|High Altitude and the Endocrine System|
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|Wednesday, 24 March 2010 11:27|
Exposure to high altitude and the subsequent hypobaric hypoxia cause many disturbances in normal physiological functions. Changes in hormone release are critical in maintaining homeostasis, and may play a part in adaptation and acclimatisation to high altitude hypoxia. Although high altitude affects secretion of growth hormone, insulin–like growth factor, the sex hormones and adipokines such as leptin, this article will focus on the changes that occur in glucose regulation and water balance, thyroid function and glucocorticoid release at high altitude.
The main physiological glucocorticoid is cortisol, which is released from the adrenal cortex in response to stress and exercise. Besides promoting amino acid and fatty acid mobilisation, cortisol increases the production of red blood cells. There is a rise in cortisol upon ascent to high altitudes, however uncertainty exists regarding the duration of these elevated levels. While some studies suggest that cortisol increases only acutely (1–2) or not at all (3), others have shown a sustained rise in cortisol, lasting up to 21 days at high altitudes. (4–5) As expected, this rise in cortisol was more rapid in individuals on a calorie–restricted diet. (4) In a case study of an individual who had a hypophysectomy and was supplemented with glucocorticosteroids, the maintenance dose of glucocorticoids was not sufficient to maintain normal function at 3500 m. (6) This suggests that the rise in cortisol is essential for acclimatisation at high altitude. It was advised that the dose of glucocorticoids should be doubled above 3000 m and tripled above 4000 m. Individuals who have adrenal insufficiency should take precautions when traveling to high altitudes, and should increase the dose of glucocorticoids appropriately.
Ascent to high altitude is generally associated with an acute rise in blood glucose levels (4, 7), which normalises after 5 days of exposure to high altitude hypoxia. (4) Since anorexia is commonly experienced by high altitude trekkers, Barnholt et al. investigated the effects of caloric restriction at 4300 m, and found that individuals who were adequately fed had a more exaggerated rise in blood glucose. (4) This rise in blood glucose is associated with a rise in insulin levels and no change in glucagon (8), which suggests some degree of insulin resistance induced at high altitude. There is little to no hepatic insulin resistance, and thus it is presumed that the insulin resistance is limited to the peripheral tissues. (7) Since elevated levels of glucocorticoids are associated with insulin resistance, it has been proposed that the hypoxia–induced changes in cortisol may contribute this high altitude associated insulin resistance; however, this has yet to be confirmed.
Insulin is an anabolic hormone, secreted in response to increased blood concentrations of glucose, fatty acids, and amino acids such as arginine, as well as to cortisol and growth hormone. Insulin is most commonly regarded as a hypoglycaemic agent, but can also stimulate the transport of amino acids into cells, and inhibit catabolism of proteins. In addition to its post–prandial function, insulin affects haematocrit, haemoglobin, and iron stores (9–10), and therefore may play a role in the acclimatisation process. In vitro, insulin and insulin like growth factor–1 stimulate proliferation of erythroid progenitor cells. (11) In non–obese men and women, hyperinsulinaemia and insulin resistance were independently associated with an increase in haemoglobin levels and in haematocrit. (9) Insulin also increases iron stores. (12–14) Along with hypoxia, both insulin and insulin like growth factor–1 can boost the activity of hypoxia inducible factor–1α (HIF–1α) which regulates many genes involved in the acclimatisation process. (10, 15)
High Altitude and Diabetes Mellitus
With the increase in both the incidence and prevalence of diabetes, and travel to high altitudes becoming more accessible, it is important to consider differences in high altitude illness in a diabetic patient. Additionally, any trek physician or guide should be prepared to deal with any complications that may arise in a diabetic patient. Table 1 outlines the supplies that should be carried when travelling with a diabetic patient at altitude. (16)
Studies have shown that cardiovascular performance in patients with type1 diabetes, who are otherwise healthy, is similar to control subjects at altitudes of up to 5800m. (17) There was no difference found in the occurrence of acute mountain sickness in diabetic patients compared with controls. (18–19) High altitude is associated with transient haemorrhages of the retina; however, there have been no studies investigating the prevalence and long term consequences of these high altitude retinal haemorrhages in diabetic patients. (16)
Travel to high altitude is associated with elevated levels of catecholamines, specifically noradrenaline. (4, 20) Individuals without diabetes usually respond to elevated catecholamine levels with an increase in insulin secretion. This leaves type 1 diabetics at particular risk of developing stress–induced hyperglycaemia. Thus, insulin levels should be adjusted adequately and blood glucose levels should be closely monitored. In type 1 diabetics ascending Mount Kilimanjaro, insulin requirements fell by 49%, which was attributed to the rapid 5–day climb. (18) However, this was followed by an increase in insulin requirements by 52% on expeditions of longer duration. The greatest changes in insulin requirements were seen between days four and ten. High altitude induced anorexia is commonly experienced during ascent. (21) It is therefore critical that diabetics are aware of their blood glucose levels, as increasing insulin doses and decreased appetite could lead to hypoglycaemia.
Glucometers are an effective method of monitoring blood glucose levels at sea level; however, they are affected by temperature, elevation and relative humidity. Elevation tended to cause underestimation of blood glucose levels by 1–2% for every 300m ascended. (22) However, a recent study showed glucose dehydrogenase based glucose blood meters significantly overestimated blood glucose levels, and thus may be appropriate to detect hypoglycaemia on ascending to high altitude. (23)
Table 1 Supplies required when traveling to high altitudes with a diabetic (reproduced with kind permission from PL Brubaker (16))
Triiodothyronine (T3) and thyroxine (T4) are hormones secreted by the thyroid gland when stimulated by thyrotropic stimulating hormone (TSH). At high altitude, there is a rise in blood T4 levels, which is independent of TSH. (4, 20) This increase peaked within 4 hours of ascent, and remained elevated for the entire duration of the stay at high altitude. (4) This increase in T4 was also independent of the cold that normally accompanies high altitude. Physiological studies have shown that thyroid hormone increases erythrocyte levels of 2,3–diphosphoglycerate (2,3–DPG), a metabolic breakdown product of glucose. (24) 2,3–DPG causes a rightward–shift in the oxyhaemoglobin dissociation curve and thus makes oxygen more available for perfusion into the tissues.
There is currently no literature on high altitude travel of patients with hypothyroidism or hyperthyroidism. The effect of high altitude on thyroid function, however, should be considered when advising patients before high altitude travel.
A problem facing most high altitude trekkers is the diuretic effect of the hypobaric atmosphere. This is due to the effect of high altitude on the secretion of aldosterone, antidiuretic hormone (ADH) and atrial natriuretic peptide (ANP).
The physiological function of the mineralocorticoid aldosterone is to increase renal tubular excretion of sodium and reabsorption of potassium, and thus ultimately cause water retention. It is thought that the main stimulus for renin release is sympathetic drive, which is induced by hypoxia and exercise. It is therefore expected that high altitude would cause an increase in aldosterone release. However, high altitude causes selective inhibition of aldosterone secretion from the adrenal cortex. (25–27) This inhibition of aldosterone secretion has been ascribed to a reduced response of aldosterone to renin levels. (28–30)
The posterior pituitary releases ADH through stimulation by osmoreceptors located in the hypothalamus. ADH causes vasoconstriction through the V1 receptor, and increased water reabsorption in the distal nephron through the V2 receptor.
Failure in the osmoregulatory mechanisms occurs at high altitude, thus altering the secretion of ADH. At high altitude, sodium, calcium and phosphate levels are higher than at sea level. However, this increased blood osmolarity did not produce a significant rise in ADH. (25, 31), suggesting impairment in osmoregulators leading to diuresis. Water deprivation tests after acute and prolonged exposure to an altitude of 4300m resulted in a rise in ADH. (32)This effect was greater at high altitude when compared to sea level, and was more pronounced after prolonged altitude exposure. Thus, high altitude may cause an increase in the osmolarity threshold for stimulating the release of ADH. (32) In acclimatised individuals, the kidney has reduced sensitivity to ADH, and infusion of exogenous ADH leads to an increase in aquaporin–2 channels. (33)
ANP is a hormone secreted by the atria in response to increased stretch. It increases sodium excretion by the kidneys and is a powerful vasodilator. Hypoxia has been shown to increase levels of ANP. (34–35) Exercise is a secondary stimulus for the release of ANP levels in high altitude trekkers. (28) A rise in ANP levels is thought to play a part in acute mountain sickness (28), which may be caused by an overproduction of 2,3–DPG. (36) While some have shown no correlation between ANP levels and AMS scores (37), others have correlated AMS and high altitude pulmonary oedema (HAPE) with higher levels of ANP. (38–40) Conversely, others have suggested that ANP may reduce hypoxic pulmonary vasoconstriction (41), although this has yet to be demonstrated in humans.
High altitude hypoxia causes many changes in hormone levels to maintain homeostasis. Glucose regulation is altered by an increase in insulin resistance, and an increase in insulin levels. (4, 7) Type 1 diabetics at high altitudes also demonstrate increased insulin requirements. (18) Ascent to high altitude leads to an increase production of glucocorticoids, and thus glucocorticoid doses need to be adjusted in those patients who are adrenocompromised. (6) An increase in T4 production independent of TSH has been demonstrated at high altitude (4, 20), although the effect of high altitude on individuals who have altered thyroid function has not been demonstrated. Lastly, high altitude hypoxia has a known diuretic effect, which can be attributed to a decrease in aldosterone (25–27) and ADH (25, 31), and an increase in ANP. (34, 35)
1. Frayser R, Rennie ID, Gray GW, Houston CS. Hormonal and electrolyte response to exposure to 17,500 ft. J Appl Physiol. 1975;38:636–642.
2. Sutton JR. Effect of acute hypoxia on the hormonal response to exercise. J Appl Physiol. 1977;42:587–592.
3. Chen KT, Chen YY, Wu HJ et al. Decreased anaerobic performance and hormone adaptation after expedition to Peak Lenin. Chin Med J (Engl). 2008;121:2229–2233.
4. Barnholt KE, Hoffman AR, Rock PB et al. Endocrine responses to acute and chronic high–altitude exposure (4,300 meters): modulating effects of caloric restriction. Am J Physiol Endocrinol Metab. 2006;290:E1078–88.
5. Ermolao A, Travain G, Facco M, Zilli C, Agostini C, Zaccaria M. Relationship between stress hormones and immune response during high–altitude exposure in women. J Endocrinol Invest. 2009;32:889–894.
6. Westendorp RG, Frolich M, Edo Meinders A. What to tell steroid–substituted patients about the effects of high altitude? Lancet. 1993;342:310–311.
7. Larsen JJ, Hansen JM, Olsen NV, Galbo H, Dela F. The effect of altitude hypoxia on glucose homeostasis in men. J Physiol. 1997;504:241–249.
8. Blume FD. Metabolism and nutrition at altitude. Prog Clin Biol Res. 1983;136:311–316.
9. Facchini FS, Carantoni M, Jeppesen J, Reaven GM. Hematocrit and hemoglobin are independently related to insulin resistance and compensatory hyperinsulinemia in healthy, non–obese men and women. Metabolism. 1998;47:831–835.
10. McCarty MF. Hyperinsulinemia may boost both hematocrit and iron absorption by up–regulating activity of hypoxia–inducible factor–1alpha. Med Hypotheses. 2003;61:567–573.
11. Miyagawa S, Kobayashi M, Konishi N, Sato T, Ueda K. Insulin and insulin–like growth factor I support the proliferation of erythroid progenitor cells in bone marrow through the sharing of receptors. Br J Haematol. 2000;109:555–562.
12. Sharifi F, Nasab NM, Zadeh HJ. Elevated serum ferritin concentrations in prediabetic subjects. Diab Vasc Dis Res. 2008;5:15–18.
13. Tuomainen TP, Nyyssonen K, Salonen R et al. Body iron stores are associated with serum insulin and blood glucose concentrations. Population study in 1,013 eastern Finnish men. Diabetes Care. 1997;20:426–428.
14. Fernandez–Real JM, Ricart–Engel W, Arroyo E et al. Serum ferritin as a component of the insulin resistance syndrome. Diabetes Care. 1998;21:62–68.
15. Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B. Insulin induces transcription of target genes through the hypoxia–inducible factor HIF–1alpha/ARNT. EMBO J. 1998;17:5085–5094.
16. Brubaker PL. Adventure travel and type 1 diabetes: the complicating effects of high altitude. Diabetes Care. 2005;28:2563–2572.
17. Pavan P, Sarto P, Merlo L et al. Metabolic and cardiovascular parameters in type 1 diabetes at extreme altitude. Med Sci Sports Exerc. 2004;36:1283–1289.
18. Moore K, Vizzard N, Coleman C, McMahon J, Hayes R, Thompson CJ. Extreme altitude mountaineering and Type 1 diabetes; the Diabetes Federation of Ireland Kilimanjaro Expedition. Diabet Med. 2001;18:749–755.
19. Moore K, Thompson C, Hayes R. Diabetes and extreme altitude mountaineering. Br J Sports Med. 2001;35:83.
20. Benso A, Broglio F, Aimaretti G et al. Endocrine and metabolic responses to extreme altitude and physical exercise in climbers. Eur J Endocrinol. 2007;157:733–740.
21. Morel OE, Aubert R, Richalet JP, Chapelot D. Simulated high altitude selectively decreases protein intake and lean mass gain in rats. Physiol Behav. 2005;86:145–153.
22. Fink KS, Christensen DB, Ellsworth A. Effect of high altitude on blood glucose meter performance. Diabetes Technol Ther. 2002;4:627–635.
23. Bilen H, Kilicaslan A, Akcay G, Albayrak F. Performance of glucose dehydrogenase (GDH) based and glucose oxidase (GOX) based blood glucose meter systems at moderately high altitude. J Med Eng Technol. 2007;31:152–156.
24. Snyder LM, Reddy WJ. Thyroid hormone control of erythrocyte 2,3–diphosphoglyceric acid concentrations. Science. 1970;169:879–880.
25. Ramirez G, Hammond M, Agosti SJ, Bittle PA, Dietz JR, Colice GL. Effects of hypoxemia at sea level and high altitude on sodium excretion and hormonal levels. Aviat Space Environ Med. 1992;63:891–898.
26. Zaccaria M, Rocco S, Noventa D, Varnier M, Opocher G. Sodium regulating hormones at high altitude: basal and post–exercise levels. J Clin Endocrinol Metab. 1998;83:570–574.
27. Raff H, Jankowski BM, Engeland WC, Oaks MK. Hypoxia in vivo inhibits aldosterone synthesis and aldosterone synthase mRNA in rats. J Appl Physiol. 1996;81:604–610.
28. West JB, Schoene RB, Milledge JS. High Altitude Medicine and Physiology. A Hodder Arnold Publication; 2007
29. Milledge JS, Catley DM. Renin, aldosterone, and converting enzyme during exercise and acute hypoxia in humans. J Appl Physiol. 1982;52:320–323.
30. De Angelis C, Ferri C, Urbani L, Farrace S. Effect of acute exposure to hypoxia on electrolytes and water metabolism regulatory hormones. Aviat Space Environ Med. 1996;67:746–750.
31. Blume FD, Boyer SJ, Braverman LE, Cohen A, Dirkse J, Mordes JP. Impaired osmoregulation at high altitude. Studies on Mt Everest. JAMA. 1984;252:524–526.
32. Maresh CM, Kraemer WJ, Judelson DA et al. Effects of high altitude and water deprivation on arginine vasopressin release in men. Am J Physiol Endocrinol Metab. 2004;286:E20–4.
33. Ramirez G, Pineda D, Bittle PA et al. Partial renal resistance to arginine vasopressin as an adaptation to high altitude living. Aviat Space Environ Med. 1998;69:58–65.
34. Kawashima A, Kubo K, Kobayashi T, Sekiguchi M. Hemodynamic responses to acute hypoxia, hypobaria, and exercise in subjects susceptible to high–altitude pulmonary edema. J Appl Physiol. 1989;67:1982–1989.
35. Vonmoos S, Nussberger J, Waeber B, Biollaz J, Brunner HR, Leuenberger P. Effect of metoclopramide on angiotensins, aldosterone, and atrial peptide during hypoxia. J Appl Physiol. 1990;69:2072–2077.
36. Ge RL, Shai HR, Takeoka M et al. Atrial natriuretic peptide and red cell 2,3–diphosphoglycerate in patients with chronic mountain sickness. Wilderness Environ Med. 2001;12:2–7.
37. Milledge JS, Beeley JM, McArthur S, Morice AH. Atrial natriuretic peptide, altitude and acute mountain sickness. Clin Sci (Lond). 1989;77:509–514.
38. Bartsch P, Shaw S, Franciolli M, Gnadinger MP, Weidmann P. Atrial natriuretic peptide in acute mountain sickness. J Appl Physiol. 1988;65:1929–1937.
39. Irwin DC, Rhodes J, Baker DC, Nelson SE, Tucker A. Atrial natriuretic peptide blockade exacerbates high altitude pulmonary edema in endotoxin–primed rats. High Alt Med Biol. 2001;2:349–360.
40. Cosby RL, Sophocles AM, Durr JA, Perrinjaquet CL, Yee B, Schrier RW. Elevated plasma atrial natriuretic factor and vasopressin in high–altitude pulmonary edema. Ann Intern Med. 1988;109:796–799.
41. Hohne C, Drzimalla M, Krebs MO, Boemke W, Kaczmarczyk G. Atrial natriuretic peptide ameliorates hypoxic pulmonary vasoconstriction without influencing systemic circulation. J Physiol Pharmacol. 2003;54:497–510.
|Last Updated on Thursday, 19 September 2013 11:56|