Stress, June 2007; 10(2): 213–219

Glucocorticoid action networks and complex psychiatric and/or somatic

disorders

GEORGE P. CHROUSOS1,2 & TOMOSHIGE KINO2

1
First Department of Pediatrics, Athens University Medical School, 11527 Athens, Greece, and 2Pediatric Endocrinology
Section, Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National
Institutes of Health, Bethesda, MD 20892-1109, USA
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(Received 31 October 2006; revised 15 February 2007; accepted 20 February 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
For personal use only.

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

Introduction in the transformation of a normal cell to a tumor cell

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 recep-
tors (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
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.

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

ISSN 1025-3890 print/ISSN 1607-8888 online q 2007 Informa UK Ltd.

DOI: 10.1080/10253890701292119
 214 G. P. Chrousos & T. Kino
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 polymorph-
isms 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
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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).
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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 pathophysiol-
ogy, 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
Table I. Expected clinical manifestations in target tissue hypersensitivity or resistance to glucocorticoids.
Target area Glucocorticoid excess ¼ glucocorticoid hypersensitivity
Central nervous system Insomnia, anxiety, depression, defective cognition
Liver þ Gluconeogenesis, þ lipogenesis
Fat Accumulation of visceral fat (metabolic syndrome)
Blood vessels Hypertension
Bone Stunted growth, osteoporosis
Inflammation/immunity Immune suppression, anti-inflammation, vulnerability
to certain infection and tumors
Modified from Chrousos et al. (2004), Chrousos and Kino (2005).
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 inflam-
matory 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, respect-
ively (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 hyper-
sensitivity 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, “compensa-
tory” changes in the activity of the HPA axis
(Figure 1A). However, absence of complete compen-
sation, 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.
We propose that this is indeed so and elaborate
below. The glucocorticoid signaling system of the
suprahypothalamic, hypothalamic and pituitary glu-
cocorticoid-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 circulat-
ing glucocorticoid levels, while the rest of the tissues
passively accept the actions of the secreted glucocor-
ticoids. Indeed, any change in one or more molecules
or processes that participate in the glucocorticoid
Glucocorticoid deficiency ¼ glucocorticoid resistance
Fatigue, somnolence, malaise, defective cognition
Hypoglycemia, resistance to diabetes mellitus
Loss of weight, resistance to weight gain
Hypotension
þ Inflammation, þ autoimmunity, þ allergy
 Glucocorticoids and pathophysiology 215

(-)
A Hypothalamus

CRH/AVP

(-) Pituitary Gland

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

Free Cortisol High Normal

High Low Normal Low

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Low Very Low

High High

Normal Normal Normal Normal

Low Low

High Very High

Low High Normal High

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
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 hyper-
cortisolism 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).
 216 G. P. Chrousos & T. Kino

Table II. Factors influencing GR functions.

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

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 hypercoagu-
lation and hypertension (Figure 2). These changes
lead to endothelial inflammation, atherosclerosis and
cardiovascular disease, ultimately resulting in pre-
mature cardiovascular morbidity and death. Gluco-
corticoids 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 program-
ming of the HPA axis by an adverse intrauterine
environment, which may lead to a postnatally
hyperactive axis, and because of chronic cortisol
(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/auto-
nomic nervous system nuclei, and two powerful
peripheral neuroendocrine limbs, the HPA axis and
the systemic sympathetic and adrenomedullary sys-
tems. The main central molecular mediators of the
stress system are corticotropin-releasing hormone,
arginine vasopressin, and norepinephrine. The key
peripheral molecular mediators are corticotropin,
 Glucocorticoids and pathophysiology 217

DEVELOPMENTAL HISTORY

GENETIC VARIATION STRESS

Real or Perceived

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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HDL APR Hypecoagulationr

Cytokines

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-
nephrine 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-a and IL-6 (Chrousos 1995,
2000a; Papanicolaou et al. 1998). Both glucocorti-
coids and IL-6 synergistically stimulate the acute
phase response, including C-reactive protein, fibrino-
gen 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
 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.
Response to survival threat Selective advantage
Combat starvation Energy conservation
Combat dehydration Fluid and electrolyte conservation
Combat infectious diseases Potent immune reaction
Anticipate adversaries Arousal/fear
Minimize exposure to danger Withdrawal from danger
Prevent tissue strain and injury Retain tissue integrity and reserve
Modified from Chrousos (2004).
system and the inflammatory reaction by stress could
increase the susceptibility of the organism to certain
neoplasias.
Conclusions
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To understand the roles of polymorphisms of multiple
genes related to the HPA axis and the glucocorticoid
signaling system in human physiology and pathophy-
siology, 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.
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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 Insti-
tute of Child Health and Human Development,
National Institutes of Health, Bethesda, MD.
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