Although decreased humidity and air temperature and increased exposure to ultraviolet light are noteworthy features of the mountain environment, the most important environmental variable is the decrease in barometric pressure that occurs with ascent. The reduction in barometric pressure decreases the Po2 all along the oxygen transport chain, from inspired air to organs and tissues, which sets in motion a series of physiological responses (Figure 1), many of which help restore the concentration of oxygen in the blood (oxygen content) and supply tissues with adequate oxygen to support metabolic demand (oxygen delivery). The specific mechanisms for these responses, collectively referred to as acclimatization, vary among organ systems, but a key mediator is hypoxia-inducible factor, a gene transcription factor that serves as the master regulator of cellular responses to hypoxia, including but not limited to cellular metabolism, angiogenesis, and erythropoiesis.

Many physiological responses show a dose–response relationship, with greater hypoxia provoking stronger responses. The timing of the responses also varies; for example, cerebral blood flow, heart rate, and ventilation increase within minutes after the ascent, whereas plasma volume and serum erythropoietin concentrations change over a period of 1 to 2 days. The full increases in ventilation and hemoglobin concentration occur over a period of weeks after the ascent. The pattern and timing of the responses are similar among persons, but their magnitude varies markedly, as indicated by interindividual differences in the hypoxic ventilatory response, hypoxic pulmonary vasoconstriction, and changes in cerebral blood flow. Recognition of this variation and the effect of medical conditions on the observed responses is critical in considering the risks of high-altitude travel, since the magnitude of the responses determines the degree of hypoxemia and the adequacy of oxygen delivery for a given altitude and barometric pressure.

Figure 1:
Caption: Physiological Responses to Hypoxia.
Description: Major responses to an ascent to high altitude involve the brain, lungs, heart, kidneys, and blood. Qualitative changes are depicted over time, ranging from minutes to weeks at high altitude. Values that increase from low to high altitude are shown in purple, and values that decrease are shown in blue. The pattern and timing of the responses are similar among persons, but the magnitude of the responses can vary markedly. EPO denotes erythropoietin, Hb hemoglobin, and RCM red-cell mass.

Key Points: Humans suffering from polycythaemia undergo multiple circulatory adaptations including changes in blood rheology and structural and functional vascular adaptations to maintain normal blood pressure and vascular shear stresses, despite high blood viscosity. During exercise, several circulatory adaptations are observed, especially involving adrenergic and non-adrenergic mechanisms within non-active and active skeletal muscle to maintain exercise capacity, which is not observed in animal models. Despite profound circulatory stress, i.e. polycythaemia, several adaptations can occur to maintain exercise capacity, therefore making early identification of the disease difficult without overt symptomology. Pharmacological treatment of the background heightened sympathetic activity may impair the adaptive sympathetic response needed to match local oxygen delivery to active skeletal muscle oxygen demand and therefore inadvertently impair exercise capacity.

Abstract: Excessive haematocrit and blood viscosity can increase blood pressure, cardiac work and reduce aerobic capacity. However, past clinical investigations have demonstrated that certain human high-altitude populations suffering from excessive erythrocytosis, Andeans with chronic mountain sickness, appear to have phenotypically adapted to life with polycythaemia, as their exercise capacity is comparable to healthy Andeans and even with sea-level inhabitants residing at high altitude. By studying this unique population, which has adapted through natural selection, this study aimed to describe how humans can adapt to life with polycythaemia. Experimental studies included Andeans with (n = 19) and without (n = 17) chronic mountain sickness, documenting exercise capacity and characterizing the transport of oxygen through blood rheology, including haemoglobin mass, blood and plasma volume and blood viscosity, cardiac output, blood pressure and changes in total and local vascular resistances through pharmacological dissection of α-adrenergic signalling pathways within non-active and active skeletal muscle. At rest, Andeans with chronic mountain sickness had a substantial plasma volume contraction, which alongside a higher red blood cell volume, caused an increase in blood viscosity yet similar total blood volume. Moreover, both morphological and functional alterations in the periphery normalized vascular shear stress and blood pressure despite high sympathetic nerve activity. During exercise, blood pressure, cardiac work and global oxygen delivery increased similar to healthy Andeans but were sustained by modifications in both non-active and active skeletal muscle vascular function. These findings highlight widespread physiological adaptations that can occur in response to polycythaemia, which allow the maintenance of exercise capacity.

T administration increases hemoglobin and hematocrit ( 88 , 89 ); these effects are related to T doses and circulating concentrations ( 89 ). In some men with hypogonadism, T therapy can cause erythrocytosis (hematocrit > 54%). The increase in hematocrit during T administration and the frequency of erythrocytosis is higher in older men than in young men ( 87 ). The commissioned meta-analysis showed that T treatment was associated with a significantly higher frequency of erythrocytosis vs placebo. The hematocrit level at which the risk of neuro-occlusive or cardiovascular events increases is not known. The frequency of neuro-occlusive events in men with hypogonadism enrolled in RCTs of T who developed erythrocytosis has been very low.
Clinicians should evaluate men who develop erythrocytosis during T-replacement therapy and withhold T therapy until hematocrit has returned to the normal range and then resume T therapy at a lower dose. Using therapeutic phlebotomy to lower hematocrit is also effective in managing T treatment–induced erythrocytosis.

Figure 2:
Caption: Effects of Testosterone on Muscle, Bone, the Erythron, and Erectile Function.
Description: Testosterone (T), directly and through conversion to DHT, increases skeletal muscle mass and strength by binding to the AR (Panel A). It promotes the differentiation of mesenchymal muscle progenitor cells into the myogenic lineage by activating the Wnt signaling pathway. Testosterone and DHT ligands that are bound to AR then interact with β-catenin, a coactivator of AR, and translocate into the nucleus, increasing the transcription of a number of Wnt target genes, including follistatin, which blocks the actions of myostatin and other transforming growth factor β (TGF-β) family members. Testosterone also stimulates polyamine synthesis, which increases myoblast proliferation. Testosterone increases secretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) and up-regulates intramuscular expression of IGF-1 receptor in muscle fibers. In addition, testosterone increases neuromuscular transmission. The effects of testosterone on bone (Panel B) are mediated largely through its aromatization to estradiol, which acts through ERα to inhibit osteoclastic bone resorption by inhibiting the receptor activator of nuclear factor κB ligand (RANKL) and sclerostin, as well as interleukin-1β and tumor necrosis factor α (TNF-α). Estradiol also stimulates the formation of both trabecular and cortical bone. Testosterone stimulates the formation of trabecular bone directly through the AR and indirectly by stimulating IGF-1 and TGF-β. The resulting increases in muscle mass and muscle strength may indirectly increase bone mass and strength. Testosterone stimulates erythropoiesis by multiple mechanisms (Panel C), all of which appear to be mediated through AR. Testosterone increases the number of myeloid series bone marrow progenitors by acting on early hematopoietic progenitors, stimulates erythropoietin, and increases iron availability for erythropoiesis by suppressing hepcidin and up-regulating ferroportin. Testosterone and DHT increase penile blood flow and improve erectile function (Panel D) through endothelium-dependent stimulation of endothelial nitric oxide (NO) synthase (eNOS) to increase NO production and endothelium-independent inhibition of voltage-operated l-type calcium channels (VOCCs) and activation of potassium channels on cavernosal smooth-muscle cells. Increased NO activates soluble guanylate cyclase, which converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP), which in turn activates cGMP-dependent protein kinase G (PKG) and sarcoplasmic–endoplasmic reticulum Ca2+–ATPase (SERCA). The latter sequesters Ca2+ in the superficial sarcoplasmic reticulum, reducing the availability of Ca2+. Inhibition of VOCCs reduces intracellular calcium, which together with the activation of potassium channels, promotes cavernosal smooth-muscle relaxation. BFU-E denotes burst-forming units–erythroid, CFU-E colony-forming units–erythroid, CMP common myeloid progenitor, HSC hematopoietic stem cell, MEP myeloid–erythroid progenitor, MPP multipotent progenitor, and TCF-4/LEF T-cell factor 4/lymphoid enhancer factor.

Erythrocytosis, a well-recognized adverse effect of testosterone treatment, appears to be associated with testosterone levels that are at the high end of the normal range or higher during treatment. The incidence of erythrocytosis was substantially higher in trials in which injectable testosterone esters were used than in those in which transdermal formulations were used, probably because of higher testosterone levels in trials with testosterone esters. For example, in the T4DM trial, in which injectable testosterone undecanoate was used, the incidence of erythrocytosis was 22%. The incidence of erythrocytosis in the TTrials and the TRAVERSE trial was low (1.8% and 0.2%, respectively), most likely because the testosterone dose in each trial was adjusted to keep the testosterone and hemoglobin levels within the normal range. These results indicate that a physiologic dose of testosterone is an uncommon cause of erythrocytosis.