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: email@example.com)
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
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.
the strong hypoxia-related sympathetic activation .
These studies relied on single leptin and ghrelin measure-ments while we evaluated mean leptin and ghrelin
concentrations over 2 h. Indeed, we found a non-significant trend toward decreased leptin levels, but
Novo Nordisk and IMONT are acknowledged for the
ghrelin levels were completely unchanged despite the
financial support of the study. Moreover, the authors
significant body weight loss. Thus, extreme HA and
wish to thank all the climbers of the expedition, Da
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2007) 157
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Sidney A. DIAMOND, Commissioner of Patents and Trademarks, Petitioner, Ananda M. CHAKRABARTY et al. *305 Mr. Chief Justice BURGER delivered the opinion of the Court. We granted certiorari to determine whether a live, human-made micro-organism is patentable subject m. In 1972, respondent Chakrabarty, a microbiologist, filed a patent application, assigned to the General Electric C
Information for Prescribing Naltrexone The patient carrying this letter to you would like your support in a highly effective treatment for alcoholism: it is called TSM and has a 78% cure rate. It requires a prescription for naltrexone. The FDA approved naltrexone in 1995 for use in the treatment of alcohol dependence. Important new evidence has been obtained since then about how to use