Long-term intermittent hypoxia increases O2-transport capacity but not VO2max

Long-term intermittent hypoxia, characterized by several days or weeks at altitude with periodic stays at sea level, is a frequently occurring pattern of life in mountainous countries demanding a good state of physical performance. The aim of the study was to determine the effects of a typical South American type of long-term intermittent hypoxia on VO2max at altitude and at sea level. We therefore compared an intermittently exposed group of soldiers (IH) who regularly (6 months) performed hypoxic-normoxic cycles of 11 days at 3550 m and 3 days at sea level with a group of soldiers from sea level (SL, control group) at 0 m and in acute hypoxia at 3550 m. VO2max was determined in both groups 1 day after arrival at altitude and at sea level. At altitude, the decrease in VO2max was less pronounced in IH (10.6 +/- 4.2%) than in SL (14.1 +/- 4.7%). However, no significant differences in VO2max were found between the groups either at sea level or at altitude, although arterial oxygen content (Ca(O(2) )) at maximum exercise was elevated (p < 0.001) in IH compared to SL by 11.7% at sea level and by 8.9% at altitude. This higher Ca(O(2) ) mainly resulted from augmented hemoglobin mass (IH: 836 +/- 103 g, SL: 751 +/- 72 g, p < 0.05) and at altitude also from increased arterial O(2)-saturation. In conclusion, acclimatization to long-term intermittent hypoxia substantially increases Ca(O(2) ), but has no beneficial effects on physical performance either at altitude or at sea level.     

Training high--living low: changes of aerobic performance and muscle structure with training at simulated altitude.

This study was undertaken to test the hypothesis that endurance training in hypoxia is superior to training of the same intensity in normoxia. To avoid adaptation to hypoxia, the subjects lived under normoxic conditions when not training. A secondary objective of this study was to compare the effect of high- vs. moderate-intensity training on aerobic performance variables. Thirty-three men without prior endurance training underwent a cycle ergometer training of 6 weeks, 5 d/week, 30 minutes/d. The subjects were assigned to 4 groups, N-high, N-low, H-high and H-low based on the training criteria normoxia (N; corresponding to a training altitude of 600 m), vs. hypoxia (H; training altitude 3850 m) and intensity (high; corresponding to 80% and low: corresponding to 67% of VO2max). VO2max measured in normoxia increased between 8.5 to 11.1%, independent of training altitude or intensity. VO2max measured in hypoxia increased between 2.9 and 7.2%. Hypoxia training resulted in significantly larger increases than normoxia training. Maximal power that subjects could maintain over a thirty-minute period (measured in normoxia or hypoxia) increased from 12.3 - 26.8% independent of training altitude. However, subjects training at high intensity increased performance more than subjects training at a low intensity. Muscle volume of the knee-extensors as measured by magnetic resonance imaging increased significantly in the H-high group only (+ 5.0%). Mitochondrial volume density measured by EM-morphometry in biopsy samples of m. vastus lat. increased significantly in all groups with the highest increase seen in the H-high group (+ 59%). Capillary length density increased significantly in the H-high group only (+ 17.2%). The main finding of this study is that in previously untrained people, training in hypoxia while living at low altitude increases performance in normoxia to the same extent as training in normoxia, but leads to larger increases of aerobic performance variables when measured under hypoxic conditions. Training intensity had no effect on the gain of VO2max. On the level of skeletal muscle tissue, the combination of hypoxia with high training intensity constitutes the most effective stimulus for increasing muscle oxidative capacity.     

Oxygen manipulation as an ergogenic aid

The benefits of living and training at high altitude (HiHi) for an improved sea-level performance have been questioned because controlled studies have shown contradictory results. HiHi increases red blood cell mass (RCM), but training in hypoxia may be either an inadequate (low-intensity) or even harmful (to heart, muscle, and brain) stimulus. Recent studies indicate that the best approach to attain the benefits and overcome the problems of altitude training is to sleep at a natural or simulated moderate altitude and train at low altitude or sea level (HiLo). HiLo training increases RCM, as well as sea-level VO2max and performance (at least in responders), if certain prerequisites are fulfilled. The minimum dose seems to be more than 12 hours per day for over 3 weeks at an altitude or simulated altitude of 2100 to 2500 m. The effects of exposure to hypoxia seem to persist for a short period during the subsequent training or racing in normoxia.     

Short-term intermittent normobaric hypoxia-haematological, physiological and mental effects

Effects on erythropoiesis and blood pressure as well as physical performance and mental effects were studied in 15 healthy subjects during intermittent exposure to normobaric hypoxia corresponding to either 2000 m (6 persons) or 2700 m (9 persons) above sea level; another group (5 persons) also served as controls at normoxia. The concept "live hightrain low" was used for 10 d consecutively and the exposure to hypoxia was 12 h/d. Blood pO₂ and oxygen saturation were significantly decreased during the 10 d at hypoxia. [Hb] and Hct decreased significantly after 2 d in hypoxia and then returned to pre-study levels. Erythropoietin was significantly elevated in both hypoxia groups during the initial 3–5 d. Reticulocytes were significantly increased during 7 d of hypoxia. Submaximal and maximal oxygen uptake, blood pressure at rest and during exercise and the profile of mood states (POMS test) did not change during the study. In conclusion, intermittent normobaric hypoxia for 10 d resulted in a significant stimulation of erythropoiesis. Staying at normobaric hypoxia may serve as a complement to an ordinary altitude level sojourn.     

Training in hypoxia and its effects on skeletal muscle tissue

It is well established that local muscle tissue hypoxia is an important consequence and possibly a relevant adaptive signal of endurance exercise training in humans. It has been reasoned that it might be advantageous to increase this exercise stimulus by working in hypoxia. However, as long-term exposure to severe hypoxia has been shown to be detrimental to muscle tissue, experimental protocols were developed that expose subjects to hypoxia only for the duration of the exercise session and allow recovery in normoxia (live low–train high or hypoxic training). This overview reports data from 27 controlled studies using some implementation of hypoxic training paradigms. Hypoxia exposure varied between 2300 and 5700 m and training duration ranged from 10 days to 8 weeks. A similar number of studies was carried out on untrained and on trained subjects. Muscle structural, biochemical and molecular findings point to a specific role of hypoxia in endurance training. However, based on the available data on global estimates of performance capacity such as maximal oxygen uptake (V_O2max) and maximal power output ( P _max), hypoxia as a supplement to training is not consistently found to be of advantage for performance at sea level. There is some evidence mainly from studies on untrained subjects for an advantage of hypoxic training for performance at altitude. Live low–train high may be considered when altitude acclimatization is not an option.     

Effects of different stay durations on attentional performance during two mountain expeditions

BACKGROUND: Hypoxia-induced deficits in intellectual performance are linked to the altitude level reached, the speed of the ascent and the time spent at high altitude. This study analyzes attentional changes during adaptation to two different types of stay at high altitude on two different expeditions: one involving a 16-d trip between 2,000 m and 5,600 m, followed by a 2-d ascent to 6,440 m and back again; the other, a 21-d stay at 6,542 m. We tested the hypothesis that, at similar high altitudes, decrements in attentional performance would only occur during a long duration stay. METHODS: Indexes for attentional performance were calculated for two experimental groups under normoxia before the climb, under acute and chronic hypoxia during the climb, and under normoxia after the climb. They were compared for two control groups tested only under normoxia. RESULTS: The altitude stay was found to have an effect on the 6,542 m group when compared with the controls. Group performance differed at 2 d and 21 d after their arrival at 6,542 m and after their return to normoxia. When all the test administrations were pooled together for this expedition we noted an interaction between the level of difficulty of the task and the experimental and control groups: namely the difference between the groups was greater for the difficult task than it was for the easy task. No effect was found for the other expedition (at 5,600 m) when the group tested was compared with the controls. CONCLUSION: For a 21-d stay at an altitude of 6,542 m with the same ascent protocol as a group climbing to a lower altitude (16 d between 2,000 m and 5,600 m followed by a 2 d ascent to 6,440 m and back again), subjects appeared to suffer from attentional performance deficits which persisted for several days after the subjects returned to normoxic conditions.     

Effects of sildenafil on the human response to acute hypoxia and exercise

We examined the effects of the 5-phosphodiesterase (5-PDE) inhibitor sildenafil on pulmonary arterial pressure and some oxygen transport and cardiopulmonary parameters in humans during exposure to hypobaric hypoxia at rest and after exercise. In a double-blind study, 100 mg sildenafil or placebo was administered orally to 14 healthy volunteers 45 min before exposure to 5,000 m of simulated altitude. Arterial oxygen saturation (SaO2), heart rate (HR), tidal volume (VT), respiratory rate (RR), left ventricular ejection fraction (EF), and pulmonary arterial pressure (PAP) were measured first at rest in normoxia, at rest and immediately after exercise during hypoxia, and after exercise in normoxia. The increase in systolic PAP produced by hypoxia was significantly decreased by sildenafil at rest from 40.9 +/- 2.6 to 34.9 +/- 3.0 mmHg (-14.8%; p = 0.0046); after exercise, from 49.0 +/- 3.9 to 42.9 +/- 2.6 mmHg (-12.6%; p = 0.003). No significant changes were found in normoxia either at rest or after exercise. Measurements of the effect of sildenafil on exercise capacity during hypoxia did not provide conclusive data: a slight increase in SaO2 was observed with exercise during hypoxia, and sildenafil did not cause significant changes in ventilatory parameters under any condition. Sildenafil diminishes the pulmonary hypertension induced by acute exposure to hypobaric hypoxia at rest and after exercise. Further studies are needed to determine the benefit from this treatment and to further understand the effects of sildenafil on exercise capacity at altitude.     

Live and/or sleep high:train low, using normobaric hypoxia

The increase in oxygen transport elicited by several weeks of exposure to moderate to high altitude is used to increase physical performance when returning to sea level. However, many studies have shown that aerobic performance may not increase at sea level after a training block at high altitude. Subsequently, the concept of living high and training low was introduced in the early 1990s and was further modified to include simulated altitude using hypobaric or normobaric hypoxia. Review is given of the main studies that have used this procedure. Hematological changes are limited to insignificant or moderate increase in red cell mass, depending on the "dose" of hypoxia. Maximal aerobic performance is increased when the exposure to hypoxia is at least over 18 days. Submaximal performance and running economy have been found increased in several, but not all, studies. The tolerance (fatigue, sleep, immunological status, cardiac function) is good when the altitude or simulated altitude is not higher than 3000 m. Virtually no data are available about the effect of this procedure upon anaerobic performance. The wide spread of these techniques deserves further investigations.     

Adrenocortical suppression in highland chick embryos is restored during incubation at sea level

By combining the chick embryo model with incubation at high altitude, this study tested the hypothesis that development at high altitude is related to a fetal origin of adrenocortical but not adrenomedullary suppression and that hypoxia is the mechanism underlying the relationship. Fertilized eggs from sea-level or high altitude hens were incubated at sea level or high altitude. Fertilized eggs from sea-level hens were also incubated at altitude with oxygen supplementation. At day 20 of incubation, embryonic blood was taken for measurement of plasma corticotropin, corticosterone, and Po(2). Following biometry, the adrenal glands were collected and frozen for measurement of catecholamine content. Development of chick embryos at high altitude led to pronounced adrenocortical blunting, but an increase in adrenal catecholamine content. These effects were similar whether the fertilized eggs were laid by sea-level or high altitude hens. The effects of high altitude on the stress axes were completely prevented by incubation at high altitude with oxygen supplementation. When chick embryos from high altitude hens were incubated at sea level, plasma hormones and adrenal catecholamine content were partially restored toward levels measured in sea-level chick embryos. There was a significant correlation between adrenocortical blunting and elevated adrenal catecholamine content with both asymmetric growth restriction and fetal hypoxia. The data support the hypothesis tested and provide evidence to isolate the direct contribution of developmental hypoxia to alterations in the stress system.     

Altitude negates the benefits of aerobic training on the vascular adaptations in rats

INTRODUCTION: This study questioned the effect of living and training at moderate altitude on aortic vasoreactivity. Considering that chronic hypoxia exposure and endurance training are able to generate opposite effects on the systemic vascular reactivity, it was hypothesized that endurance training benefits on the vascular function could be limited by chronic hypoxia. METHODS: Sea-level native rats were randomly assigned to N (living in normoxia), NT (living and training 5 d.wk for 5 wk in normoxia), CH (living in hypoxia, 2800 m), and CHT (living and training 5 d.wk for 5 wk in hypoxia, 2800 m) groups. Concentration response curves to epinephrine, norepinephrine, endothelin-1, acetylcholine, and sodium nitro-prusside were assessed on aortic isolated rings. Left ventricular resting and maximal (during Tyrode's infusion) stroke volumes were evaluated by Doppler-echocardiography and used as indexes of chronic aortic volume overload. RESULTS: The main finding was that favorable aortic vasoreactivity adaptations consecutive to sea-level training were not observed when training was conducted at altitude. An improvement in the endothelium-dependent vasorelaxation (maximal relaxation, R(max), N = 60.4 +/- 10.0 vs NT = 91.7 +/- 3.2%; P < 0.05) and a reduced sensitivity to ET-1 were observed in NT rats. Such an enhancement in endothelium-dependent vasorelaxation was not found in CHT rats (R(max): 48.4 +/- 7.8%). Moreover, a higher sensitivity to ET-1 was reported in this group. Altitude-induced limitation in aortic blood flow and shear stress could play a major role in the explanation of these specific altitude-training adaptations. CONCLUSION: If extrapolated to the peripheral vascular bed, our results have practical significance for aerobic performance as aortic vasoreactivity adaptations after altitude training could contribute to limit blood delivery to exercising muscles.     

Intraocular pressure at a simulated altitude of 9000 m with and without 100% oxygen

INTRODUCTION: Exposure to high altitude may affect intraocular pressure (lOP). This study aimed to determine how IOP was altered by two different inspired oxygen tensions at altitude. METHODS: There were 34 healthy male pilots, ages 26-39 yr (mean 31.9 yr), who were studied at the Air Health Examination and Physiological Training Centre in Eskisehir, Turkey. They were studied at ground level, which is 792 m (2414 ft), and during a training session in a hypobaric chamber at a simulated altitude of 9144 m (30,000 ft). IOP was measured with a Tone-pen XL tonometer before subjects entered the chamber, at altitude while breathing 100% oxygen by mask and after removing the mask, and again 30 min after leaving the chamber. RESULTS: Ground level values for IOP (mean +/- SD) were 12.31 +/* 2.98 mmHg. Levels increased significantly at altitude on oxygen (16.75 +/- 4.14 mmHg) and decreased slightly on breathing ambient air (14.37 +/- 3.44 mmHg). In 30 min after leaving the chamber, IOP was 12.81 +/- 1.74 mmHg, indistinguishable from pre-test values. DISCUSSION: Healthy subjects whose baseline IOP is in the normal range experience only a small, temporary elevation of IOP during passive exposure to high altitude with either normoxia or acute hypoxia.     

Physiological characteristics of elite high‐altitude climbers

Factors underlying the amplitude of exercise performance reduction at altitude and the development of high‐altitude illnesses are not completely understood. To better describe these mechanisms, we assessed cardiorespiratory and tissue oxygenation responses to hypoxia in elite high‐altitude climbers. Eleven high‐altitude climbers were matched with 11 non‐climber trained controls according to gender, age, and fitness level (maximal oxygen consumption, VO_2max). Subjects performed two maximal incremental cycling tests, in normoxia and in hypoxia (inspiratory oxygen fraction: 0.12). Cardiorespiratory measurements and tissue (cerebral and muscle) oxygenation were assessed continuously. Hypoxic ventilatory and cardiac responses were determined at rest and during exercise; hypercapnic ventilatory response was determined at rest. In hypoxia, climbers exhibited similar reductions to controls in VO_2max (climbers ?39 ± 7% vs controls ?39 ± 9%), maximal power output (?27 ± 5% vs ?26 ± 4%), and arterial oxygen saturation (SpO₂). However, climbers had lower hypoxic ventilatory response during exercise (1.7 ± 0.5 vs 2.6 ± 0.7 L/min/%; P < 0.05) and lower hypercapnic ventilatory response (1.8 ± 1.4 vs 3.8 ± 2.5 mL/min/mmHg; P < 0.05). Finally, climbers exhibited slower breathing frequency, larger tidal volume and larger muscle oxygenation index. These results suggest that elite climbers show some specific ventilatory and muscular responses to hypoxia possibly because of genetic factors or adaptation to frequent high‐altitude climbing.     

Effects of intermittent exposure to high altitude on blood volume and erythropoietic activity

The purpose of this review is to describe changes in blood volume and erythropoietic activity occurring under different types of intermittent exposure to hypoxia. These hypoxic episodes can vary from a few seconds or minutes to hours, days, or even weeks. Short hypoxic episodes like sleep apnea only lead to a small increase in hemoglobin concentration, which is mainly due to a hormonal-mediated decrease in plasma volume. In most of these cases the cumulative time spent under hypoxia does not exceed the critical threshold of about 90 min. Endurance athletes and mountaineers who voluntarily expose themselves to hypoxia for some hours or during the night while spending the day at normoxia ("sleep high-train low" concept) do improve their physical performance. Despite raising erythropoietic activity, indicated by elevated plasma concentrations of EPO and the transferrin receptor, the postulated increase in red cell volume has not satisfactorily been proved. Frequent changes between low and high altitudes, which are usual in some South American and Asian countries, provoke similar adaptations in red cell mass as occur in high altitude residents. However, the plasma volume decreases at altitude and increases again when staying at sea level. Even after more than 20 yr of regular moving between low and high altitude, the total blood volume, hemoglobin concentration and hematocrit, as well as the plasma EPO concentration, noticeably oscillate during every hypoxic-normoxic cycle. We assume these changes to be an optimal rapid adaptation of the oxygen transport system to the prevailing hypoxic or normoxic environment. However, possible risks for the organism cannot be excluded.     

低氧训练对大鼠骨骼肌血红素氧合酶mRNA表达的影响

目的:探讨不同低氧训练模式对机体骨骼肌血红素合酶(HO-1)mRNA表达的影响。方法:选用6周龄SD雄性大鼠120只,经3周适应性训练和力竭实验筛选出90只,随机分成9组:常氧安静对照组、持续低氧安静组、间歇低氧安静组、低住低练组、高住高练组、高住低练组、低住高练组、高住高练后复氧训练组、高住低练后复氧训练组。采用常压低氧舱以13.6%的氧浓度(相当于海拔3500m的氧浓度)进行低氧训练,根据血乳酸-速度曲线确定大鼠常氧训练的强度为35m/min,低氧训练的强度为30m/min。低氧训练持续时间为6周,每周训练5天。第6周末最后一次运动后休息48h后处死、取材。采用实时荧光定量PCR技术测试大鼠骨骼肌HO-1mRNA表达。结果:与常氧安静对照组相比,低住低练组大鼠骨骼肌HO-1mRNA表达显著升高(P<0.05),高住高练组、低住高练组非常显著升高(P<0.01);高住低练组与低住低练组比较显著降低(P<0.05);高住高练后复氧训练组大鼠骨骼肌HO-1mRNA表达与高住高练组相比显著降低(P<0.01),基本回到常氧安静对照组水平。结论:高住高练和低住高练可提骨骼肌HO-1mRNA表达。     

慢性缺氧与暗适应

探讨机体持续性慢性缺氧对人光觉系统的影响及可逆性程度 ;方法 :采用暗房夜光表测验法[1 ] ,对驻守在海拔 5 380m 6个月的 46名健康青年官兵现场进行吸氧 1 5分钟前后的暗适应检测 ;结果 :吸氧 1 5分钟后暗适应时间较吸氧前显著缩短 (P <0 .0 1 ) ;结论 :海拔 5 380m持续性慢性缺氧 6个月光感系统可发生功能性的改变 ,暗适应时间延长 ,供氧后光觉功能在短时间内迅速恢复至平原水平。     

Cardiopulmonary transition in the high altitude infant

The perinatal cardiopulmonary transition at high altitude differs from that at sea level because oxygen plays a fundamental role in the developmental changes from fetus to newborn infant. Under conditions of high altitude hypoxia, arterial oxygen saturations are lower, breathing patterns and maturation of respiratory control reflexes differ, and regression of fetal characteristics of the pulmonary vasculature proceeds more slowly. Several aspects of transition vary not only with postnatal age and altitude, but also with population group, suggesting an effect of genetic adaptation on perinatal physiology. Exposure to chronic high altitude hypoxia during the perinatal transition also results in apparent lifelong alterations in respiratory reflex responses and pulmonary vasoreactivity. Disruption of the normal process of cardiopulmonary transition can result in symptomatic high altitude pulmonary hypertension. The exaggerated hypoxemia associated with acute respiratory infections in young infants still undergoing transition contributes to infant mortality at high altitude.     

Effect of hypobaric hypoxia on auditory sensitivity

INTRODUCTION: Previous studies on the effect of hypobaric hypoxia on auditory sensitivity are not readily interpretable, in most cases because the potential effect of ambient pressure on stimulus level was not considered. In this study, auditory sensitivity to 1, 8, 12, and 16 kHz tones was compared between conditions of hypoxia and normoxia at the same simulated altitude (3700 m). METHOD: In the hypoxic condition, the partial pressure of oxygen in the inspired air was allowed to decrease with increasing altitude. In the normoxic condition, the partial pressure of oxygen was maintained at a level equivalent to that experienced at mean sea level (MSL). This comparison also controlled for any effect resulting from physiological consequences of hypobaria other than hypoxia (such as a change in middle-ear impedance). RESULTS: A small (2.57 dB) reduction in sensitivity across the frequency range tested was observed. CONCLUSION: A reduction in sensitivity of this magnitude would not be expected to have a large impact on the effectiveness of information transfer via the auditory modality.     

MIBG scintigraphic assessment of cardiac adrenergic activity in response to altitude hypoxia

High altitude hypoxia induces a decrease in the cardiac chronotropic function at maximal exercise or in response to isoproterenol infusion, suggesting an alteration in the cardiac sympathetic activation. Iodine-123 metaiodobenzylguanidine [( 123I]MIBG) was used to map scintigraphically the cardiac sympathetic neuronal function in six male subjects (aged 32 +/- 7 yr) after an exposure to high altitude that created hypoxic conditions. Results obtained just after return to sea level (RSL) were compared with the normal values obtained after 2 or 3 mo of normoxia (N). A static image was created as the sum of the 16-EKG gated images recorded for 10 min in the anterior view of the chest at 20, 60, 120, and 240 min after injection. Regions of interest were located over the heart (H), lungs (L), and mediastinum (M) regions. There was a significant decrease in the H/M and the L/M ratios in RSL compared to N condition. Plasma norepinephrine concentration was elevated during the stay at altitude but not significantly different in RSL compared to N. In conclusion, cardiac [123I]MIBG uptake is reduced after an exposure to altitude hypoxia, supporting the hypothesis of an hypoxia-induced reduction of adrenergic neurotransmitter reserve in the myocardium. Furthermore, the observed significant decrease in pulmonary MIBG uptake suggests an alteration of endothelial cell function after exposure to chronic hypoxia.     

模拟高原缺氧对慢性牙周炎大鼠牙龈组织中基质金属蛋白酶-2活性的影响

目的 观察常氧与缺氧条件下慢性牙周炎大鼠牙龈组织中基质金属蛋白酶-2(MMP-2)的活性变化,探讨MMP-2在高原牙周病发生发展中的作用.方法 健康成年SD大鼠32只,随机分为正常对照组(N组)、常氧牙周炎组(P1组)、缺氧对照组(H组)、缺氧牙周炎组(P2组),每组8只.P1、P2组分别在常氧与模拟海拔5000m缺氧条件下建立常氧与缺氧牙周炎模型,N、H组作为对照.采用明胶酶活性分析方法检测各组大鼠牙龈组织中活化形式MMP-2的表达水平.结果 N、P1、H、P2组牙龈组织中活化形式MMP-2灰度值分别为13.72±6.22,37.23±4.40、14.45±6.51、45.44±4.79,其中N组与N组(P<0.05)、P2组与P1组(P<0.05)、P1组与N组(P<0.01)、P2组与H组(P<0.01)比较差异均有统计学意义,以P2组牙龈组织中活化形式MMP-2灰度值最高.结论 模拟高原缺氧环境可提高慢性牙周炎大鼠牙龈组织中活化形式IMMP-2含量,进而促进牙周病的发生、发展.     

Nonhematological mechanisms of improved sea-level performance after hypoxic exposure

Altitude training has been used regularly for the past five decades by elite endurance athletes, with the goal of improving performance at sea level. The dominant paradigm is that the improved performance at sea level is due primarily to an accelerated erythropoietic response due to the reduced oxygen available at altitude, leading to an increase in red cell mass, maximal oxygen uptake, and competitive performance. Blood doping and exogenous use of erythropoietin demonstrate the unequivocal performance benefits of more red blood cells to an athlete, but it is perhaps revealing that long-term residence at high altitude does not increase hemoglobin concentration in Tibetans and Ethiopians compared with the polycythemia commonly observed in Andeans. This review also explores evidence of factors other than accelerated erythropoiesis that can contribute to improved athletic performance at sea level after living and/or training in natural or artificial hypoxia. We describe a range of studies that have demonstrated performance improvements after various forms of altitude exposures despite no increase in red cell mass. In addition, the multifactor cascade of responses induced by hypoxia includes angiogenesis, glucose transport, glycolysis, and pH regulation, each of which may partially explain improved endurance performance independent of a larger number of red blood cells. Specific beneficial nonhematological factors include improved muscle efficiency probably at a mitochondrial level, greater muscle buffering, and the ability to tolerate lactic acid production. Future research should examine both hematological and nonhematological mechanisms of adaptation to hypoxia that might enhance the performance of elite athletes at sea level.