by nitric oxide), which helps preserve tissue oxygenation and blood flow despite higher Hct. There is no significant increase in total blood volume at altitude – in fact, plasma volume tends to be lower or normal, meaning high-altitude polycythemia is a euvolemic or hypovolemic polycythemia, unlike the hypervolemia of TRT-induced erythrocytosis. In short, high-altitude erythrocytosis is a natural, hypoxia-driven process geared toward enhancing oxygen carriage, accompanied by plasma volume contraction and vascular changes that mitigate the effects of increased Hct.

Clinical Implications and Outcomes of Elevated Hematocrit
Blood Viscosity and Oxygen Delivery: Hematocrit is a major determinant of blood viscosity. In both TRT-induced and altitude-induced polycythemia, rising Hct increases blood viscosity, which can impair microcirculatory flow and oxygen delivery when Hct gets too high. There is an optimal range of hematocrit for oxygen transport; beyond that, the viscosity-related flow limitations outweigh the benefit of extra oxygen capacity. High altitude researchers note that excessive erythrocytosis (as seen in chronic mountain sickness) increases blood viscosity and hampers microcirculation, leading to tissue perfusion issues. In the context of TRT, a 2019 review noted that changes in Hct can alter both microvascular and macrovascular blood flow characteristics, potentially affecting oxygen delivery to different tissues. Thus, while moderate increases in Hct may enhance aerobic capacity up to a point (improved oxygen carrying capacity), further elevation can become counterproductive, reducing tissue oxygenation due to sluggish blood flow.

Cardiovascular Health and Thrombotic Risk: Elevated hematocrit has important implications for cardiovascular risk. High blood viscosity increases cardiac workload and may contribute to higher blood pressure and endothelial stress. In men on TRT, studies have begun to document associations between Hct elevation and cardiovascular events. For example, a large 2024 retrospective cohort analysis found that men whose hematocrit rose after starting testosterone therapy had a significantly higher incidence of major adverse cardiovascular events (MACE) – including myocardial infarction, stroke, or death – compared to those whose Hct remained stable. Another analysis showed that TRT-induced secondary polycythemia was linked to increased risk of MACE and even venous thromboembolism (VTE) in the first year of therapy. These findings align with earlier epidemiological data from the general population: even in otherwise healthy individuals, higher Hct correlates with greater risks of arterial thrombosis and VTE. In fact, the Framingham study (34-year follow-up) observed that elevated hematocrit was associated with increased cardiovascular mortality. High Hct can produce symptoms of hyperviscosity (headache, dizziness, blurred vision, fatigue) and, in extreme cases, precipitate complications like stroke, heart attack, or blood clots. The FDA has issued warnings about blood clots (including stroke and myocardial infarction) in patients using testosterone products, underscoring this concern.
In high-altitude dwellers, the relationship between polycythemia and cardiovascular outcomes is complex. Many lifelong high-altitude residents tolerate hematocrit levels that would be considered dangerous at sea level (male Hct often 50–60% at ~4000 m altitude) without widespread cardiovascular collapse. Indeed, indigenous high-altitude populations (e.g. many Andeans and Tibetans) generally do not show markedly higher mortality from cardiovascular disease attributable to their elevated hematocrit alone. Their bodies have balanced the increased RBC count with adaptations (like lower blood volume and vasodilation) that allow adequate circulation. However, this does not mean altitude-induced erythrocytosis is benign in all cases. When hematocrit rises beyond the normal adaptive range, individuals can develop Chronic Mountain Sickness (Monge’s disease), characterized by excessive Hct (often >60% in men) along with symptoms of chronic hypoxia and hyperviscosity. Chronic mountain sickness is associated with headaches, fatigue, dizziness, heart strain, and increased risk of thrombosis (including cerebral vein clots and stroke). High-altitude polycythemia has been positively linked to higher rates of pulmonary hypertension and heart failure in susceptible individuals. A recent study at 4700 m in Tibet found that men with high-altitude polycythemia had 3-fold higher odds of systemic hypertension compared to those without polycythemia, likely due to blood viscosity and hypoxia-related vascular changes. In summary, moderate polycythemia at altitude is a physiologic adaptation and often well-tolerated, whereas extreme polycythemia (either at altitude or via TRT) can pose significant cardiovascular and thrombotic risks.

Differences in Risk Profiles: TRT-Induced vs Altitude-Induced Hematocrit Elevation
Despite superficial similarities (elevated Hct in both scenarios), TRT-induced erythrocytosis and high-altitude erythrocytosis have distinct risk profiles due to underlying physiological differences:

Driving Cause: In high-altitude residents, polycythemia is driven by environmental hypoxia – a necessary adaptation to improve oxygen delivery. The increase in RBC mass is generally constrained to what is beneficial for oxygen needs (often reaching a plateau once acclimatization is achieved). In TRT, the driver is an exogenous hormone signal that can overshoot physiological needs. Testosterone’s stimulation of EPO is not limited by oxygen sensing in the same way; in some men, hematocrit can continue rising with ongoing therapy, potentially exceeding the individual’s optimal range.
Blood Volume and Blood Pressure: Men on TRT experience concurrent increases in blood volume (due to androgen-stimulated fluid retention) along with increased RBC count. This combination – more viscous blood and a greater volume of it – can raise systemic blood pressure and strain the heart. By contrast, high-altitude polycythemia occurs without an increase in total blood volume. In fact, altitude exposure initially causes a contraction of plasma volume. Thus, an acclimatized person at altitude has thicker blood, but not more blood circulating than normal; this mitigates excessive hypertension. Men on TRT may also have underlying hypertension or other risk factors, and adding hypervolemic polycythemia further elevates cardiovascular risk.
Vascular Adaptations: Chronic hypoxia induces vasodilatory adaptations in high-altitude dwellers. Greater nitric oxide activity and expanded capillary networks help maintain perfusion and oxygen delivery. This vasodilation offsets some viscous effects of high Hct by reducing systemic vascular resistance. In TRT-induced erythrocytosis, there is no equivalent trigger for vasodilation – oxygen levels are normal, so vessels do not automatically dilate. In fact, androgens can sometimes promote vasoconstriction or platelet aggregation in certain contexts, and TRT recipients do not gain protective vascular remodeling from their increased Hct. The result is that blood viscosity rises without compensatory circulatory adjustments in men on TRT, whereas altitude natives have built-in compensations.
Plateau vs. Progressive Rise: High-altitude residents typically reach a new steady-state hematocrit that meets oxygen demands. There is an upper limit to beneficial polycythemia, and if Hct continues to rise beyond that (often due to unresolved hypoxia or individual susceptibility), it is considered maladaptive (i.e., chronic mountain sickness). In many men on high-dose or unmonitored TRT, however, hematocrit may keep climbing over time if no intervention is made. Especially in older men, studies have noted a dose-dependent and age-augmented effect of testosterone on Hct, with some individuals reaching Hct >55% over a few months of therapy. In other words, altitude-induced Hct elevation tends to be physiologically self-limited, whereas TRT-induced elevation can be more unpredictable and might not self-regulate, continuing into a higher risk zone if unchecked.
Baseline Health and Demographics: The typical man on TRT is often middle-aged or older with hypogonadism – a population that may carry other cardiovascular risk factors (e.g. metabolic syndrome, obesity, or borderline polycythemia to start with). Indeed, a baseline Hct >50% is considered a relative contraindication to starting testosterone because such patients are likely to exceed 54% on therapy. High-altitude dwellers, on the other hand, often are lifelong residents adapted from a young age, or healthy trekkers/climbers who (if not acclimatizing well) will descend rather than persist at a dangerously high Hct. The risk context is different: TRT erythrocytosis arises in an artificial setting on top of whatever vascular disease a patient may have, compounding risk, whereas altitude erythrocytosis usually occurs in otherwise healthy individuals whose lifestyles and genetics have adjusted over generations to mitigate risk. That said, non-native individuals (or those with cardiopulmonary conditions) at high altitude can certainly experience exacerbated risk if polycythemia develops.

In summary, TRT-related high hematocrit generally confers a higher risk profile than the equivalent hematocrit at high altitude. The TRT scenario combines increased Hct and plasma volume, normal oxygen tensions (no hypoxia-triggered safeguards), and often an at-risk patient population. High-altitude erythrocytosis is a necessity for survival in low-oxygen environments and is buffered by physiological adaptations; it becomes risky primarily when pushed beyond normal adaptive ranges. These distinctions underlie why a hematocrit of, say, 55–60% might be acceptable for a young man at 4000 m altitude (part of normal variation), whereas the same value in a sea-level man on TRT would be alarming and require intervention.

Management and Clinical Recommendations
Managing elevated hematocrit depends on its cause and the individual’s clinical context. Below is a comparison of current management strategies for TRT-induced vs altitude-induced erythrocytosis:

Monitoring and Thresholds: Clinical guidelines universally recommend monitoring hematocrit in men on TRT. Baseline Hct should be checked before therapy, then 3–6 months after starting, and at least annually thereafter. If Hct approaches or exceeds a critical threshold (commonly 54%), action is required. The Endocrine Society and other bodies advise that TRT be stopped or the dose reduced if Hct >54% until levels return to safe range. In practice, some clinicians even intervene at Hct >52% if the rise is rapid or symptomatic. A baseline Hct above ~50% is often viewed as a contraindication to starting TRT at all. By contrast, high-altitude residents are assessed for chronic mountain sickness if their hematocrit exceeds the normal range for that altitude (e.g. >61% in men at 4000 m). Routine blood count monitoring isn’t typically needed for healthy individuals at altitude, but those with extreme polycythemia or symptoms of chronic mountain sickness are evaluated and followed closely.

Therapeutic Phlebotomy (Venesection): Removing blood to lower Hct is a common intervention, but its use differs by scenario. In TRT-induced erythrocytosis, therapeutic phlebotomy or periodic blood donation is a straightforward way to promptly reduce hematocrit and viscosity. For men who require continued TRT (e.g. for symptom control) and develop high Hct, many doctors will prescribe phlebotomy (typically 500 mL removed) to bring Hct down into the 40s%. This can relieve hyperviscosity symptoms and reduce short-term risk. Current European guidelines actually suggest considering phlebotomy once Hct >54% in a man on TRT. However, phlebotomy is a temporary fix – if the testosterone dose remains the same, the Hct will trend up again, so it’s often combined with dose adjustment. In high-altitude polycythemia, phlebotomy is also used, but usually in the context of chronic mountain sickness. Periodic phlebotomy (e.g. removing 1–2 units of blood at intervals) can improve symptoms of chronic mountain sickness by reducing Hct and improving cerebral blood flow. The relief, however, is temporary if the person stays at altitude, since the hypoxic drive for erythropoiesis persists. Thus, phlebotomy at altitude is seen as a stop-gap measure; the definitive treatment is to reverse the hypoxia. In both cases, care must be taken to avoid iron deficiency with repeated phlebotomies – especially in TRT patients, overzealous blood donation can deplete ferritin and paradoxically limit exercise capacity.

Addressing Root Cause: For TRT users, the root cause of polycythemia is the testosterone dose or formulation. Management includes adjusting TRT: lowering the dosage, switching from an injectable to a transdermal formulation, or spacing injections differently. For instance, injectable testosterone tends to cause higher peaks in hormone levels (and thus more erythrocytosis) than daily gels; switching to gels or smaller, more frequent injections can mitigate Hct rise. Ensuring the patient actually requires TRT (re-evaluate symptoms and labs) is important – unnecessary therapy should be discontinued to avoid unwarranted risks. Identify and treat co-factors: If a man on TRT has undiagnosed obstructive sleep apnea or chronic lung disease (both cause hypoxia and secondary RBC elevation), treating those conditions can help control Hct. In fact, guidelines say untreated severe sleep apnea is a contraindication to starting TRT, as it can exacerbate erythrocytosis. For high-altitude polycythemia, the fundamental solution is oxygenation. The most effective “cure” is to descend to lower altitude, eliminating the hypoxic stimulus. Even a moderate reduction in elevation or periodic stays at low altitude will usually allow Hct to normalize toward sea-level values as EPO drive falls. If relocation is not feasible, supplemental oxygen therapy can be used, especially during sleep (when oxygen desaturation is worst). Night-time oxygen or portable oxygen during daily activities raises blood O₂ saturation and can trick the body into easing RBC production. Another strategy is pharmacological acclimatization: Acetazolamide (a carbonic anhydrase inhibitor) is often used to prevent acute mountain sickness, but in chronic use it can stimulate ventilation, reduce apnea episodes, and cause a mild metabolic acidosis that improves oxygenation – all of which may help blunt EPO production. Some studies have found acetazolamide helpful in reducing hematocrit and symptoms in chronic mountain sickness. Other measures include optimizing pulmonary health (inhalers for high-altitude residents with chronic bronchitis, etc.) and avoiding smoking, since CO and airway disease will worsen hypoxemia and drive Hct higher.

Lifestyle and Supportive Measures: Regardless of cause, patients with high Hct are advised on general measures to lower risk. Hydration status is important because dehydration further concentrates blood. Men on TRT are counseled to stay well-hydrated and avoid excessive diuretics or alcohol when Hct is high. Regular cardiovascular exercise may improve plasma volume and vascular health, though intense exercise acutely can hemoconcentrate (so moderation and monitoring are key). For altitude dwellers, gradual acclimatization is the best preventive strategy – ascend slowly to allow the body to adjust without overshooting RBC production. Iron intake might be monitored; interestingly, some high-altitude populations instinctively consume lower iron diets which may naturally limit polycythemia, whereas TRT patients should avoid iron supplements unless needed (to not feed excess RBC production). Finally, both groups should be educated on recognizing hyperviscosity symptoms (headache, vision changes, etc.) and seek medical care if they occur. In the case of TRT, if hematocrit continues to rise despite dose adjustment and phlebotomy, clinicians might halt TRT permanently due to intolerance.

Current expert consensus emphasizes proactive management for TRT-induced high hematocrit. Unlike high-altitude polycythemia which is an expected adaptation, elevated Hct on TRT is considered an adverse effect to be mitigated. As one endocrinology paper framed it: evidence for improved outcomes with therapeutic phlebotomy in TRT patients is limited, but given known thrombotic risks, it is sensible to manage Hct and “there appears no scientific basis for allowing hematocrit to remain >54%” in men on TRT. In high-altitude medicine, the focus is on preventing chronic mountain sickness; beyond descent or oxygen, no long-term drug has proven completely effective for safely reducing Hct in high-altitude residents, making periodic phlebotomy and oxygen therapy the mainstays when needed.

Analysis of Claims from the ExcelMale Forum Thread
In the ExcelMale forum thread “WARNING: Do not believe Internet ‘gurus’ proclaiming no need to manage hematocrit on TRT,” community experts vehemently refute the notion that “TRT-induced high hematocrit is nothing to worry about because high-altitude people have high hematocrit without issues.” This claim – spread by some online personalities – is considered an oversimplified and dangerous myth. The discussion highlights that TRT-related and altitude-related hematocrit elevations are fundamentally different physiological conditions, as we have detailed above. Nelson Vergel (the forum founder) explains in the thread that men on TRT experience a unique combination of increased hematocrit and increased blood volume, often alongside higher blood pressure – a scenario that does raise cardiovascular risk. By contrast, high-altitude natives have high hematocrit in a context of normal or reduced blood volume and hypoxia-driven vasodilation, which helps maintain circulation and avoid blood pressure spikes. As Vergel succinctly states, “men on TRT with high hematocrit are NOT the same as people living at high altitude with high hematocrit” – conflating the two can be scientifically flawed and unsafe.

The forum contributors back their position with emerging clinical evidence. The thread references a 2024 study which provided real-world data that increases in hematocrit during TRT are linked to higher rates of heart attacks and strokes. This directly contradicts the internet “gurus” who suggest one can ignore hematocrit. In the forum, members also discuss how altitude erythrocytosis tends to plateau (once sufficient oxygenation is achieved via RBC increase), whereas TRT can drive Hct higher and higher without a built-in stop signal. One member pointed out that the HIF (hypoxia-inducible factor) pathway regulates EPO at altitude, but testosterone can bypass some of these controls by directly stimulating renal EPO production (even via certain transport proteins in the kidney) – meaning TRT can push some men’s Hct above what altitude alone would. These nuanced biological insights underscore that unmanaged hematocrit on TRT can lead to polycythemia that is not benign. Indeed, users in the thread share personal experiences of hematocrit continuously climbing on TRT until interventions were done.

In summary, the ExcelMale thread serves as a cautionary advisory: Do not be lulled into complacency by comparisons to high-altitude residents. The consensus is that men on TRT must monitor and manage hematocrit if it rises. Failing to do so ignores both the current scientific evidence and the clear physiological differences between therapeutic androgen use and natural high-altitude adaptation. The takeaway from the discussion – echoed by medical literature – is that while high-altitude polycythemia is an evolutionary adaptation with its own limits, TRT-induced erythrocytosis is a drug effect that carries real risks. Proper clinical management (through monitoring, dose adjustment, or phlebotomy) is essential to mitigate those risks and ensure long-term safety for men on testosterone therapy.

Conclusion
Elevated hematocrit in men can arise from distinct causes – most commonly TRT or high-altitude living – and these scenarios should not be conflated. Mechanistically, testosterone drives erythrocytosis via hormonal stimulation of RBC production (often alongside increased blood volume and normal oxygen levels), whereas high-altitude adaptation is a hypoxia-driven increase in RBCs (with reduced plasma volume and vascular changes to accommodate low oxygen). Clinically, both situations can lead to hyperviscosity, but the risk profiles differ: TRT-induced high Hct has been linked to increased cardiovascular events and requires medical management, while altitude-induced high Hct is generally well-tolerated up to an optimal point, beyond which it too can cause chronic mountain sickness and needs intervention. Management strategies for TRT focus on moderating the therapy (dose/formulation changes, phlebotomy) and treating any contributing factors, whereas for altitude the emphasis is on relieving hypoxia (descent, oxygen therapy) and periodic phlebotomy if necessary. The discussion in patient communities like ExcelMale reinforces that ignoring a rising hematocrit on TRT is ill-advised – physiological high-altitude polycythemia is not a valid excuse to dismiss TRT-related erythrocytosis. Both patients and providers should remain vigilant: monitor blood counts, understand the underlying mechanisms, and intervene promptly to maintain hematocrit in a safe range appropriate to the individual’s context. By respecting the differences between these conditions, one can optimize the benefits of TRT while minimizing potential harms, and appropriately manage those living at altitude to prevent complications of excessive polycythemia.

Table: Comparison of TRT-Induced vs High-Altitude-Induced Elevated Hematocrit

Aspect	Testosterone (TRT) Induced Erythrocytosis	High-Altitude Adaptation Polycythemia
Trigger for RBC Increase	Exogenous testosterone → ↑EPO, ↓hepcidin, direct marrow stimulation. Not driven by oxygen need.	Chronic hypoxia (low O₂) → ↑HIF → ↑EPO from kidneys. Physiological need to improve O₂ delivery.
Plasma Volume	Expanded (androgen-induced fluid retention) – leads to hypervolemia.	Normal or reduced (initial altitude diuresis ↓plasma vol). No increase in total blood volume.
Vascular Response	No hypoxia = no special vasodilation; possible slight ↑BP due to volume.	Systemic vasodilation (↑NO and other factors) occurs, offsetting viscosity. Pulmonary vasoconstriction can occur (risk of high-altitude pulmonary HTN).
Typical Hematocrit Levels	Can rise above normal sea-level range; Hct >54% is considered high risk on TRT. (Baseline >50% is a caution.)	Elevated compared to sea level. Example: ~45–61% is normal range for men at 4000 m. Hct >60% may indicate chronic mountain sickness.
Cardiovascular Impact	↑Hct + ↑ volume = ↑viscosity + hyperdynamic circulation → higher risk of hypertension, thrombosis. Documented ↑ risk of heart attack, stroke, VTE with rising Hct.	Moderate polycythemia improves O₂ carrying; many adapted individuals have normal cardiac function. Excessive polycythemia (CMS) → hyperviscosity, risk of stroke, pulmonary hypertension.
Natural “Brake” on Hct	None intrinsic (exogenous hormone can keep stimulating RBC production). Hct may keep rising unless intervention.	Oxygen homeostasis provides feedback – once tissue O₂ improves, EPO drops. Hct tends to plateau at a new set-point; overshoot leads to symptoms prompting descent.
Management	Monitor Hct frequently. If high: hold or reduce TRT dose; consider switch to transdermal or address OSA. Therapeutic phlebotomy or blood donation to quickly reduce Hct. Ensure hydration; avoid high iron unless needed. Restart TRT at lower dose after Hct <50%.	No intervention if asymptomatic and within normal range for altitude. If Hct too high with symptoms (CMS): descent to lower altitude (definitive). Supplemental oxygen (especially at night). Periodic phlebotomy for temporary relief. Acetazolamide or other measures to improve oxygenation/ventilation.
Outcome if Unmanaged	Persistent high Hct on TRT can lead to headaches, ruddy complexion, blurred vision, erythrocytosis-related complications (stroke, MI, clots). Long-term risk to cardiovascular health if not addressed.	Chronic mountain sickness: headache, fatigue, cyanosis, heart failure risk, stroke, cognitive impairment. Untreated CMS can be debilitating; severe polycythemia (>70% Hct) is life-threatening. Most altitude dwellers without CMS do fine.