Invited reviewThe potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders
Introduction
In recent years, a novel and paradox phenomenon has emerged from neurobiological studies on the effects of stress. There is increasing evidence for a relatively decreased, rather than an increased cortisol secretion in individuals who have been exposed to severe stress or suffer from stress-related disorders. The phenomenon of hypocortisolism has received growing attention in the field of stress research, inasmuch as it challenges, or virtually reverses, prevailing concepts on the neuroendocrinology of stress.
Ever since the seminal studies by Selye (1936), stress has been associated with activation of the hypothalamic–pituitary–adrenal (HPA) axis, ultimately resulting in an increased secretion of cortisol from the adrenal glands. The physiological effects of cortisol help the organism to maintain homeostasis under conditions of stress. The association between stress and increased cortisol secretion has been consolidated over the past decades to such an extent that stress and increased cortisol secretion merely have become synonyms in the literature and, moreover, the presence of cortisol hypersecretion has been used to define states of stress.
In a remarkable series of studies, however, Yehuda and her colleagues have most prominently described the phenomenon of hypocortisolism for patients who have experienced a traumatic event and subsequently developed post-traumatic stress disorder (PTSD; DSM-IV 309.81; for review see Yehuda, 1997). In the face of these striking observations, earlier studies from the 1960s and 1970s have regained consideration. These studies revealed hypocortisolism in healthy individuals who lived under conditions of ongoing stress (Friedman et al., 1963, Bourne et al., 1967, Bourne et al., 1968, Mason et al., 1968, Caplan et al., 1979). More recently, hypocortisolism has also been reported for patients suffering from bodily disorders, such as burnout with physical complaints, chronic fatigue syndrome, fibromyalgia, chronic pelvic pain and asthma among others (Hellhammer, 1990, Demitrack et al., 1991, Crofford et al., 1994, Kruger and Spiecker, 1994, Heim et al., 1998a). Taken together, these findings suggest that hypocortisolism is not a specific correlate of PTSD, but may be a more widespread phenomenon.
Another line of evidence suggests that the above bodily disorders may be related to chronic or traumatic stress as well as PTSD. For example, increased numbers of major life events and high rates of sexual or physical abuse have been reported for patients with fibromyalgia and other chronic pain syndromes (Ahles et al., 1984, Boisset-Pioro et al., 1995, Heim et al., 1998a). Similar associations have also been reported for patients with rheumatoid arthritis or asthma (Wallace, 1987, Boxer et al., 1988). Interestingly, high rates of comorbidity between PTSD and such physical disorders have been reported in several studies (Baker et al., 1982, Davidson et al., 1991, Culclasure et al., 1993, Amir et al., 1997, Iowa Persian Gulf Study Group, 1997, Heim et al., 1998a). These findings suggest that these disorders may represent a family of stress-related disorders with similar psychological antecedents and endocrine features, namely hypocortisolism.
The mechanisms involved in the development of hypocortisolism have received limited attention to date and, as yet, are a matter of speculation. Alterations on several levels of the HPA axis may contribute to the presence of hypocortisolism and, in addition, many factors, such as genetics, gender or early stress experiences among others, may determine the development of hypocortisolism. To complicate the picture, mechanisms and determining factors may vary across and within patient populations. Based on experimental data and theoretical considerations, several authors have posited theories on the development and the physiological meaning of hypocortisolism (Dienstbier, 1989, Hellhammer and Wade, 1993, Henry, 1993, Yehuda et al., 1993b, McEwen, 1998).
The findings of hypocortisolism in bodily disorders have led us to posit the following hypothesis: Hypocortisolism may be a relevant factor in the pathogenesis of bodily disorders, inasmuch as a lack of cortisol availability may promote an increased vulnerability to bodily disorders, such as autoimmune disorders, inflammation, chronic pain, asthma and allergies. In the following pages, we outline findings of hypocortisolism in PTSD, in stress-related bodily disorders as well as for chronic stress. Hypocortisolism refers to a deficiency of cortisol, including: (a) reduced adrenocortical secretion, at least temporarily during the circadian cycle; (b) reduced adrenocortical reactivity; or (c) enhanced negative feedback inhibition of the HPA axis. Furthermore, reduced effects of cortisol on target cells may occur due to an increased clearance or binding of cortisol as well as due to a reduced sensitivity of target cells for cortisol. The concept of hypocortisolism has not yet been sufficiently elaborated. We here summarize some of the available findings and we further discuss potential mechanisms underlying the phenomenon of hypocortisolism and theoretical concepts on the meaning of hypocortisolism that have been suggested in the literature. Finally, we elaborate on implications of hypocortisolism for immune function and disease vulnerability. The overall goal of this article is to provide an integrated overview of current knowledge and speculations on the phenomenon of hypocortisolism and to propose a medical hypothesis, which may form an important basis for future research.
Section snippets
HPA axis abnormalities in post-traumatic stress disorder
Since PTSD is a sequel of extreme stress experience and often coincides with major depression, it has been investigated whether patients with PTSD demonstrate specific alterations of the HPA axis (Yehuda et al., 1991a). Initial studies revealed decreased 24 h-urinary cortisol excretion in Vietnam veterans suffering from PTSD as compared to healthy controls and patients with other psychiatric disorders (Mason et al., 1986, Yehuda et al., 1990, Yehuda et al., 1993a). Decreased 24 h-urinary
Hypocortisolism in stress-related bodily disorders
The phenomenon of hypocortisolism, however, has not only been reported for patients with PTSD, but was also observed in patients with several bodily disorders, many of which have been related to stress experience in general as well as, more recently, to trauma and PTSD.
In an initial study, our group observed decreased basal salivary cortisol levels in the morning along with relatively high cortisol levels in the afternoon and evening in a group of nurses who suffered from burnout and multiple
Hypocortisolism in chronic stress
Hypocortisolism, however, does not seem to be an exclusive correlate of stress-related pathology, but has also been reported for healthy subjects living under ongoing stress as well as for some animal models of chronic stress. There are a small number of studies in humans suggesting reduced adrenocortical activity or reactivity in states of chronic stress. Friedman et al. (1963) measured urinary excretion of the cortisol metabolite, 17-hydroxycorticosterone (17-OHCS), over several months in
Potential mechanisms and determinants of hypocortisolism
Several mechanisms may underlie the development and persistence of hypocortisolism. Among potential mechanisms of hypocortisolism are: (1) reduced biosynthesis or depletion at several levels of the HPA axis (CRF, ACTH, cortisol); (2) CRF hypersecretion and adaptive down-regulation of pituitary CRF receptors; (3) increased feedback sensitivity of the HPA axis; and (4) morphological changes. Besides these basic mechanisms, superimposed factors, such as the nature of the stressor, coping styles,
Theoretical concepts of hypocortisolism
Few authors have formulated theoretical concepts regarding the phenomenon of hypocortisolism. In these concepts, the above mechanisms and determinants have been differentially combined or emphasized, and diverse ideas on the physiological meaning of adrenal hypoactivity have been suggested.
Henry (1993) conceptualizes hypocortisolism in the context of variables that have been generally associated with the stress response, including ego involvement, perceived control, and active coping. He
Implications of hypocortisolism for disease vulnerability
Traumatic or chronic stress may promote a specific dysfunction of the HPA axis, characterized by decreased adrenal activity. Several, maybe differential, mechanisms may be involved on higher levels of the axis, and central CRF secretion could be increased or decreased. Based on the physiological effects of these hormones, we suggest that the HPA axis dysfunction promoted by traumatic or chronic stress may have important implications for the vulnerability to develop stress-related bodily
The role of glucocorticoid receptors in mediating the effects of hypocortisolism on target cells
The protective effects of cortisol on metabolism and immune function are mediated by binding of the hormone to specific receptor proteins in target cells. According to the prevailing model of adrenal steroid action, the unbound GR, which resides in the cytoplasm, undergoes a conformational change when bound to steroid and translocates to the nucleus of the cell to affect gene transcription. The GR proteins may adapt in number and affinity to changes in physiological conditions. For example,
Conclusion and future directions
In the face of the seminal findings in patients with PTSD, the phenomenon of hypocortisolism has gained considerable attention over the past decade. However, many aspects regarding the specificity, development and physiological meaning of phenomenon of hypocortisolism remain unexplored. The present work brings together findings of basic and clinical research addressing these issues. Based on these findings, we draw the following conclusions:
- 1.
Hypocortisolism is not a specific correlate of PTSD.
- 2.
Acknowledgements
The authors gratefully thank Dr. Bruce McEwen for reviewing an early version of this manuscript and for providing numerous stimulating and encouraging comments. This work was supported by grants of the Deutsche Forschungsgemeinschaft He 2561/2-1 and He 1013/13-1 and 2.
References (210)
- et al.
Posttraumatic Stess Disorder, tenderness, and fibromyalgia
J. Psychosom. Res.
(1997) - et al.
Neuroendocrine responses to d-fenfluramine and insulin-onduced hypoglycemia in chronic fatigue syndrome
Biol. Psychiatry
(1995) - et al.
Neglect contributing to tertiary hospitalization in childhood asthma
Child Abuse Negl.
(1988) - et al.
White collar work load and cortisol: disruption of a circadian rhythm by job stress?
J. Psychosom. Res.
(1979) - et al.
Progeny of mothers drinking corticosterone during lactation has lower stress-induced corticosterone secretion and better cognitive performance
Brain Res.
(1993) - et al.
Low dose hydrocortisone in chronic fatigue syndrome: a randomized crossover trial
Lancet
(1999) - et al.
Alexithymia in somatoform disorder patients with chronic pain
J. Psychosom. Res.
(1994) - et al.
Posttraumatic stress disorder presenting as fibromyalgia
Am. J. Med.
(1993) - et al.
Repaeted stress enhances vasopression synthesis in corticotropin releasing factor neurons in the paraventricular nucleus
Brain Res.
(1992) - et al.
Stress response, adrenal steroid receptor levels and corticosteroid binding globulin levels—a comparison between Sprague-Dawley, Fischer 344 and Lewis rats
Brain Res.
(1993)
Acute stress enhances while chronic stress suppresses immune function in vivo: a potential role for leukocyte trafficking
Brain, Behav. Immun.
Hormonal changes in headache patients
J. Neurol. Sci.
Effects of hyperactivity of the maternal hypothalamic-pituitary-adrenal (HPA) axis during pregnancy on the development of the HPA axis and brain monoamiines in the offspring
Int. J. Dev. Neurosci.
The dexamethasone suppression test as a biologic marker of depression in chronic pain
Pain
Inhibition by cortisol of human natural killer (NK) cell activity
J. Steroid Biochem.
Single or repeated mild stress increases synthesis and release of hypothalamic corticotropin-releasing factor
Brain Res.
Prostacyclin enhances the evoked release of substance P and calcitonin gene related peptide from rat sensory neurons
Brain Res.
The effects of corticosteroids on the antigen presenting properties of human monocytes and endothelial cells
Clin. Immunol. Immunopathol.
ACTH, cortisol and corticosterone output after ovine corticotropin-releasing factor challenge during depression and after recovery
Biol. Psychiatry
The concept of affective spectrum disorder: releationship of fibromyalgia and other syndromes of chronic fatigue and chronic muscle pain
Bailliere’s Clin. Rheumatol.
The corticotropin-releasing hormone challenge in depressed abused, depressed nonabused, and normal control children
Biol. Psychiatry
Psychological factors associated with primary fibromyalgia syndrome
Arthritis Rheum.
Depressed concentrations of oxytocin and cortisol in children with recurrent abdominal pain of non-organic origin
Acta Paediatr.
Aspirin—now we can see it
Nat. Med.
Relationship between posttraumatic stress disorder and self-reported physical symptoms in Persian gulf war veterans
Arch. Intern. Med.
The immune hypothalamic pituitary adrenal axis
Endocr. Rev.
Control and intrusive memories as possible determinants of chronic stress
Psychosom. Med.
Eicosanoids in primary dysmenorrhea, endometriosis and menstrual migraine
Gynecol. Endocrinol.
Glucocorticoids induce the formation and release of anti-inflammatory and anti-phospholipase proteins into the peritoneal cavity of the rat
Br. J. Pharmacol.
Sexual and physical abuse in women with fibromyalgia syndrome
Arthritis Rheum.
Posttraumatic stress disorder, exposure to combat, and lower plasma cortisol among Vietnam veterans: Findings and clinical implications
J. Clin. Consult. Psychol.
17 OHCS levels in combat. Special forces ‘A’ team under threat of attack
Arch. Gen. Psychiatry
Urinary 17 OHCS levels. Data on seven helicopter ambulance medics in combat
Arch. Gen. Psychiatry
MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder
Am. J. Psychiatry
Elevated CSF corticotropin-releasing factor concentrations in PTSD
Am. J. Psychiatry
Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse—a preliminary report
Biol. Psychiatry
Childhood physical abuse and combat-related posttraumatic stress disorder in Vietnam veterans
Am. J. Psychiatry
Review of laboratory findings for patients with chronic fatigue syndrome
Rev. Infect. Dis.
Attenuated free cortisol response to psychosocial stress in children with atopic dermatitis
Psychosom. Med.
Pituitary-adrenal axis responsiveness to ovine corticotropin releasing hormone in patients with rheumatoid arthritis treated with low dose prednisone
J. Rheumatol.
Cortisol and immune interferon can interact in the modulation of human natural killer cell activity
Experimentia
Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis
Arthritis Rheum.
A double blind crossover trial of prednisone versus placebo in the treatment of fibrositis
J. Rheumatol.
Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early life stressors: Implications for the pathophysiology of mood and anxiety disorders
Proc. Natl. Acad. Sci. USA
Glucocorticoid resistance in chronic asthma. Glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitro
Am. Rev. Respir. Dis.
Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia
Arthritis Rheum.
A diagnostic and family study of posttraumatic stress disorder
Am. J. Psychiatry
Posttraumatic stress disorder in the community: an epidemiological study
Psychol. Med.
Hypothalamic pituitary adrenal axis dysregulation in sexually abused girls
J. Clin. Endocrinol. Metab.
Antinuclaer autoantibodies and thyroid function in sexually abused girls
J. Trauma. Stress
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