Abstract
Critical illness is characterized by striking alterations in the hypothalamic–anterior-pituitary–peripheral-hormone axes, the severity of which is associated with a high risk of morbidity and mortality. Most attempts to correct hormone balance have been shown ineffective or even harmful because of a lack of pathophysiologic insight. There is a biphasic (neuro)endocrine response to critical illness. The acute phase is characterized by an actively secreting pituitary, but the concentrations of most peripheral effector hormones are low, partly due to the development of target-organ resistance. In contrast, in prolonged critical illness, uniform (predominantly hypothalamic) suppression of the (neuro)endocrine axes contributes to the low serum levels of the respective target-organ hormones. The adaptations in the acute phase are considered to be beneficial for short-term survival. In the chronic phase, however, the observed (neuro)endocrine alterations appear to contribute to the general wasting syndrome. With the exception of intensive insulin therapy, and perhaps hydrocortisone administration for a subgroup of patients, no hormonal intervention has proven to beneficially affect outcome. The combined administration of hypothalamic releasing factors does, however, hold promise as a safe therapy to reverse the (neuro)endocrine and metabolic abnormalities of prolonged critical illness by concomitant reactivation of the different anterior-pituitary axes.
Key Points
-
The (neuro)endocrine responses to acute and prolonged critical illness are substantially different; in the acute phase, the adaptations are probably beneficial in the struggle for short-term survival, whereas the chronic alterations participate in the wasting syndrome of prolonged critical illness and can be maladaptive
-
Thorough understanding of the pathophysiology underlying endocrine disturbances in critical illness is of vital importance when considering new therapeutic strategies to correct these abnormalities; indeed, the choice of hormone and corresponding dosage are crucial and lack of insight has been shown to be dangerous.
-
In contrast to the classic dogma that stress-induced hyperglycemia is beneficial to organs that largely rely on glucose for energy supply but do not require insulin for glucose uptake, it is now clear that the development of hyperglycemia is an important risk factor in terms of mortality and morbidity of critically ill patients; importantly, strict blood glucose control with intensive insulin therapy improves survival and largely prevents several critical-illness-induced complications
-
A remarkable interaction has been demonstrated among the different (neuro)endocrine axes; the concomitant administration of several hypothalamic releasing factors holds promise as an effective and safe intervention to jointly restore the corresponding axes and to counteract the hypercatabolic state of prolonged critical illness
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Takala J et al. (1999) Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 341: 785–792
CRASH trial collaborators (2004) Effect of intravenous corticosteroids on death within 14 days in 10,008 adults with clinically significant head injury (MRC CRASH trial): a randomized placebo-controlled trial. Lancet 364: 1321–1328
Debaveye YA and Van den Berghe GH (2004) Is there still a place for dopamine in the modern intensive care unit? Anesth Analg 98: 461–468
Van den Berghe G et al. (1998) Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 83: 1827–1834
Weekers F et al. (2002) A novel in vivo rabbit model of hypercatabolic critical illness reveals a biphasic neuroendocrine stress response. Endocrinology 143: 764–774
Bowers CY et al. (1984) On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology 114: 1537–1545
Howard AD et al. (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 27: 974–977
Kojima M et al. (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402: 656–660
Van den Berghe G et al. (2000) A paradoxical gender dissociation within the growth hormone/insulin-like growth factor I axis during protracted critical illness. J Clin Endocrinol Metab 85: 183–192
Ross R et al. (1991) Critically ill patients have high basal growth hormone levels with attenuated oscillatory activity associated with low levels of insulin-like growth factor-I. Clin Endocrinol (Oxf) 35: 47–54
Baxter RC et al. (1998) Thirty day monitoring of insulin-like growth factor and their binding proteins in intensive care unit patients. Growth Horm IGF Res 8: 455–463
Hermansson M et al. (1997) Measurement of human growth hormone receptor messenger ribonucleic acid by a quantitative polymerase chain reaction-based assay: demonstration of reduced expression after elective surgery. J Clin Endocrinol Metab 82: 421–428
Defalque D et al. (1999) GH insensitivity induced by endotoxin injection is associated with decreased liver GH receptors. Am J Physiol Endocrinol Metab 276: 565–572
Van den Berghe G et al. (1997) The somatotropic axis in critical illness: effect of continuous growth hormone (GH)-releasing hormone and GH-releasing peptide-2 infusion. J Clin Endocrinol Metab 82: 590–599
Van den Berghe G et al. (1998) Neuroendocrinology of prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone secretagogues. J Clin Endocrinol Metab 83: 309–319
Van den Berghe G et al. (1999) Reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormone in patients with protracted critical illness. J Clin Endocrinol Metab 84: 1311–1323
Yen PM (2001) Physiological and molecular basis of thyroid hormone action. Physiol Rev 81: 1097–1142
Bianco AC et al. (2002) Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23: 38–89
Friesema ECH et al. (2005) Thyroid hormone transporters. Biochem Soc Trans 33: 228–232
Michalaki M et al. (2001) Dissociation of the early decline in serum T3 concentration and serum IL-6 rise and TNFα in nonthyroidal illness syndrome induced by abdominal surgery. J Clin Endocrinol Metab 86: 4198–4205
Van den Berghe G (2000) Novel insights into the endocrinology of critical illness. Eur J Endocrinol 143: 1–13
Romijn JA and Wiersinga WM (1990) Decreased nocturnal surge of thyrotropin in nonthyroidal illness. J Clin Endocrinol Metab 70: 35–42
van der Poll T et al. (1995) Interleukin-1 receptor blockade does not affect endotoxin-induced changes in plasma thyroid hormone and thyrotropin concentrations in man. J Clin Endocrinol Metab 80: 1341–1346
Lim CF et al. (1993) Inhibition of thyroxine transport into cultured rat hepatocytes by serum of nonuremic critically ill patients: effects of bilirubin and nonesterified fatty acids. J Clin Endocrinol Metab 76: 1165–1172
Gardner DF et al. (1979) Effect of triiodothyronine replacement on the metabolic and pituitary responses to starvation. N Engl J Med 300: 579–584
De Groot LJ (1999) Dangerous dogmas in medicine: the nonthyroidal illness syndrome. J Clin Endocrinol Metab 84: 151–164
Van den Berghe G et al. (1997) Thyrotrophin and prolactin release in prolonged critical illness: dynamics of spontaneous secretion and effects of growth hormone-secretagogues. Clin Endocrinol (Oxf) 47: 599–612
Fliers E et al. (1997) Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with non-thyroidal illness. J Clin Endocrinol Metab 82: 4032–4036
Van den Berghe G et al. (1994) Dopamine and the euthyroid sick syndrome in critical illness. Clin Endocrinol (Oxf) 41: 731–737
Faglia G et al. (1973) Reduced plasma thyrotropin response to thyrotropin releasing hormone after dexamethasone adminstration in normal subjects. Horm Metab Res 5: 289–292
Peeters RP et al. (2003) Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab 88: 3202–3211
Peeters RP et al. (2005) Serum rT3 and T3/rT3 are prognostic markers in critically ill patients and are associated with post-mortem tissue deiodinase activities. J Clin Endocrinol Metab 90: 4559–4565
Weekers F et al. (2004) Endocrine and metabolic effects of growth hormone (GH) compared with GH-releasing peptide, thyrotropin-releasing hormone, and insulin infusion in a rabbit model of prolonged critical illness. Endocrinology 145: 205–213
Debaveye Y et al. (2005) Tissue deiodinase activity during prolonged critical illness: effects of exogenous thyrotropin releasing hormone and its combination with growth hormone releasing peptide-2. Endocrinology 146: 5604–5611
Spratt DI (2001) Altered steroidogenesis in critical illness: is treatment with anabolic steroids indicated? Best Pract Res Clin Endocrinol Metab 15: 479–494
Wang C et al. (1978) Effect of surgical stress on pituitary–testicular function. Clin Endocrinol (Oxf) 9: 255–266
Wang C et al. (1978) Effect of acute myocardial infarction on pituitary–testicular function. Clin Endocrinol (Oxf) 9: 249–253
Dong Q et al. (1992) Circulating immunoreactive inhibin and testosterone levels in men with critical illness. Clin Endocrinol (Oxf) 36: 399–404
Rivier C and Vale W (1989) In the rat, interleukin-1α acts at the level of the brain and the gonads to interfere with gonadotropin and sex steroid secretion. Endocrinology 124: 2105–2109
Guo H et al. (1990) Interleukin-2 is a potent inhibitor of Leydig cell steroidogenesis. Endocrinology 127: 1234–1239
Vogel AV et al. (1985) Pituitary–testicular axis dysfunction in burned men. J Clin Endocrinol Metab 60: 658–665
Woolf PD et al. (1985) Transient hypogonadotropic hypogonadism caused by critical illness. J Clin Endocrinol Metab 60: 444–450
Van den Berghe G et al. (1994) Luteinizing hormone secretion and hypoandrogenemia in critically ill men: effect of dopamine. Clin Endocrinol (Oxf) 41: 563–569
Van den Berghe G et al. (2001) Five-day pulsatile gonadotropin-releasing hormone administration unveils combined hypothalamic–pituitary–gonadal defects underlying profound hypoandrogenism in men with prolonged critical illness. J Clin Endocrinol Metab 86: 3217–3226
Cicero TJ et al. (1975) Function of the male sex organs in heroin and methadone users. N Engl J Med 292: 882–887
Ben-Jonathan N (1985) Dopamine: a prolactin-inhibiting hormone. Endocr Rev 6: 564–589
Noel GL et al. (1972) Human prolactin and growth hormone release during surgery and other conditions of stress. J Clin Endocrinol Metab 35: 840–851
Meakins JL et al. (1977) Delayed hypersensitivity: indicator of acquired failure of host defenses in sepsis and trauma. Ann Surg 186: 241–250
Devins SS et al. (1992) Effects of dopamine on T-lymphocyte proliferative responses and serum prolactin concentrations in critically ill patients. Crit Care Med 20: 1644–1649
Cooper MS and Stewart PM (2003) Corticosteroid insufficiency in acutely ill patients. N Engl J Med 348: 727–734
Rivier C and Vale W (1983) Modulation of stress-induced ACTH release by corticotropin-releasing factor, catecholamines and vasopressin. Nature 305: 325–327
Marik PE and Zaloga GP (2002) Adrenal insufficiency in the critically ill. A new look at an old problem. Chest 122: 1784–1796
Pemberton PA et al. (1988) Hormone binding globulins undergo serpin conformational change in inflammation. Nature 336: 257–258
Hammond GL et al. (1990) A role for corticosteroid-binding globulin in delivery of cortisol to activated neutrophils. J Clin Endocrinol Metab 71: 34–39
Beishuizen A et al. (2001) Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma. Intensive Care Med 27: 1584–1591
Hamrahian AH et al. (2004) Measurements of serum free cortisol in critically ill patients. N Engl J Med 350: 1629–1638
Finlay WEI and McKee JI (1982) Serum cortisol levels in severely stressed patients. Lancet 1: 1414–1415
Rothwell PM et al. (1991) Cortisol response to corticotropin and survival in septic shock. Lancet 337: 582–583
Span LFR et al. (1992) Adrenocortical function: an indicator of severity of disease and survival in chronic critically ill patients. Intensive Care Med 18: 93–96
Annane D et al. (2000) A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 283: 1038–1045
Annane D et al. (2002) Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288: 862–871
Sam S et al. (2004) Cortisol levels and mortality in severe sepsis. Clin Endocrinol (Oxf) 60: 29–35
Bornstein SR and Chrousos GP (1999) Adrenocorticotropin (ACTH)- and non-ACTH-mediated regulation of the adrenal cortex: neural and immune inputs. J Clin Endocrinol Metab 84: 1729–1736
Vermes I and Beishuizen A (2001) The hypothalamic–pituitary–adrenal response to critical illness. Best Pract Res Clin Endocrinol Metab 15: 495–511
Barquist E and Kirton O (1997) Adrenal insufficiency in the surgical intensive care unit patient. J Trauma 42: 27–31
den Ouden DT and Meinders AE (2005) Vasopressin: physiology and clinical use in patients with vasodilatory shock: a review. Neth J Med 63: 4–13
Boldt J et al. (1996) Influence of different volume therapy regimens on regulators of the circulation in the critically ill. Br J Anaesth 77: 480–487
Viquerat CE et al. (1985) Endogenous catecholamine levels in chronic heart failure. Relation to the severity of hemodynamic abnormalities. Am J Med 78: 455–460
Russell-Jones DL et al. (1994) Use of a leucine clamp to demonstrate that IGF-I actively stimulates protein synthesis in normal humans. Am J Physiol Endocrinol Metab 267: 591–598
Minneci PC et al. (2004) Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 141: 47–56
Stathatos N et al. (2001) The controversy of the treatment of critically ill patients with thyroid hormone. Best Pract Res Clin Endocrinol Metab 15: 465–478
Ferrando AA et al. (2001) Testosterone administration in severe burns ameliorates muscle catabolism. Crit Care Med 29: 1936–1942
Angele MK et al. (1998) Testosterone: the culprit for producing splenocyte immune depression after trauma hemorrhage. Am J Physiol Cell Physiol 274: 1530–1536
Holmes CL (2005) Vasoactive drugs in the intensive care unit. Curr Opin Crit Care 11: 413–417
Van den Berghe G et al. (2002) The combined administration of GH-releasing peptide-2 (GHRP-2), TRH and GnRH to men with prolonged critical illness evokes superior endocrine and metabolic effects compared to treatment with GHRP-2 alone. Clin Endocrinol (Oxf) 56: 655–669
Vanhorebeek I et al. (2005) Glycemic and nonglycemic effects of insulin: how do they contribute to a better outcome of critical illness? Curr Opin Crit Care 11: 304–311
Van den Berghe G et al. (2001) Intensive insulin therapy in critically ill patients. N Engl J Med 345: 1359–1367
Van den Berghe G et al. (2005) Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology 64: 1348–1353
Van den Berghe G et al. (2003) Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 31: 359–366
Van den Berghe G (2004) How does blood glucose control with insulin save lives in intensive care? J Clin Invest 114: 1187–1195
Acknowledgements
The work was supported by research grants from the Catholic University of Leuven (OT/03/56) and the Fund for Scientific Research (FWO), Flanders, Belgium (G.0278.03). Ilse Vanhorebeek and Lies Langouche are Postdoctoral Fellows of the FWO, Flanders, Belgium.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
G Van den Berghe holds an unrestrictive Catholic University of Leuven Novo Nordisk Chair of Research.
Rights and permissions
About this article
Cite this article
Vanhorebeek, I., Langouche, L. & Van den Berghe, G. Endocrine aspects of acute and prolonged critical illness. Nat Rev Endocrinol 2, 20–31 (2006). https://doi.org/10.1038/ncpendmet0071
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ncpendmet0071
This article is cited by
-
Identification of the toxic threshold of 3-hydroxybutyrate-sodium supplementation in septic mice
BMC Pharmacology and Toxicology (2021)
-
Low testosterone predicts hypoxemic respiratory insufficiency and mortality in patients with COVID-19 disease: another piece in the COVID puzzle
Journal of Endocrinological Investigation (2021)
-
Proliferation and differentiation of adipose tissue in prolonged lean and obese critically ill patients
Intensive Care Medicine Experimental (2017)
-
Effect of vitamin D3 on bone turnover markers in critical illness: post hoc analysis from the VITdAL-ICU study
Osteoporosis International (2017)
-
Recent advances in the pathophysiology and management of protein-energy wasting in chronic kidney disease
Renal Replacement Therapy (2016)