Glucocorticoid action networks and complex psychiatric and/or somatic disorders

Abstract

Glucocorticoids contribute fundamentally to the maintenance of basal and stress-related homeostasis in all higher organisms. These hormones influence a large percentage of the expressed human genome and their effects spare almost no organs or tissues. Glucocorticoids influence many functions of the central nervous system, such as arousal, cognition, mood and sleep, the activity and direction of intermediary metabolism, the maintenance of a normal cardiovascular tone, the activity and quality of the immune and inflammatory reaction, including the manifestations of the sickness syndrome, as well as growth and reproduction. The numerous actions of glucocorticoids are mediated by a set of at least 16 glucocorticoid receptor (GR) isoforms forming homo- or hetero-dimers. The GRs consist of multifunctional domain proteins operating as ligand-dependent transcription factors that interact with many other cell signaling systems. The presence of multiple GR monomers and dimers expressed in a cell-specific fashion at different quantities with quantitatively and qualitatively different transcriptional activities suggests that the glucocorticoid signaling system is highly stochastic. Based on ample evidence, we present our conception that glucocorticoids are heavily involved in human pathophysiology and influence life expectancy. Common psychiatric and/or somatic complex disorders, such as anxiety, depression, insomnia, chronic pain and fatigue syndromes, obesity, the metabolic syndrome, essential hypertension, diabetes type 2, atherosclerosis with its cardiovascular sequelae, and osteoporosis, as well as autoimmune inflammatory and allergic disorders, all appear to have a glucocorticoid component.

• Chronic stress
• cortisol
• Cushing's syndrome
• hypothalamic–pituitary–adrenal axis
• inflammation
• insulin resistance

Introduction

Glucocorticoids are among the most pervasive hormones in mammalian organisms (Chrousos 2001; Franchimont et al. 2003). These steroid molecules reach all tissues, including the brain, readily penetrate the cell membrane, and interact with ubiquitous cytoplasmic/nuclear glucocorticoid receptors (GR), through which they exert markedly diverse actions. Using DNA microarray technology, we found that about 20 percent of the expressed human leukocyte genome was positively or negatively affected by glucocorticoids (Galon et al. 2002). This is many-fold higher than the proportion of genes that change in the transformation of a normal cell to a tumor cell and involves a broad array of functions, affecting every aspect of resting and stress-related homeostasis, as well as a large number of genes expressed by the immune system (Chrousos 1998; Galon et al. 2002). The pervasive nature of glucocorticoids, the rapid advances in our general knowledge of the human and other mammalian genomes, and the massive amount of information that increasingly accumulates, dictate a new model of thinking and testing of hypotheses regarding the actions of these hormones and their involvement in human physiology and pathophysiology.

Glucocorticoid receptor gene polymorphisms and complex human pathophysiology

Wust et al. (2004) recently reported a convincing association between the hypothalamic–pituitary–adrenal (HPA) axis response to a standardized socio–emotional stimulus (Trier test) and polymorphisms of the GR gene. This study followed others that used a similar rationale and examined HPA axis indices and other end-points, such as arterial blood pressure, body mass index (BMI) and markers of the metabolic syndrome, and bone mineral density (Weaver et al. 1992; Buemann et al. 1997; Huizenga et al. 1998; Panarelli et al. 1998; Lin et al. 1999; Rosmond et al. 2000; Dobson et al. 2001; Ukkola et al. 2001). These studies have in part overlapped and have produced mostly concordant results, but have also shown inconsistencies. This should have been expected because they were performed on a limited number of subjects in different ethnic populations, and because the altered GR would have been expected to function differently in the context of different genetic backgrounds characterized by different panels of genes with differing epistatic effects upon the ability of the GR to exert its actions (Chrousos 2000b).

Glucocorticoid effects—physiology, pathophysiology

Empirically, experimentally and intuitively, physicians and scientists have made major advances in the general understanding of glucocorticoids and their involvement in human physiology and pathophysiology, and in using these hormones extensively and effectively in the treatment of a wide spectrum of human diseases (Chrousos 2001; Franchimont et al. 2003). As the end product of the HPA axis, glucocorticoids are clearly involved in every organ system of the human organism, in almost every physiologic, cellular and molecular network, and in many crucial modules of these networks (Chrousos 2000b; Galon et al. 2002; Franchimont et al. 2003). Glucocorticoids, furthermore, participate in a pivotal fashion in the unfolding of vital biological programs employing several networks synchronously or in tandem, including the behavioral and physical response to stress, the inflammatory reaction and the consequent “sickness syndrome”, i.e. the collections of “nonspecific symptoms” caused by excessive inflammatory cytokines during infectious or inflammatory illness, as well as the process of sleep, and long-term functions, such as growth and reproduction (Chrousos 1998, 2000b).

As happens with many other homeostatic systems, too much, as well as too little, of HPA axis and/or glucocorticoid activity signify pathology, for instance Cushing's syndrome vs. Addison's disease, respectively (Chrousos et al. 1993; McEwen 1998; Chrousos 2000a). Since the responsiveness of the target tissues to glucocorticoids is crucial for the end-effect of these hormones, similar pathology may result from hypersensitivity or resistance of these target tissues to these hormones, respectively (Chrousos et al. 1993; Kino et al. 2003b) (Table I). However, because the brain and the pituitary are also targets for glucocorticoids, and because the organism strives for homeostasis during time-integrated free cortisol exposure, any generalized change in the glucocorticoid signaling system would be followed by corrective, “compensatory” changes in the activity of the HPA axis (Figure 1A). However, absence of complete compensation, be it slightly excessive or deficient, could result in allostasis leading to target tissue pathology, as occurs in chronically stressed or depressed individuals (Chrousos 2000a; Gold and Chrousos 2002). But this has been known for several decades. A key question is whether it is possible to have discordance between HPA axis feedback regulation by glucocorticoids and peripheral target tissue sensitivity to these hormones in totally normal individuals.

Table I.  Expected clinical manifestations in target tissue hypersensitivity or resistance to glucocorticoids.

Target area	Glucocorticoid excess = glucocorticoid hypersensitivity	Glucocorticoid deficiency = glucocorticoid resistance
Central nervous system	Insomnia, anxiety, depression, defective cognition	Fatigue, somnolence, malaise, defective cognition
Liver	+ Gluconeogenesis, + lipogenesis	Hypoglycemia, resistance to diabetes mellitus
Fat	Accumulation of visceral fat (metabolic syndrome)	Loss of weight, resistance to weight gain
Blood vessels	Hypertension	Hypotension
Bone	Stunted growth, osteoporosis
Inflammation/immunity	Immune suppression, anti-inflammation, vulnerability to certain infection and tumors	+ Inflammation, + autoimmunity, + allergy

Modified from Chrousos et al. (2004), Chrousos and Kino (2005).

Figure 1 A: Feedback regulation of the HPA axis. ACTH, Adrenocorticotropic hormone; AVP, arginine vasopressin; CRH, corticotropin-releasing hormone; DOC, deoxycorticosterone; B, corticosterone. B: Feedback-regulated compensatory changes in the activity of the HPA axis and their effects in peripheral tissues, such as the liver, fat and blood vessels. Note that glucocorticoid sensitivity in the HPA axis and the peripheral tissues can be independently regulated and the former determines the serum free cortisol levels, thus combination of their directions of change from normal influence net peripheral action of this hormone. Modification from Kino et al. (2001), Charmandari et al. (2004).

We propose that this is indeed so and elaborate below. The glucocorticoid signaling system of the suprahypothalamic, hypothalamic and pituitary glucocorticoid-sensing network is different from the signaling systems of the reward, arousal, associative, cardiovascular, metabolic and immune systems that are influenced by glucocorticoids. The hypothalamic-pituitary axis senses and thus determines the circulating glucocorticoid levels, while the rest of the tissues passively accept the actions of the secreted glucocorticoids. Indeed, any change in one or more molecules or processes that participate in the glucocorticoid signaling system could potentially have a different impact in the HPA feedback system and the other target tissues. Such discrepancy in the glucocorticoid sensing network between the HPA axis and peripheral tissues could, thus, produce peripheral tissue hypercortisolism or hypocorticosolism depending on their combinations (Figure 1B and Table I) (Chrousos et al. 1993). In a recent study by Alevizaki et al. (2007), both high HPA axis reactivity to stress and increased peripheral tissue sensitivity to glucocorticoids were associated with increased severity of coronary artery disease. However, naturally the GR is not alone in defining the sensitivity of the feedback system and other tissues to glucocorticoids. Numerous GR isoforms with different activities, other molecules or processes with important input into the activity of the cellular glucocorticoid signaling system have been described (Table II) (Kino et al. 2003a; Kino et al. 2003b; Chrousos and Kino 2005; Lu and Cidlowski 2005; Kino et al. 2006).

Table II.  Factors influencing GR functions.

Ligands	Membrane transporters of glucocorticoids
	11β-hydroxysteroid dehydrogenases
	Agonists, antagonists (ex. RU 486)
Chemical compounds	Ursodeoxycholic acid, cortivazol, thiredoxin, carnitine
Chemical modifications	Phosphorylation, nitrosylation, acetylation, methylation
Chaperones, co-chaperones	Heat shock proteins, RAP46, FK506-binding proteins
Receptor isoforms	Glucocorticoid receptor α and β isoforms (16 or more, 256 or more combinations of dimers)
Transcriptional co-regulators	Coactivators/corepressors, SWI/SNF, TRAP/DRIP complex, SMAD6
	Viral proteins: adenoviral E1A, human immunodeficiency virus type-1 Vpr and Tat
Transcription factors	Nuclear factor-κB, activator protein-1, CREB-binding protein, p53, chicken ovalbumin upstream promoter-transcription factor-II, GATA-1, SP-1, nuclear factor-1, PPARα
Other proteins	14-3-3, FLASH, Rho-type guanine nucleotide exchange factors (Brx and c-Lbc), autoimmune regulator gene (AIRE), guanine nucleotide-binding protein β
RNAs	SRA, Gas5

Data from Lanz et al. (1999), Kino and Chrousos (2003, 2004), Kino et al. (2003b, 2003c, 2004, 2006), Chrousos and Kino (2005), Lu and Cidlowski (2005), Ichijo et al. (2005).

Glucocorticoids and the metabolic syndrome

Endogenous or exogenous Cushing's syndrome is associated with the full metabolic profile of the metabolic syndrome and with substantially increased cardiovascular morbidity and mortality (Friedman et al. 1996; Miller and Chrousos 2001). Glucocorticoids directly cause insulin resistance of peripheral target tissues in proportion to their levels and to the particular target tissue's sensitivity to these hormones. Over time, glucocorticoids also cause progressive accumulation of visceral fat, leading to worsening manifestations of the metabolic syndrome. Thus, when polymorphisms of the glucocorticoid receptor gene lead to an unfavorable discordance between the activity of the HPA axis and the sensitivity of muscle, fat and liver to glucocorticoids, the increased glucocorticoid effect in these tissues could influence the metabolic profile and the longevity of humans in a negative fashion, similar to what occurs in Cushing's syndrome (Chrousos 2000a; Dobson et al. 2001; Stevens et al. 2004; Buemann et al. 2005; DeRijk and de Kloet 2005; Marti et al. 2006).

Genetic and developmental factors, nutrition, lifestyle and cumulative chronic or intermittent stress may lead to development of obesity, primarily of the visceral type, and hence the metabolic syndrome with its components of insulin resistance, dyslipidemia, chronic smoldering inflammation, blood hypercoagulation and hypertension (Figure 2). These changes lead to endothelial inflammation, atherosclerosis and cardiovascular disease, ultimately resulting in premature cardiovascular morbidity and death. Glucocorticoids contribute to the pathogenesis of obesity and the metabolic syndrome not only through unfavorable genetic variations that increase both the activity of the HPA axis and the sensitivity of tissues to glucocorticoids, but also because of fetal programming of the HPA axis by an adverse intrauterine environment, which may lead to a postnatally hyperactive axis, and because of chronic cortisol hypersecretion owing to real or perceived stress (Chrousos 1998, 2000a; Phillips et al. 1998).

Figure 2 Endogenous/exogenous inputs to the stress system and their effects on the metabolic and cardiovascular systems and bone. ABP, arterial blood pressure; APR, acute phase reactants; AVP, arginine vasopressin; CRH, corticotropin-releasing hormone; E, epinephrine; E2, estradiol; GH, growth hormone; HDL, high-density lipoprotein; HPA axis, hypothalamic–pituitary–adrenal axis; IGF-1, insulin-like growth factor-1; IL-6, interleukin-6; LC, locus caeruleus; LDL, low-density lipoprotein; LH, luteinizing hormone; NE, norepinephrine; T, testosterone; T3, triiodothyronine; TG, triglyceride; TSH, thyroid-stimulating hormone.

The opposite result is possible as well. Patients may be protected from obesity, the metabolic syndrome, and premature death because of favorable genetic variations causing a decreased activity of their HPA axis and their tissue sensitivity to glucocorticoids, as well as by advantageous fetal programming and, or, decreased exposure to real or perceived stress (Chrousos 1998, 2000a; Phillips et al. 1998). In several studies favorable genetic variations in the glucocorticoid receptor gene, in which carriers of a particular polymorphism had peripheral target tissues with decreased sensitivity to glucocorticoids, were found to result in increased sensitivity of the same tissues to insulin and hence a healthier metabolic profile (van Rossum et al. 2002, 2004; van Rossum and Lamberts 2004; DeRijk and de Kloet 2005; Syed et al. 2006).

Beyond glucocorticoids and the metabolic syndrome

Despite their obvious importance, glucocorticoids and their signaling system are only one of several physiologic and molecular networks that participate in the development of obesity and the metabolic syndrome, with a resultant adverse effect on longevity. Other major hormones of the stress system and their receptors also participate in these phenomena (Figure 2) (Chrousos 1998; McEwen 1998).

The stress system includes brain nuclei, such as the paraventricular nucleus of the hypothalamus, and the brainstem locus caeruleus–norepinephrine/autonomic nervous system nuclei, and two powerful peripheral neuroendocrine limbs, the HPA axis and the systemic sympathetic and adrenomedullary systems. The main central molecular mediators of the stress system are corticotropin-releasing hormone, arginine vasopressin, and norepinephrine. The key peripheral molecular mediators are corticotropin, cortisol, arginine vasopressin, norepinephrine, epinephrine and interestingly, interleukin-6 (IL-6) (Chrousos 1995, 1998, 2000a). The genes that code for the synthesis, regulation, actions and metabolism of these mediators and their receptors are major participants in the adaptation to stress. The stress system is activated in a coordinated fashion during stress, influencing central and peripheral functions that are important for adaptation and survival (Chrousos 1998). Chronic activation of the stress system, however, is associated with many negative sequelae, including obesity/metabolic syndrome and loss of bone mineral density, i.e. osteopenia or osteoporosis (Chrousos 1998).

In addition to noninflammatory stress, even very mild, asymptomatic inflammation stimulates secretion of IL-6 and other inflammatory cytokines, while adipose tissue is a major source of circulating tumor necrosis factor-α and IL-6 (Chrousos 1995, 2000a; Papanicolaou et al. 1998). Both glucocorticoids and IL-6 synergistically stimulate the acute phase response, including C-reactive protein, fibrinogen and plasminogen activator inhibitor 1, all of which increase the ability of blood to coagulate and through their pro-atherosclerosis action have a negative effect on longevity. Thus, chronic stress, an indolent infection, an active autoimmune process and visceral obesity are all associated with mild hypercytokinemia and low-grade inflammation, which ultimately results in blood hypercoagulability, endothelial dysfunction, atherosclerosis and cardiovascular disease. Finally, it is evident that the metabolic syndrome, regardless of its cause, is a major risk factor for the development of diabetes type 2 and the polycystic ovary syndrome in patients with a genetic propensity to develop these very common disorders.

We have survived and been “selected” as a species because we were able to adapt to potentially lethal evolutionary stressors during our life on earth. Thus, selective pressures on our genome have produced adaptive changes that, at this time in our evolutionary history, have become somewhat maladaptive in a large proportion of the population (Chrousos 1995, 1998; Papanicolaou et al. 1998; Gold and Chrousos 2002) (Table III). Thus, gene networks dedicated to adaptation and survival, with a finite number of members, are probably responsible for much of the contemporary nosology of Western societies presented in Table III. Even though cancer is not included in this Table, it is evident that modification of the immune system and the inflammatory reaction by stress could increase the susceptibility of the organism to certain neoplasias.

Table III.  Gene networks subserving functions important for human survival and species preservation, which may produce pathology in contemporary western societies.

Response to survival threat	Selective advantage	Contemporary diseases
Combat starvation	Energy conservation	Obesity
Combat dehydration	Fluid and electrolyte conservation	Hypertension
Combat infectious diseases	Potent immune reaction	Autoimmunity/allergy
Anticipate adversaries	Arousal/fear	Anxiety/insomnia
Minimize exposure to danger	Withdrawal from danger	Depression
Prevent tissue strain and injury	Retain tissue integrity and reserve	Pain and fatigue syndromes

Modified from Chrousos (2004).

Conclusions

To understand the roles of polymorphisms of multiple genes related to the HPA axis and the glucocorticoid signaling system in human physiology and pathophysiology, one will have to study large populations of normal subjects, including adequate numbers of representative racial and ethnic subpopulations, as well as populations of patients afflicted by states and diseases that may result from dysfunction of this system, which are summarized in Tables I and III. Once we have defined the crucial genes and their polymorphisms, we could employ existing new and constantly improving methods to screen for changes in the entire gene networks of choice, which, in the appropriate context, could predict the relative risk for developing common disorders. Also, granted that a large subgroup of this gene network plays a major role in regulating immune function, this information could be useful in predicting vulnerability to certain infections and tumors. Finally, this knowledge might help individualize medications and doses for subjects with the above conditions depending on their genetics in a rational way, an effort that is developing into the field of pharmacogenomics.

Acknowledgements

The work that has led to this article was funded by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.