European Journal of Endocrinology (2007) 157 733–740 Endocrine and metabolic responses to extreme altitude andphysical exercise in climbers Andrea Benso, Fabio Broglio, Gianluca Aimaretti, Barbara Lucatello, Fabio Lanfranco, Ezio Ghigo andSilvia Grottoli Division of Endocrinology and Metabolism, Department of Internal Medicine, Molinette Hospital, University of Turin, Corso Dogliotti 14,10126 Turin, Italy (Correspondence should be addressed to S Grottoli; Email: Context: Chronic hypoxia induces complex metabolic and endocrine adaptations. High-altitude (HA)exposure is a physiological model of hypoxia.
Objective: To further investigate the endocrine and metabolic responses to extreme HA.
Methods: We studied nine male elite climbers at sea level and at 5200 m after climbing Mt. Everest.
Results: After 7 weeks at HA, body weight was reduced (P!0.05); regarding endocrine variables weobserved: a) an increase of 2-h mean GH concentration (P!0.05) as well as of total IGF-I and IGFbinding protein-3 levels (P!0.05 for both); b) a prolactin increase (P!0.05) coupled withtestosterone decrease (P!0.01) and progesterone increase (P!0.05) without any change in estradiollevels: c) no change in cortisol, ACTH, and dehydroepiandrosterone sulfate (DHEAS) levels; d) anincrease in free thyroxine (P!0.05) and free tri-iodothyronine (T3) decrease (P!0.05) but no changein TSH levels; e) a plasma glucose decrease (P!0.05) without any change in insulin levels; f)an increase in mean free fatty acid levels (P!0.05); g) despite body weight loss, leptin levels showednon-significant trend toward decrease, while ghrelin levels did not change at all.
Conclusions: The results of the present study in a unique experimental human model of maximalexposure to altitude and physical exercise demonstrate that extreme HA and strenuous physicalexercise are coupled with specific endocrine adaptations. These include increased activity of theGH/IGF-I axis and a low T3 syndrome but no change in ghrelin and leptin that was expected takinginto account body weight decrease. These findings would contribute to better understanding humanendocrine and metabolic physiology in hypoxic conditions.
European Journal of Endocrinology 157 733–740 An increase in thyroid hormones explained as a response to the hypoxic stress or, alternatively, The adaptive processes to hypoxia imply complex as a function of altered regulation of thyrotrophin (TSH) modifications in the homeostatic steady state of several secretion has been originally reported On the other endocrine and metabolic functions . Apart from hand, other authors have reported HA-induced increase clinical conditions characterized by low oxygen avail- in progesterone levels but no change in pituitary, ability (such as obstructive sleep apnea syndrome and gonadal, and adrenal hormones in subjects who had a cardiopathy), a widely studied model of hypoxia is prolonged stay at HA but were not performing any represented by the high-altitude (HA) hypoxia. In fact, physical activity . Conflicting with this study, other the reduced availability of oxygen owing to low data reported that a prolonged exposure to HA was barometric pressure is the basic problem associated coupled with an increase in prolactin but decrease in with HA. The acute exposure to reduced partial luteinizing hormone and testosterone levels . There pressure of oxygen at HA decreases arterial oxygen is no knowledge about the response of the growth saturation, stimulates the sympathoadrenal system, hormone (GH)/insulin-like growth factor-I (IGF-I) axis and provokes shifts in substrate metabolism .
to extreme HA, while more is known about the Indeed, the response to HA in terms of energy utilization has been deeply investigated but data about Some studies investigated glucose and lipid metab- endocrine adaptations are scanty and discrepant, likely olism at HA in detail. In particular, physical exercise at reflecting different experimental models and wide 4300 m after prolonged acclimatization greatly relative ranges of altitudes, and generally investigating increased dependence on blood glucose as a fuel and the short-term endocrine response only.
on insulin action but decreased reliance on lipid q 2007 Society of the European Journal of Endocrinology EUROPEAN JOURNAL OF ENDOCRINOLOGY (2007) 157 substrate . A transition from a state of reduced to testosterone, estradiol, progesterone, glucose, insulin, increased insulin sensitivity during the progressive course of acclimatization to HA hypoxia in men has After overnight fasting, blood samples were taken in the also been reported by other authors .
morning at 0700–0730 h, 30 min after an indwelling More recently, the emerging role of leptin and ghrelin in catheter had been placed into an antecubital vein of the the regulation of energy balance prompted an evaluation forearm kept patent by slow infusion of isotonic saline.
of leptin response to HA Subjects exposed to HA Climbers had free access to palatable foods and their lose significant amounts of body mass from fat mass as diet was balanced in carbohydrate (w58%), lipid well as fat-free mass, particularly if involved in physical (w30%), and protein (w12%) contents.
performance such as climbing As a consequence Blood samples were appropriately treated and stored, there is an energy imbalance, likely reflecting increased and biochemical variables were then all measured in energy expenditure and decreased, or at least inadequate, food intake probably due to hypoxia-related satiety Serum GH levels (ng/ml) were measured by IRMA In this context, significant variations in leptin and (hGH IRMA CT, RADIM SpA, Pomezia, Roma, Italy).
ghrelin secretion were expected but the data available so The sensitivity of the assay was 0.15 ng/ml. The inter- far are discrepant. Leptin levels have been reported as and intra-assay coefficients of variation were 3.7 and either increased , decreased , or unchanged while a trend towards decreased ghrelin levels has Plasma total ghrelin levels (pg/ml) were measured for immunoreactive ghrelin concentration by a commercially Based on the foregoing, we aimed to further investigate available RIA (Phoenix Pharmaceuticals, Mountain View, the endocrine and metabolic responses to prolonged CA, USA). The inter- and intra-assay coefficients of exposure to extreme HA hypobaric hypoxia, in association variation were 13.6 and 5.3% respectively.
with physical exercise, as that performed by elite climbers.
Serum IGF-I levels (1 ng/mlZ0.131 nmol/l) were measured by RIA (SM-C-RIA-CT, Pantec, Torino, Italy).
The sensitivity of the assay was 0.25 ng/ml. The inter-and intra-assay coefficients of variation were 9.8 and Serum IGFBP-3 levels (ng/ml) were measured by IRMA This study was part of a larger scientific project (IRMA IGFBP-3, Immunotech, Marsiglia, Francia). The organized by ‘Ev-K2-CNR’ Committee and by the Italian sensitivity of the assay was 50 ng/ml. The inter- and intra- National Institute of Mountain (IMONT) during the assay coefficients of variation were 9.5 and 6.0% celebration of the 50th anniversary of the K2 Italian Nine male well-trained elite climbers (age (mean IRMA (PRL IRMA, Immunotech distr. PANTEC). The S.E.M.): 40.2G1.4 years) of the Italian expedition ‘K2- sensitivity of the assay was 0.5 ng/ml. The inter- and 2004 50 years later’ to the north face of Mt. Everestwere studied; none of them had a significant medical intra-assay coefficients of variation were 8.0 and 2.8% history. All of them gave written informed consent to participate in the study which had been previously Serum testosterone levels (1 ng/mlZ3.47 nmol/l) approved by the Ethical Committee of the University of were measured by RIA (Testosterone, ICN Pharma- ceuticals inc. MP Biomedicals, Costa Mesa, CA, USA).
All climbers had previous experience of climbing in The inter- and intra-assay coefficients of variation were the Himalayas and spent 2 months at an altitude no lower than 5200 m of the base camp (BC), with a step- Serum estradiol levels (1 pg/mlZ3.67 pmol/l) were measured by RIA (ESTRADIOL RIA, DSL, Webster, TX, Five of the climbers reached the summit at 8852 m USA). The sensitivity of the assay was 2.2 pg/ml. The , three of them reached an altitude of 8600 m and inter- and intra-assay coefficients of variation were 9.9 one an altitude of 7500 m. None used oxygen supplementation in the 2 months at HA.
Serum progesterone levels (1 ng/mlZ3.18 nmol/l) All the subjects studied underwent the following were measured by IRMA (PROGESTERONE CT, RADIM hormonal and metabolic evaluations at sea level one SpA). The sensitivity of the assay was 0.12 ng/ml. The month before the expedition and immediately after their inter- and intra-assay coefficients of variation were 12.1 return to the BC following the attempt of ascending Mt.
Everest: a) spontaneous GH, ghrelin, and leptin Plasma ACTH levels (1 pg/mlZ0.22 pmol/l) were secretion (sampling every 30 min for 2 h); b) single measured by IRMA (ACTH, Nichols Institute Diagnostic, measurements of IGF-I, IGF binding protein-3, prolac- San Juan Capistrano, CA, USA). The sensitivity of the tin, adrenocorticotrophin (ACTH), cortisol, DHEAS, free assay was 1 pg/ml. The ranges of inter- and intra-assay tri-iodothyronine (fT3), free thyroxine (fT4), TSH, coefficients of variation were 6.9 and 5.5% respectively.
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2007) 157 Serum cortisol levels (1 ng/mlZ27.59 nmol/l) were Mean GH concentration (over 2 h) increased (AUC measured by RIA (RIA CORTISOLO, IMMUNOTECH (meanGS.E.M.): 755.6G110.4 vs 284.2G104.8 mg/l min; distrib. PANTEC). The sensitivity of the assay was P!0.01). This change in GH status was coupled with a 10 nM. The inter- and intra-assay coefficients of concomitant increase (P!0.05) in mean total IGF-I variation were 7.3 and 4.3% respectively.
(219.6G31.1 vs 167.5G22.7 mg/l) and IGFBP-3 Serum DHEAS levels (1 mg/dl Z0.2714 mmol/l) were measured by RIA (DHEA-S CT, RADIM SpA). The Prolactin levels increased (7.8G0.8 vs 6.0G0.6 mg/l; sensitivity of the assay was 2 mg/dl. The inter- and P!0.05), whereas testosterone levels decreased (3.6G intra-assay coefficients of variation were 8.5 and 7.3% 0.4 vs 5.5G0.6 ng/ml, P!0.01). These changes were associated with a concomitant increase in progesterone Serum insulin levels (1 mU/mlZ7.175 pmol/l) were (1.8G0.1 vs 1.4G0.1 ng/ml; P!0.05). Despite these measured by IRMA (INSIK-5, DIASORIN, Saluggia, significant changes, these variables at HA persisted Italy). The sensitivity of the insulin assay was 4 mU/ml.
within the normal range. No change in estradiol levels The coefficient of variation was 6.1% for both inter- and Cortisol, ACTH, and DHEAS levels did not change.
Plasma glucose levels (1 mg/dlZ0.05556 mmol/l) Although TSH levels were not modified, fT4 levels were measured by a gluco-oxidase colorimetric method increased (13.7G0.7 vs 10.4G0.6 ng/l; P!0.05) (Glucofix, by Menarini Diagnostici, Florence, Italy).
while free T3 levels decreased (2.0G0.1 vs 2.7G Serum leptin levels (ng/ml) were measured by RIA 0.1 ng/l; P!0.05); fT3 levels at HA were below the (HUMAN-LEPTIN-RIA-SENSITIVE, MEDIAGNOST, Reu- tlingen, Germany). The sensitivity of the assay was After maximal physical exercise at HA, morning 0.04 ng/ml. The inter- and intra-assay coefficients of plasma glucose levels were significantly reduced variation were 7.6 and 5.0% respectively.
(70.1G3.7 vs 80.0G2.6 mg/dl; P!0.05) without Serum free fatty acids levels (mEq/l) were measured any significant change in insulin levels (10.9G0.8 vs by an enzymatic colorimetric method (NEFA C, WAKO 10.1G0.8 mU/l). However, over the 2-h evaluation, Chemicals GmbH, Neuss, Germany). The sensitivity of there was no significant change in the two variables, the assay was 1 mEq/l. The inter- and intra-assay though insulin showed a trend toward decrease (glucose coefficients of variation were 4.1 and 1.1% respectively.
AUC: 9051.7.0G316.8 vs 9671.7G365.1 mg/dl min; Serum fT3 levels (pmol/l) were measured by RIA (Kit pbr-system RIA, Bouty Laboratories, Milan, Italy). The sensitivity of the assay was 0.76 pmol/l. The inter- and Mean FFA levels after maximal physical exercise at intra-assay coefficients of variation were 6.3 and 3.9% HA increased (0.53G0.11 vs 0.36G0.05 mEq/l).
Despite the decrease in body weight after the performance Serum fT4 levels (pmol/l) were measured by RIA (Kit at HA, 2-h mean leptin secretion showed a trend toward pbr-system RIA, Bouty). The sensitivity of the assay was decrease (60.1G3.6 vs 90.5G7.2 ng/ml min, p: ns), while 0.38 pmol/l. The inter- and intra-assay coefficients of ghrelin levels did not change (18 312.5G1934.5 vs variation were 6.6 and 3.8% respectively.
Serum TSH levels (mU/l) were measured by IRMA (TSH-CTK-3, SORIN Biomedica, Saluggia, Italy). Thesensitivity of the assay was 0.04 mU/l. The inter- and intra-assay coefficients of variation were 8.0 and 3.3%respectively.
The results of the present study in a unique experi- Biochemical variables are expressed as meanGS.E.M. of mental human model of maximal exposure to altitude absolute values and also of areas under curves (AUC) and physical exercise demonstrate that extreme HA and calculated by trapezoidal integration. Statistical analysis strenuous physical exercise are coupled with specific was carried out using non-parametric Mann–Whitney test.
endocrine adaptations. Particularly, these includeincreased activity of the GH/IGF-I axis and a low T3syndrome but no significant change in ghrelin and leptin although some could have been expected, takinginto account the decrease in body weight. On the other None of the climbers developed severe altitude sickness hand, the effects of extreme physical performance at HA also included: (i) some increase in prolactin and Over the period of 2 months at HA, we observed an progesterone but decrease in testosterone levels; (ii) no average weight loss of 5 kg (weight at HA: 66.1G2.2 kg, change in the variables exploring the function of weight at sea level: 71.1G1.9 kg, P!0.05; hypothalamus–pituitary–adrenal axis; and (iii) some With respect to values recorded at sea level, endocrine expected changes in glucose and lipid metabolism.
and metabolic variables were modified or unchanged by The Italian expedition ‘K2-2004 50 years later’ to Mt. Everest represented the opportunity to further Table 1 Individual climber anthropometric, hormonal, and metabolic values.
BMI, body mass index; PRL, prolactin; T, testosterone; PG, progesterone; E2, estradiol; fT3, free T3; fT4, free T4; SL, sea level; BC, base camp.
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2007) 157 Figure 1 Mean (GS.E.M.) GH, IGF-I,and IGFBP-3 levels in nine male eliteclimbers at sea level and after high-altitude chronic hypoxia exposure(*P!0.05).
investigate the endocrine and metabolic responses to This metabolic profile would have also been prolonged exposure to extreme HA hypobaric hypoxia in determined by the remarkable changes in the function association with physical exercise such as that performed of the GH/IGF-I axis. The information about the adaptation, if any, of this axis to extreme HA was A large variety of factors, including environmental scarce. We found that well-trained acclimatized clim- conditions, have been found to influence the hormonal bers show clear-cut increases in mean GH concen- response to exercise at HA such as reduced tration and this agrees with evidence that physical oxygen availability, hypohydration, and alterations in exercise represents a neuroendocrine-mediated stimu- lus of somatotropic secretion as well as with the Our present findings are consistent with the enhancement of the GH response to GH-releasing adaptations of glucose and lipid metabolism reported hormone recorded in subjects chronically living at HA to occur during HA exposure, indicating increased Again, it had been also reported that low-altitude dependence on blood glucose as a fuel with a natives adapted to HA show a more marked GH increase concomitant increase in insulin sensitivity and lipolysis coupled with a decreased reliance on lipid substrate The most intriguing aspect is, however, that the increased GH secretion was coupled with an increase in Figure 2 Mean (GS.E.M.) prolactin,testosterone, progesterone, and estra-diol levels in nine male elite climbers atsea level and after high-altitude chronichypoxia exposure (*P!0.05; **P!0.01;dotted line indicates the lower limit ofnormality in our laboratory).
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2007) 157 prolactin secretion most likely via neuroendocrinemechanisms Like others we found thatsignificant increase in prolactin levels was coupled withreduction in testosterone levels; in agreement with someprevious data, this would likely indicate stress-induceddepression in the function of the gonadal axis that, in turn,would be negatively affected by prolactin increase Testosterone decrease in climbers at HA would, however,simply reflect the combined negative influence of hypoxiaand strenuous physical exercise; in fact, reduced testoster-one levels have been recorded in men in hypoxic conditionsof any physical exercise as well as in subjectsundergoing endurance training Moreover, the factthat the GH/IGF-I axis is activated while testosterone isdecreased may explain the lack of anabolism and theincreased dependence on glucose utilization.
The hypothesis that the athletes were particularly stressed seems contradicted by the lack of anysignificant change in cortisol and ACTH as well asDHEAS levels. The single basal evaluation of thesevariables is, on the other hand, not enough toadequately investigate the hypothalamus–pituitary–adrenal axis function and therefore to exclude somestress-induced derangement. In this context, however, itis noteworthy that our findings confirm significantHA-induced elevation in progesterone levels Therole of progesterone as a potent respiratory stimulant inthe physiological regulation of breathing has beenrecently emphasized in fact, it has been demon-strated that progesterone is able to increase sensitivity ofthe respiratory center to CO2 Thus, theincrease of progesterone levels in hypoxic conditions atHA could be viewed as a stimulus for the respiratorydrive; this would be favored by the decline intestosterone levels that are known to exert reduceddown-regulation of progesterone receptors The effects of HA, hypoxia, and physical exercise on Figure 3 Mean (GS.E.M.) TSH, free T4, and free T3 levels in nine the thyroid axis have been more extensively studied male elite climbers at sea level and after high-altitude chronic . Although physical exercise per se is not hypoxia exposure (*P!0.05; dotted line indicates the lower limit ofnormality in our laboratory).
considered as having a significant influence on thyroidfunction , environmental conditions have been either IGF-I or IGFBP-3 levels. Indeed, IGF-I is the best reported to play a relevant role. A previous study in marker of GH status although IGFBP-3, a GH-dependent subjects who had a short-term stay at extreme HA IGF-I binding protein, also well reflects chronic during Mt. Everest climbing reported an increase in variations in the status of somatotropic function total T4 and T3 concentration associated with an The clear increase of IGF-I and IGFBP-3 together with increase in TSH levels. On the other hand, significant the enhancement of mean GH levels therefore clearly elevation of free T4 levels after 3 weeks at 4300 m points toward increased activity of an anabolic axis like without any change in TSH levels have been reported the GH/IGF-I at HA. In fact, increased activity of the . Our present findings recorded after a 2-month stay GH/IGF-I axis is likely to trigger protein anabolism and at HA confirm the lack of change in TSH levels as well as might also play a role in the adaptations occurring in the increase in fT4 levels, while they show significant reduction of fT3 levels that were below the lowest limit of An adaptive metabolic purpose would also explain the the normal range. This picture suggests an HA-induced significant increase in lactotropic secretion that followed low T3 syndrome that would reflect an impairment of the exposure to HA in our subjects as well as in another peripheral fT4 to free T3 conversion under chronic study . In fact, prolactin has been shown to markedly exposure to HA hypoxia. Indeed, it is reasonable that affect glucose metabolism but, on the other hand, prolonged exposure to hypobaric hypoxia at extreme chronic stressful conditions are known to increase HA induces a low T3 syndrome that would also be EUROPEAN JOURNAL OF ENDOCRINOLOGY (2007) 157 Figure 4 Mean (GS.E.M.) leptin andghrelin secretion in nine male eliteclimbers at sea level and after high-altitude chronic hypoxia exposure.
explained by the status of negative energy balance strenuous physical exercise do not allow the normal caused by strenuous physical exercise The physiological response of leptin and ghrelin to significantly negative energy balance is shown by the clear decrease decrease body weight and cause negative energy balance.
in body weight that was recorded in our study as well as The mechanism(s) underlying this lack of leptin and in other studies in subjects at HA .
ghrelin responses are, at present, unknown. Evidence Despite the expected decrease in body weight that ghrelin secretion was not coupled with the clear reflecting the negative energy balance, we did not increase in GH and IGF-I secretion is relevant record any significant variation in either leptin or considering that ghrelin has been discovered as a ghrelin secretion. That either leptin, an adipocyte natural GH secretagogue and is supposed to play a hormone, or ghrelin, a gastric hormone, play a major major role in the positive control of somatotropic role in the regulation of energy balance, appetite, and function However, more recent studies questioned food intake as well as in peripheral metabolism has been the physiological importance of ghrelin in the control of well demonstrated Particularly, decrease in body GH secretion and our present results in elite weight is generally associated with leptin decrease and climbers agree with these latter studies indicating that ghrelin increase, while the opposite picture is associated the HA-induced enhancement in the activity of GH/IGF-I axis was not mediated by ghrelin.
In conclusion, the results of the present study in a Since the loss of fat mass and fat-free mass occurring unique experimental human model demonstrate that during a climb to and/or a stay at HA mainly reflects the extreme HA and strenuous physical exercise are coupled inability to maintain energy balance , alterations with peculiar endocrine adaptations. Particularly, these in leptin and ghrelin secretion at HA had been include hyperactivity of the GH/IGF-I axis and a low T hypothesized. An increase in leptin coupled with ghrelin syndrome but no significant change in ghrelin and decrease has been described after acute exposure to HA leptin as was likely to be expected, also taking into , but other authors reported that prolonged HA account body weight decrease. These findings would exposure is associated with a reduction of leptin contribute to better understanding human endocrine concentrations, likely due to the loss of body mass and and metabolic physiology in hypoxic conditions.
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