M. Christ-Crain¹

¹Dept. of Endocrinology, University Hospital Basel, Switzerland

Stress is an often used but bad defined term. It is either defined as resistance of an object against an effort or, in physiology, as a condition of disturbed balance or homeostasis. The first description of the term “stress” derives from Hans Selye who published three phases of “stress” in the Journal Nature 1936: 1) alarm phase, a reaction of our body to mobilize resources, 2) resistance phase, where our body tries to cope with the stressor and 3) exhaustion phase where reserves are depleted.
One important question is whether and how we can measure the stress response of our body.
One of the most classical and important stress hormones is cortisol which is produced under the stimulus of corticotrophin-releasing hormone (CRH) from the hypothalamus and adrenocorticotropin (ACTH) from the pituitary. Cortisol circulates in blood largely bound to corticosteroid-binding protein and albumin, with the much smaller amount of unbound hormone responsible for its metabolic effects. In general, it is assumed that the biologically active level of cortisol to which tissues are exposed is free cortisol. Routinely available assays of adrenal function measure serum total cortisol and not the biologically active free cortisol, but it is usually considered that total cortisol broadly correlates with the biologically free fraction. However, it has been shown that in critically ill patients there is a fall in binding proteins such that total cortisol levels no longer accurately reflect the free fraction, and this could potentially cause misdiagnosis of adrenal function. Serum total cortisol levels after major surgery approach the levels during the acute phase of septic shock. In this context, major surgery can serve as a standardized model for studying acute and major stress. Previous studies have also demonstrated that, under the most stressful conditions, total cortisol levels in response to major stress are mirrored by similar changes in the response to a pharmacological dose of ACTH. It has therefore been assumed that responsivity to the ACTH stimulation test will reflect the pituitary-adrenal response to surgery, trauma or other types of stress, and can be used as a surrogate to decide on the appropriateness of corticosteroid replacement therapy in surgery or acute illness. Our results, however, show that in major stress the relative increase in free cortisol is significantly more pronounced as compared to the increase in total cortisol. Furthermore, after ACTH stimulation, total cortisol levels increase to a similar extent as compared to major stress, whereas free cortisol levels in major stress increase to a significantly greater extent after surgical stress as compared to after ACTH stimulation. This suggests that the ACTH test does not adequately anticipate the free cortisol levels needed during severe stress.
Another less well known but equally important stress hormone is vasopressin. Vasopressin has important hemodynamic and osmoregulatory effects. During stress, vasopressin is a potent synergistic factor of CRH as a hypothalamic stimulator of the hypothalamo-pituitary-adrenal axis. Copeptin is co-synthesized with vasopressin, directly mirroring vasopressin levels, but is more stable in plasma and serum. Interestingly, copeptin levels show a more gradual increase with increasing stress levels as compared to cortisol. Copeptin levels mirror moderate stress even more subtly as compared to cortisol levels. Copeptin might thus provide a novel tool to mirror the individual stress level at the hypothalamic level.
Stress hormones have recently been shown to be useful predictors for outcome in different diseases. In lower respiratory tract infections, total and free cortisol levels as well as copeptin levels were better predictors of survival as compared to usually measured parameters like C-reactive protein, body temperature or leukocyte count. In patients with acute ischemic stroke, copeptin levels were independent predictors for 3 months outcome and were able to improve the prognostic accuracy of the clinical scoring systems. In this context, measurement of stress hormones might be useful for a better risk stratification of patients with various diseases.