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Chrousos 2007
Chrousos 2007
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
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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.
Keywords: Chronic stress, cortisol, Cushing’s syndrome, hypothalamic –pituitary– adrenal axis, inflammation, insulin
resistance
Correspondence: G. P. Chrousos, National Institutes of Health, Clinical Research Center, Building 10, Room 1-3140, 10 Center Drive MSC
1109, Bethesda, MD 20892-1109, USA. E-mail: chrousog@mail.nih.gov
Glucocorticoid receptor gene polymorphisms response to stress, the inflammatory reaction and the
and complex human pathophysiology consequent “sickness syndrome”, i.e. the collections
of “nonspecific symptoms” caused by excessive
Wust et al. (2004) recently reported a convincing
inflammatory cytokines during infectious or inflam-
association between the hypothalamic – pituitary –
matory illness, as well as the process of sleep, and
adrenal (HPA) axis response to a standardized
long-term functions, such as growth and reproduction
socio – emotional stimulus (Trier test) and polymorph-
(Chrousos 1998, 2000b).
isms of the GR gene. This study followed others that
As happens with many other homeostatic systems,
used a similar rationale and examined HPA axis
too much, as well as too little, of HPA axis and/or
indices and other end-points, such as arterial blood
glucocorticoid activity signify pathology, for instance
pressure, body mass index (BMI) and markers of the
Cushing’s syndrome vs. Addison’s disease, respect-
metabolic syndrome, and bone mineral density
ively (Chrousos et al. 1993; McEwen 1998; Chrousos
(Weaver et al. 1992; Buemann et al. 1997; Huizenga
2000a). Since the responsiveness of the target tissues
et al. 1998; Panarelli et al. 1998; Lin et al. 1999;
to glucocorticoids is crucial for the end-effect of these
Rosmond et al. 2000; Dobson et al. 2001; Ukkola et al.
hormones, similar pathology may result from hyper-
2001). These studies have in part overlapped and have
sensitivity or resistance of these target tissues to these
produced mostly concordant results, but have also
hormones, respectively (Chrousos et al. 1993; Kino
shown inconsistencies. This should have been
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Target area Glucocorticoid excess ¼ glucocorticoid hypersensitivity Glucocorticoid deficiency ¼ glucocorticoid resistance
Central nervous system Insomnia, anxiety, depression, defective cognition Fatigue, somnolence, malaise, defective cognition
Liver þ Gluconeogenesis, þ 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 þ Inflammation, þ autoimmunity, þ allergy
to certain infection and tumors
(-)
A Hypothalamus
CRH/AVP
ACTH
Androgens
Adrenal Gland
DOC, B
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Cortisol
Glucocorticoid Effects in
B Glucocorticoid Sensitivity
Liver/Fat/Blood Vessels
HPA Axis Liver/Fat/Blood Vessels
High High
Low Low
Low Normal
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).
signaling system could potentially have a different associated with increased severity of coronary artery
impact in the HPA feedback system and the other disease. However, naturally the GR is not alone in
target tissues. Such discrepancy in the glucocorticoid defining the sensitivity of the feedback system and
sensing network between the HPA axis and peripheral other tissues to glucocorticoids. Numerous GR
tissues could, thus, produce peripheral tissue hyper- isoforms with different activities, other molecules or
cortisolism or hypocorticosolism depending on their processes with important input into the activity of the
combinations (Figure 1B and Table I) (Chrousos et al. cellular glucocorticoid signaling system have been
1993). In a recent study by Alevizaki et al. (2007), described (Table II) (Kino et al. 2003a; Kino et al.
both high HPA axis reactivity to stress and increased 2003b; Chrousos and Kino 2005; Lu and Cidlowski
peripheral tissue sensitivity to glucocorticoids were 2005; Kino et al. 2006).
216 G. P. Chrousos & T. Kino
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).
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Glucocorticoids and the metabolic syndrome hypersecretion owing to real or perceived stress
(Chrousos 1998, 2000a; Phillips et al. 1998).
Endogenous or exogenous Cushing’s syndrome is
The opposite result is possible as well. Patients may
associated with the full metabolic profile of the
be protected from obesity, the metabolic syndrome,
metabolic syndrome and with substantially increased
and premature death because of favorable genetic
cardiovascular morbidity and mortality (Friedman
variations causing a decreased activity of their HPA
et al. 1996; Miller and Chrousos 2001). Glucocorti-
axis and their tissue sensitivity to glucocorticoids, as
coids directly cause insulin resistance of peripheral
well as by advantageous fetal programming and, or,
target tissues in proportion to their levels and to the
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DEVELOPMENTAL HISTORY
AGING
Stress System
CRH/AVP-LC/NE
Systemic Sympathetic
HPA Axis
GH/IGF-1 Adrenomedullary Systems
LH, T, E2
Cortisol Target Tissues NE, E, IL-6
TSH, T3
Insulin Resistance
Visceral Obesity,
TG Metabolic Syndrome ABP
LDL
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Endothelial Dysfunction
Atherosclerosis
Cardiovascular Disease
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Osteoporosis
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.
cortisol, arginine vasopressin, norepinephrine, epi- on longevity. Thus, chronic stress, an indolent
nephrine and interestingly, interleukin-6 (IL-6) infection, an active autoimmune process and visceral
(Chrousos 1995, 1998, 2000a). The genes that code obesity are all associated with mild hypercytokinemia
for the synthesis, regulation, actions and metabolism and low-grade inflammation, which ultimately results
of these mediators and their receptors are major in blood hypercoagulability, endothelial dysfunction,
participants in the adaptation to stress. The stress atherosclerosis and cardiovascular disease. Finally, it is
system is activated in a coordinated fashion during evident that the metabolic syndrome, regardless of its
stress, influencing central and peripheral functions cause, is a major risk factor for the development of
that are important for adaptation and survival diabetes type 2 and the polycystic ovary syndrome in
(Chrousos 1998). Chronic activation of the stress patients with a genetic propensity to develop these
system, however, is associated with many negative very common disorders.
sequelae, including obesity/metabolic syndrome and We have survived and been “selected” as a species
loss of bone mineral density, i.e. osteopenia or because we were able to adapt to potentially lethal
osteoporosis (Chrousos 1998). evolutionary stressors during our life on earth. Thus,
In addition to noninflammatory stress, even very selective pressures on our genome have produced
mild, asymptomatic inflammation stimulates adaptive changes that, at this time in our evolutionary
secretion of IL-6 and other inflammatory cytokines, history, have become somewhat maladaptive in a large
while adipose tissue is a major source of circulating proportion of the population (Chrousos 1995, 1998;
tumor necrosis factor-a and IL-6 (Chrousos 1995, Papanicolaou et al. 1998; Gold and Chrousos 2002)
2000a; Papanicolaou et al. 1998). Both glucocorti- (Table III). Thus, gene networks dedicated to
coids and IL-6 synergistically stimulate the acute adaptation and survival, with a finite number of
phase response, including C-reactive protein, fibrino- members, are probably responsible for much of the
gen and plasminogen activator inhibitor 1, all of which contemporary nosology of Western societies presented
increase the ability of blood to coagulate and through in Table III. Even though cancer is not included in this
their pro-atherosclerosis action have a negative effect Table, it is evident that modification of the immune
218 G. P. Chrousos & T. Kino
Table III. Gene networks subserving functions important for human survival and species preservation, which may produce pathology in
contemporary western societies.
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