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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 6 1842-1845
Copyright © 1998 by The Endocrine Society

Special Articles

A Healthy Body in a Healthy Mind—and Vice Versa—The Damaging Power of "Uncontrollable" Stress

George P. Chrousos and Philip W. Gold

National Institutes of Health Bethesda, Maryland 20892

Address correspondence and requests for reprints to: George P. Chrousos, M.D., NIH, Building 10, Room 10N262, 10 Center Drive MSC 1862, Bethesda, MD 20892-1862. E-mail: George_Chrousos{at}NIH.Gov


   Introduction
Top
 Introduction
References
 
The hypothalamic-pituitary-adrenal (HPA) axis together with the sympathetic system connect the brain with the periphery of the body (1) (Fig. 1Go). The central nervous system (CNS) centers of the HPA axis and the sympathetic system are, respectively, the parvicellular corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) neurons of the paraventricular nuclei of the hypothalamus and the noradrenergic neurons of the locus ceruleus/norepinephrine (LC/NE) nuclei of the brain stem. These neuronal centers innervate and stimulate each other and have both a baseline circadian and stress-related activity. The CRH/AVP and LC/NE neurons and their peripheral axes are heuristically known as the stress system. The secretion of the end-product of the HPA axis, cortisol, is kept by an elaborate negative feedback system within an optimal time-integrated narrow range, which is quite stable in an individual subject. That the body would have such a tightly regulated servo-control system suggests that excessive, unchecked activity could be detrimental to the organism.



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  		Figure 1. A schematic representation of the stress system. The CRH/AVP neurons are reciprocally connected with the noradrenergic neurons of the LC/NE system in a positive reverberatory circuit. The HPA axis is controlled by several negative feedback loops, which tend to normalize the time-integrated secretion of cortisol, yet glucocorticoids stimulate the amygdala and, hence, the fear center. Activation of the HPA axis leads to suppression of the GH/IGF-1, LH/testosterone/estradiol, and TSH/T3 axes; activation of the sympathetic system increases IL-6 secretion. Chronic increases in cortisol, catecholamines, and IL-6 and chronic suppression of the GH/IGF-1, LH/T and TSH/T3 axes lead to visceral obesity, hypertension, atherosclerosis, osteoporosis, and immune dysfunction and their sequelae resulting in increased morbidity and mortality. Symbols: Solid lines indicate stimulation; interrupted lines indicate inhibition. Abbreviations: HPA, hypothalamic-pituitary-adrenal; CRH, corticotropin-releasing hormone; AVP, arginine-vasopressin; LC/NE, locus ceruleus/norepinephrine system; GH, growth hormone; IGF-1, insulin-like growth factor-1; LH, luteinizing hormone; T, testosterone; TSH, thyrotropin; T3, triiodothyronine; F, cortisol; NE, norepinephrine; E, epinephrine; IL-6, interleukin-6.

 
Indeed, excessive and sustained cortisol secretion or chronic pharmacologic doses of glucocorticoids (endogenous or exogenous Cushing syndrome, respectively) have been long associated with depression, hypertension, osteoporosis, immunosuppression and the entire spectrum of metabolic syndrome X, including visceral obesity, insulin resistance, dyslipidemia, dyscoagulation, and hypertension, along with their morbid sequelae of atherosclerosis and cardiovascular disease (2, 3) (Fig. 1Go, Table 1Go). Each and every one of these manifestations could in theory be produced, despite the presence of normal, nonhyperfunctioning HPA axis, by tissue-specific hypersensitivity to glucocorticoids of, respectively, the amygdala or mesocorticolimbic system, cardiovascular system, bone, immune system, or adipose tissue (4, 5). The papers by Rosmond et al. (6) and Panarelli et al. (7) in this issue of JCEM (see pages 1853 and 1846) represent pioneering attempts to respectively define whether normal life stress-related hypersecretion of cortisol or tissue-limited hypersensitivity to glucocorticoids could affect important physiologic parameters, such as systemic blood pressure, or functions, such as carbohydrate and lipid metabolism, with potential deleterious effects on the organism in the long-term.


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  		Table 1. Physiologic/somatic consequences of chronic stress system activation/target tissue effects

 
After the seminal discovery of CRH in the early 80’s and following a series of studies in experimental animals and patients with melancholic depression, we described the marked clinical, physiologic, and biochemical similarities between acute stress and the melancholic depression syndrome (8, 9). Both conditions are indeed associated with a hyperactive HPA axis and LC/NE system and, hence, with increased CRH, cortisol, and catecholamine secretion, plus consequent inhibition of the growth, thyroid, and reproductive axes, suppression of the immune system, and elevation of catecholamine-stimulated interleukin-6 (IL-6) concentrations (10). In the case of melancholic depression, the hyperactivity of the stress system can be chronic or in repeated bouts, which could potentially produce the long-term consequences of Cushing syndrome (Fig. 1Go, Table 1Go). Indeed, we recently demonstrated that earlier history of melancholic depression was associated with marked osteoporosis in premenopausal women carefully matched for body mass index (BMI) to premenopausal controls (11). Furthermore, patients with depressive symptomatology, including properly diagnosed melancholic depression, have a markedly decreased life expectancy due to increased mortality from primarily cardiovascular causes (relative risk 2–3 over gender- and age-matched controls) (12, 13, 14). Although only 10–15% of the adult population may fulfill the criteria for major depression, it is quite likely that there is a continuum of depressive symptomatology, with only the upper cut of patients qualifying as melancholics.

Rosmond et al. (6) examined a large unselected population of 53-yr-old men by obtaining a detailed history, by performing physical examinations—including anthropometric measurements, by obtaining a series of diurnal salivary cortisol determinations in parallel with an acceptable measure of stress perception, and by performing a low-dose overnight dexamethasone suppression test. They analyzed the results in a complex, yet quite logical fashion, which revealed that the increases in blood pressure and body mass index, earlier seen in Cushing syndrome as a result of hypercortisolism, could also be seen in a general population of nonCushingoid middle-aged men in correlation with the degree of stress perception and stress-related cortisol secretion.

A crucial observation was made upon the initial analysis of data, modeled and extended in Fig. 2AGo. A nonstressed HPA axis was characterized by increased variance, mostly due to a wide circadian variation, with distant morning zeniths and evening nadirs, a discrete but small lunch-induced cortisol peak and an appropriate suppression of the morning cortisol levels in response to low-dose dexamethasone; a chronically stressed HPA axis, on the other hand, was characterized by a decreased variance mostly due to evening nadir elevations and morning zenith decreases, a large lunch-induced cortisol response and an inadequate suppression of morning cortisol by overnight dexamethasone. These findings suggest chronic hypersecretion of CRH in chronically stressed individuals and a reset of their HPA axis as previously suggested. How about the total time-integrated cortisol secretion? Is it not important? We are sure that it is; however, in the presence of a properly functioning glucocorticoid negative feedback system, around-the-clock cortisol secretion would be minimized to the greatest extent and, hence, would be less indicative of a chronically stressed HPA axis than the other features suggested by Rosmond et al.



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  		Figure 2. A, (Left) Circadian pattern of cortisol secretion in nonstressed (NS, —) and chronically stressed (CS, .....), individuals. Note the blunting of the circadian rhythm in the latter, along with an augmented cortisol elevation in response to lunch. (Right) Cortisol response to a low dose of overnight dexamethasone (D). Note the increased suppressibility of nonstressed individuals vs. chronically stressed subjects. B, Dose-response curves of target tissue responses to cortisol: N, normal; HS, hypersensitive; R, resistant. The interrupted horizontal line represents a threshold effect beyond which long-term harm is done (Fig. 1Go, Table 1Go). Depending on the shift of the dose response curve to the left or right one would expect harmful or protective effects.

 
The ability of the glucocorticoid negative feedback system to limit the production of cortisol during stress can be impaired by chronic emotional or physical stress and by old age (15, 16, 17). Glucocorticoid-induced hippocampal neuron damage and deficient transmission of suprahypothalamic negative feedback has been proposed as a major mechanism mediating this phenomenon (18) (Fig. 1Go, Table 1Go). Indeed, in patients with melancholic depression, the 24-h urinary free cortisol excretion increases with age, while studies of the HPA axis in aging populations that include persons with chronic emotional or physical diseases have shown progressive elevations of evening plasma cortisol concentrations with age.

But can an altered daily cortisol secretion variance result in the somatic sequelae of chronic hypercortisolism? Despite the attempt of the brain to correct for the evening excess cortisol production by suppressing the morning cortisol surge, it is possible that no complete such correction is attained, and the body tissues are overexposed to cortisol. On the other hand, blunting of the circadian rhythm could result in evening exposure to cortisol, which could be detrimental on its own, in spite of an adequate correction of time-integrated cortisol secretion. We recently reported an adult man with Carney complex treated in childhood with unilateral adrenalectomy (19). Although his 24-h urinary free cortisol excretion remained normal for many years, he developed severe osteoporosis, possibly as a result of constant exposure of his bones to "normal" levels of plasma cortisol. The most impressive data of the Rosmond study (6) are those described in their Table 5, in which they correlate stress-related cortisol secretion ({delta}i) corrected for the inverse of the daily variance (vi) ({omega}=1÷vi) to amplify the effect of the low variance observed in chronically stressed subjects. One can see all the correlations one would have expected from the scheme in Fig. 1Go and the effects outlined in Table 1Go.

Panarelli et al. (7) studied a smaller group of younger males, ages 18–40 y. They focused their studies on a previously described polymorphism of the glucocorticoid receptor, which was earlier associated with hypertension and visceral obesity (20, 21). This polymorphism was associated with an increased blanching skin reaction to butesonide, but not with systemic blood pressure, plasma biochemistries known to be affected by glucocorticoids (Table 1Go), the affinity or concentration of glucocorticoid receptors in cultured leukocytes, or the dexamethasone-induced inhibition of lysozyme production by cultured leukocytes in vitro. Thus, these authors found one hypersensitive dose-response curve to glucocorticoids-skin vasoconstriction—but not others (Fig. 2BGo). Why—or why not? The finding of the correlation between an undefined noncoding polymorphism of the glucocorticoid receptor gene and a hypersensitive curve is proof that tissue-limited hypersensitivity to glucocorticoids, or its mirror image glucocorticoid resistance, do exist, as theoretically hypothesized (4). Huizenga et al. (22) recently demonstrated in this journal that another polymorphism of the glucocorticoid receptor, which we described, tested, and found not to have an effect on function of the receptor in vitro (23), was present in 6% of normal Dutch men and was associated with a significantly greater cortisol suppression by dexamethasone, a higher BMI and a lower bone mineral density (BMD) in polymorphism carriers than in noncarriers. These findings are compatible with hypersensitivity of the hippocampus, adipose tissue, and bone to glucocorticoids in the carriers. Finally, experimental expression of increased levels of glucocorticoid receptors in the pancreatic ß-cells of transgenic mice caused defective insulin secretion and carbohydrate intolerance (24). A similarly defective insulin secretion has been observed in patients with Cushing syndrome as well (3). Our opinion is that, within the human population, there is variation in target-gene-specific responsiveness to glucocorticoids, which is the result of not only mutations in the gene of the glucocorticoid receptor, but also in genes that are involved in the glucocorticoid signal transduction pathway, including cortisol metabolizing enzymes, heat shock proteins, coactivators/corepressors, etc (5). These normal variations could be harmful or protective, depending on the gene and the direction of the variation.

In summary, the studies of Rosmond et al. (6) and Panarelli et al. (7) have addressed two prongs of a highly complex, multifactorial, polygenically determined, developmental, and environmentally-dependent phenomenon of major importance to medicine and society. The complex picture of this phenomenon has been unraveling since the fields of stress and depression coalesced, to give us a clear biological view of this huge area, with the potential to intervene rationally to both prevent and treat (8, 9). Now the appropriate changes of lifestyle will be based on solid biomedical evidence, and the treatment of emotional disorders will also be therapy for devastating organic diseases. A healthy mind will define a healthy body, and vice versa.

Received March 17, 1998.

Accepted March 23, 1998.


   References
Top
 Introduction
 References
 

  1. Chrousos GP, Gold PW. 1992 The concepts of stress and stress system disorders: Overview of physical and behavioral homeostasis. JAMA. 267:1244–1252.[Abstract]
  2. Tsigos C, Chrousos GP. 1996 Differential diagnosis and management of Cushing’s syndrome. Ann Rev Med. 47:443–461.[CrossRef][Medline]
  3. Friedman TC, Mastorakos G, Newman TD, et al. 1996 Carbohydrate and lipid metabolism in endogenous hypercortisolism: shared features with metabolic syndrome X and noninsulin-dependent diabetes mellitus. Endocr J. 43:645–656.[Medline]
  4. Chrousos GP, Detera-Wadleigh S, Karl M. 1993 Syndromes of glucocorticoid resistance. Ann Intern Med. 119:1113–1124.[Abstract/Free Full Text]
  5. Bamberger CM, Schulte HM, Chrousos GP. 1996 Molecular determinants of glucocorticoid receptor function and tissue sensitivity. Endo Rev. 17:221–244.[CrossRef][Medline]
  6. Rosmond R, Dallman MF, Björntorp P. 1998 Stress-related cortisol secretion in men: Relationships with abdominal obesity, endocrine, metabolic and hemodynamic abnormalities. J Clin Endocrinol Metab. 83:1853–1859.[Abstract/Free Full Text]
  7. Panarelli M, Holloway CD, Fraser F, McConnell J, Ingram MC, Anderson NH, Kenyon CJ. 1998 Glucocorticoid receptor polymorphism, skin vasoconstriction and other metabolic intermediate phenotypes in normal human subjects. J Clin Endocrinol Metab. 83:1846–1852.[Abstract/Free Full Text]
  8. Gold PW, Goodwin FK, Chrousos GP. 1988 Clinical and biomedical manifestations of depression: Relationship to the neurobiology of stress (Part I). N Engl J Med. 319:348–353.[Medline]
  9. Gold PW, Goodwin FK, Chrousos GP. 1988 Clinical and biomedical manifestations of depression: Relationship to the neurobiology of stress (Part II). N Engl J Med. 319:413–420.[Abstract]
  10. Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. 1998 The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med. 128:127–137.[Abstract/Free Full Text]
  11. Michelson D, Stratakis C, Hill LY, Reynolds J, Galliven E, Chrousos GP, Gold PW. 1996 Bone mineral density is decreased in women with depression. N Engl J Med. 335:1176–1181.[Abstract/Free Full Text]
  12. Barefoot JC, Scholl MD. 1993 Symptoms of depression, acute myocardial infarction, and total mortality in a community sample. ACP J Club 93:1976–1980.
  13. Anda R, Williamson D, Jones C, et al. 1993 Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of U.S. adults. Epidemiology. 4:285–294.[Medline]
  14. Silverstone PH. 1990 Depression increases mortality and morbidity in acute life-threatening medical illness. J Psychosom Res. 34:651–657.[CrossRef][Medline]
  15. Halbreich U, Asnis GM, Zumoff B, Nathan RS, Shindledecker R. 1984 Effects of age and sex on cortisol secretion in depressives and normals. Psychiatry Res. 13:221–229.[CrossRef][Medline]
  16. Kling MA, Roy A, Doran AR, et al. 1991 Cerebrospinal fluid immunoreactive corticotropin-releasing hormone and adrenocorticotropin secretion in Cushing’s disease and major depression: Potential clinical implications. J Clin Endocrinol Metab. 72:260–271.[Abstract]
  17. Van Cauter E, Leproult R, Kupfer DJ. 1996 Effects of gender and age on the levels of circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab. 81:2468–2473.[Abstract]
  18. McEwen BS. Protective and damaging effects of stress mediators. 1998 N Engl J Med. 338:171–179.[Free Full Text]
  19. Sarlis NJ, Chrousos GP, Doppman JL, Carney JA, Stratakis CA. 1997 Primary pigmented nodular adrenocortical disease: Reevaluation of a patient with Carney Complex 27 years after unilateral adrenalectomy. J Clin Endocrinol Metab. 82:1274–1278.
  20. Watt GCM, Harrap SB, Roy CJW, Holton DW, Edwards HW, Davidson HR, Connor JM, Lever AF, Fraser R. 1992 Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: A four corners approach to the identification of the genetic determinants of blood pressure. J Hypertension 10:473–482.
  21. Weaver JU, Hitman GA, Kopelman PG. 1992 An association between B11 restriction fragment length polymorphism of the glucocorticoid receptor locus and hyperinsulinemia in obese women. J Mol Endocrinol. 9:295–300.[Abstract]
  22. Huizenga NATM, Koper JW, De Lange P, Pols HAP, Stolk RP, Burger H, Grobbee DE, Brinkman AO, De Jong FH, Lamberts SWJ. 1998 A polymorphism in the glucocorticoid receptor gene may be associated with an increased sensitivity to glucocorticoids in vivo. J Clin Endocrinol Metab. 83:144–151.[Abstract/Free Full Text]
  23. Karl M, Lamberts SW, Detera-Wadleigh S, Encio IJ, Stratakis CA, Hurley DM, Accili D, Chrousos GP. 1993 Familial glucocorticoid resistance caused by a splice site deletion in the human glucocorticoid receptor gene. J Clin Endocrinol Metab. 76;683–689.
  24. Delaunay F, Khan A, Cintra A, et al. 1997 Pancreatic ß cells are important targets for the diabetogenic effects of glucocorticoids. J Clin Invest. 100:2094–2098.[Medline]



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