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Abstract
Glucocorticoids (GCs) represent the most important and frequently used class of anti-inflammatory drugs. While the therapeutic effects of
GCs have been known and used for more than 50 years, major progress in discovering the underlying molecular mechanisms has only been
made in the last 10 15 years. There is consensus that the desired anti-inflammatory effects of GCs are mainly mediated via repression of
gene transcription. In contrast, the underlying molecular mechanisms for GC-mediated side effects are complex, distinct, and frequently only
partly understood. Recent data suggest that certain side effects are predominantly mediated via transactivation (e.g., diabetes, glaucoma),
whereas others are predominantly mediated via transrepression (e.g., suppression of the hypothalamic-pituitary-adrenal axis). For a
considerable number of side effects, the precise molecular mode is either so far unknown or both transactivation and transrepression seem to
be involved (e.g., osteoporosis). The differential molecular regulation of the major anti-inflammatory actions of GCs and their side effects is
the basis for the current drug-finding programs aimed at the development of dissociated GC receptor (GR) ligands. These ligands
preferentially induce transrepression by the GR, but only reduced or no transactivation. This review summarizes the current knowledge of the
most important GC-mediated side effects from a clinical to a molecular perspective. The focus on the molecular aspects should be helpful in
predicting the potential advantages of selective GR agonists in comparison to classical GCs.
D 2002 Elsevier Science Inc. All rights reserved.
Keywords: Adverse effects; Immunotherapy; Immunosuppression; Pharmacology
Abbreviations: AAT, aspartate aminotransferase; ACTH, adrenocorticotropic hormone; AP, activator protein; CMV, cytomegalovirus; CRH, corticotrophinreleasing hormone; ECM, extracellular matrix; ENaC, epithelial Na+ channel; GC, glucocorticoid; G6Pase, glucose-6-phosphatase; GR, glucocorticoid
receptor; GRE, glucocorticoid-response element; HPA, hypothalamic-pituitary-adrenal; HSP, heat shock protein; 5-HT, serotonin; IL, interleukin; MR,
mineralocorticoid receptor; MYOC, myocillin; NF-kB, nuclear factor-kB; NSAID, nonsteroidal anti-inflammatory drug; OPG, osteoprotegerin; OPG-L,
osteoprotegerin ligand; PEPCK, phosphoenolpyruvate carboxykinase; POMC, pro-opiomelanocortin; PTDM, post-transplant diabetes mellitus; SEGRA,
selective glucocorticoid receptor agonist; sgk, serum- and glucocorticoid-regulated kinase; TAT, tyrosine aminotransferase; TGF, transforming growth factor;
TIGR, trabecular meshwork-induced glucocorticoid response; TM, trabecular meshwork; TNF, tumor necrosis factor.
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1. Current clinical value of glucocorticoid therapy . . . . . . .
1.2. Mechanisms of glucocorticoid receptor action. . . . . . . .
Mechanisms of glucocorticoid receptor-mediated therapeutic effects
Mechanisms of glucocorticoid-mediated side effects . . . . . . . .
3.1. Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.1. Skin atrophy . . . . . . . . . . . . . . . . . . . .
3.1.2. Disturbed wound healing . . . . . . . . . . . . . .
3.2. Skeleton and muscle . . . . . . . . . . . . . . . . . . . . .
3.2.1. Osteoporosis . . . . . . . . . . . . . . . . . . . .
3.2.2. Muscle atrophy/myopathy . . . . . . . . . . . . .
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24
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24
3.3.
Eye . . . . . . . . . . . . . . . .
3.3.1. Cataract . . . . . . . . . .
3.3.2. Glaucoma . . . . . . . . .
3.4. Central nervous system . . . . . .
3.5. Metabolism and endocrine system .
3.5.1. Diabetes mellitus . . . . .
3.5.2. Adrenal insufficiency . . .
3.6. Cardiovascular system . . . . . . .
3.7. Gastrointestinal system . . . . . .
3.8. Immune system . . . . . . . . . .
4. Summary/conclusion . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . .
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1. Introduction
1.1. Current clinical value of glucocorticoid therapy
Since the successful use of hydrocortisone (cortisol), the
principal glucocorticoid (GC) of the human adrenal cortex,
in 1948 in the suppression of the clinical manifestations of
rheumatoid arthritis, numerous compounds with GC activity
have been synthesized. Today, they represent the standard
therapy for reducing inflammation and immune activation in
asthma, as well as allergic, rheumatoid, collagen, vascular,
dermatological, inflammatory bowel, and other systemic
diseases, and in allotransplantation. The therapeutic usage
of GCs has risen continuously in recent years. In Germany,
6.6 million prescriptions were written in 1995 (Schwabe,
1996) and 10 million new prescriptions are written just
for oral corticosteroids each year in the United States.
Overall, the total market size is considered to reach 10
billion US dollars per year. GCs are used in almost all
medical specialties for systemic therapies, as well as topical
therapy. Apart from application to the skin, the latter
includes the respiratory route for asthma and via the gut
for inflammatory bowel diseases.
GCs are 21-carbon steroid hormones. The clinical
potency of the various synthetic steroids depends on the
rate of absorption, the concentration in the target tissues, the
affinity for the steroid receptor, and the rate of metabolism
and subsequent clearance. The plasma half-life ranges
between 80 (cortisol) and 270 (dexamethasone) min.
Approximately 90% of endogenous circulating cortisol is
bound with high affinity to the plasma protein corticosteroid-binding globulin. Most synthetic steroids, with the
exception of prednisolone, however, have low affinity for
the corticosteroid-binding globulin and are bound predominantly to albumin. Only the small fraction of circulating
corticosteroids that are not protein-bound are free to exert
biological action, whereas those associated with proteins are
protected from metabolic degradation. GCs are metabolized
in the liver. The kidney excretes 95% of the conjugated
metabolites, and the remainder are lost in the gut (Goodwin,
1994).
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31
32
32
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25
26
Fig. 2. Molecular mechanisms of GR action. A: Transactivation: the ligandactivated GR homodimer binds to GREs in the promoter region of GCsensitive genes, inducing gene transcription. B: Transrepression: the ligandactivated GR homodimer binds to negative GREs in a promoter region of
GC-regulated genes (e.g., osteocalcin and POMC gene), inhibiting gene
transcription by interfering with the binding of activating transcription
factors [e.g., TATA-binding protein (TBP)]. C: Transrepression: the ligandactivated GR monomer binds to a subunit of another transcription factor
(e.g., c-Fos subunit of AP-1 or p65 subunit of NF-kB), thus inhibiting the
induction of gene transcription by these factors.
27
28
29
Table 2
Effects of GCs on gene expression in normal and wounded mouse skin
Gene
Normal skin
Wounded skin
Reference
IL-1
IL-1
TNF-
KGF
Tenascin-C
PDGF-A
PDGF-B
PDGF-RA
TGF-1
TGF-2
TGF-3
TGF-RI
TGF-RII
MME
iNOS
Collagen I
Collagen III
Tenascin C
No regulation
Not detectable
Not detectable
Down-regulated
Not detectable
Down-regulated
Not detectable
Down-regulated
Down-regulated
Down-regulated
Up-regulated
Up-regulated
Down-regulated
Down-regulated
Not detectable
Down-regulated
Down-regulated
Down-regulated
Down-regulated
Down-regulated
Down-regulated
Down-regulated
Down-regulated
Down-regulated
Down-regulated
Down-regulated
Down-regulated
Down-regulated
Up-regulated
Up-regulated
Down-regulated
Down-regulated
Down-regulated
N.D.
N.D.
N.D.
Elastin
Down-regulated
N.D.
30
6.0-mg prednisone per day for 6 months may cause significant bone loss and may increase the rate of osteoporotic
fractures within 1 year (Pearce et al., 1998; Chiu et al.,
1998). In asthma patients treated with oral GCs for more
than 1 year, 86% demonstrated a decrease in bone mineral
density at either the hip or lumbar spine. Furthermore,
decreases of bone mineral density were dose-related and
observed in 80% of high-dose, 71% of medium-dose, and
33% of low-dose patients (Goldstein et al., 1999).
Fracture risk is related to the dose and duration of GC
use, age, body weight, and female sex (Reid, 2000). Both
cross-sectional and longitudinal studies demonstrate significantly stronger losses of trabecular than of cortical bone
(Lane & Lukert, 1998). Since GCs have their strongest
effect on cancellous bone, fractures are most common in
regions of the skeleton that are predominantly cancellous,
such as the vertebral bodies and ribs. Approximately onethird of patients have evidence of vertebral fractures after
5 10 years of GC treatment. Even higher incidences of
vertebral fractures are observed in post-menopausal women
(Adachi et al., 1997). In selected populations (older men
with chronic obstructive lung disease), the risk may
increase to up to 60% (McEvoy et al., 1998). The risk of
hip fracture is also increased nearly 3-fold (Cooper et al.,
1995). Considering this data, it seems of concern that only
10% of patients taking GCs for longer periods also
receive treatment for osteoporosis (Walsh et al., 1996;
Ettinger et al., 2001).
Bone tissue undergoes a constant metabolic turnover and
remodeling process, a periodic replacement of old bone by
new bone throughout adult life. As a consequence, a
complete regeneration of the adult skeleton takes place
every 10 years. Remodeling is carried out by a team of
osteoclasts (bone resorption) and osteoblasts (bone formation), comprising the basic multicellular unit. GCs affect
bone metabolism via several pathways (Fig. 4). (1) GCs
inhibit bone formation by suppressing osteoblast prolifera-
Fig. 4. Mechanism of GC-induced bone loss. GC-induced osteoporosis is a very elaborately regulated side effect. GCs may affect osteoblasts and osteoclasts
directly and/or indirectly, resulting in bone loss. GH, growth hormone; IGF, insulin-like growth factor; PTH, parathormone. Modified from Ziegler and Kasperk
(1998).
31
32
3.3.1. Cataract
An increased risk for the development of posterior
subcapsular cataracts has long been known for systemic
GC treatment (Black et al., 1960). Whereas an effect of
inhaled or intranasal corticosteroids also on cataract risk was
not verified in younger patients (Simons et al., 1993; Derby
& Maier, 2000), a recent study strongly implicated an
enhanced incidence of cataract extractions after prolonged
(> 2 years) administration of high (> 1 mg/day) and low to
medium ( < 1 mg/day) average daily doses of inhaled
corticosteroid in elderly patients (relative risks, 3.06 and
1.63, respectively) (Garbe et al., 1998).
The mechanisms that are involved in cataract development include increased glucose levels, caused by an
increased gluconeogenesis rate (described in Section
3.5.1); inhibition of Na + /K + -ATPase; increased cation
permeability; inhibition of glucose-6-phosphate-dehydrogenase; inhibition of RNA synthesis; loss of ATP; and
covalent binding of steroids to lens proteins (Kojima et
al., 1995). GCs constitute stable covalent adducts with the
lysine residues of lens proteins in a non-enzymatic way
(Manabe et al., 1984). These adducts are observed in
steroid-induced cataracts only, but not in other human
cataracts or normal human lenses. Overall, mainly DNAindependent nongenomic mechanisms seem to be involved
in developing these GR-mediated effects.
3.3.2. Glaucoma
Local and systemic GC application is associated with a
high incidence of ocular hypertension. In 30% of patients
receiving dexamethasone eye drops for 4 weeks, an increase
in ocular pressure was found (Armaly, 1963). The frequency
of such GC responders is even greatly increased in patients
with primary open-angle glaucoma (46 92%) (Tripathi et
al., 1999). In particular, in those patients with established
glaucoma, a further dangerous increase of the intraocular
pressure due to a necessary GC therapy is often problematic.
In a retrospective epidemiological study of elderly
patients receiving oral GCs, an overall odds ratio of 1.41
with regard to glaucoma induction was observed. The odds
ratios showed a dose-related increase: 1.26 for < 40 mg/day
hydrocortisone; 1.37 for patients on 40 79 mg/day, and
1.88 for patients on 80 mg or more per day. The odds ratios
also increased with the duration of treatment (Garbe et al.,
1997a). In contrast, the use of inhaled and nasal GCs was
not found to be associated in general with an increased
glaucoma risk. Prolonged users of high doses of inhaled
GCs and persons with a family history of glaucoma,
however, exhibit an enhanced risk for elevated intraocular
pressure and open-angle glaucoma (odds ratios, 1.44 and
2.6, respectively) (Garbe et al., 1997b; Mitchell et al., 1999).
GC-induced morphological and functional changes in the
trabecular meshwork (TM) are considered to be main
mechanisms leading to increased intraocular pressure during
GC treatment. These changes are a result of several cooperative GC-induced effects on TM cells, causing crucial
et al., 1999) dealing with exogenous GC-induced psychiatric side effects, frequencies between 2% and 36% have
been found, depending on the GC dosage. Disturbances of
affect and behavior may occur in up to 50% of the patients
(Satel, 1990). It has been suggested from several case
reports that psychiatric side effects are also possible, but
not common, in inhalative GC therapy.
The first insights regarding the underlying mechanisms
have been gained in recent years. It was shown that hippocampal damage can be induced by direct GC exposure
(Sapolsky et al., 1990). Further studies in various animal
species (Sapolsky et al., 1988) demonstrated that direct GC
exposure results in decreased dendritic branching (Watanabe
et al., 1992), alteration in synaptic terminal structure (Magarinos et al., 1997), a loss of neurons (Uno et al., 1990), and
inhibition of neuronal regeneration (Gould et al., 1998). The
mechanistic spectrum of GC-mediated CNS effects ranges
from disruption of cellular metabolism (Lawrence & Sapolsky, 1994) to an increase in the vulnerability of hippocampal neurons (Virgin et al., 1991) and an augmented
extracellular glutamate accumulation (Stein-Behrens et al.,
1994).
Abnormalities of hypothalamic-pituitary-adrenal (HPA)
axis function, as well as dysregulation of the serotonin (5HT) system, are also involved in neuropsychiatric disorders
caused by increased GC levels. The 5-HT system is composed of a family of related receptors (5-HTA receptors)
(Lopez et al., 1998; Hoyer & Martin, 1996). Particular
attention was focused on the 5-HT1A receptor (Julius,
1991). Suppression of this 5-HT1A receptor expression by
GCs may play a central role in the pathophysiology of
depression. In the promoter of the 5-HT1A receptor gene,
two NF-kB elements were identified. The NF-kB-mediated
induction of gene transcription, in turn, was shown to be
inhibited by GCs (Wissink et al., 2000).
In summary, one of the most important mechanisms, the
repression of the 5-HT1A receptor by GCs, presents a
transrepression process via a GR-protein interaction.
3.5. Metabolism and endocrine system
The effects of GCs on metabolism in general and on
multiple endocrine glands are very complex. From a clinical
point of view, the relevant GC-induced side effects are of
particular importance. These include the disturbance in
glucose metabolism, which may lead to induction or
aggravation of a pre-existing diabetes; adrenal insufficiency;
and hypogonadism.
3.5.1. Diabetes mellitus
GC therapy is associated with the risk of hyperglycemia
in patients without known diabetes mellitus (induction of
diabetes) and worsened glycemic control in diabetic patients
(aggravation of diabetes). GC excess causes both decreased
b-cell insulin production and insulin resistance, i.e., reduced
effectiveness of insulin in suppressing hepatic glucose
33
34
Fig. 5. Proposed model for the feedback regulation of the HPA axis by the
GR. DNA-dependent and -independent mechanisms of the GR are involved
in the negative feedback regulation of the HPA axis. CRF, corticotropinreleasing factor; PRL, prolactin; PVN, paraventricular nucleus. Reproduced
from Reichardt et al. (1998), with permission of the copyright holder,
Elsevier Science, Oxford.
35
lular volume, and increased cardiac contractility. The finding that both high-dose treatment and reduction of GCs after
long-term therapy can induce hypertension (Sanders et al.,
1992) underlines the complexity of GC effects on blood
pressure regulation.
Blood pressure in humans is subjected to tight control
by several physiologic systems that have pleiotropic
effects and interact together in a complex fashion. Baroreceptors, natriuretic peptides, the renin-angiotensin-aldosterone system, the kinin-kallikrein system, the adrenergic
receptor system, nitric oxides, and endothelin are all
among them (Lifton et al., 2001). An excessive GC
therapy can cause Na + retention, hypokalemia, and hypertension by influencing these systems in different ways.
The resulting hypertension can increase the risk of bleeding, in particular of gastric bleeding, which might even
become life threatening. Hypokalemia can cause severe
heart problems.
Several distinct GC-induced mechanisms mediated either
via the MR or the GR are responsible for these cardiovascular side effects. GCs enhance the number of ENaCs and
their activity by GC-regulated kinases. The major regulator
of the ENaCs is the MR, which is normally activated by
aldosterone. The specificity of the MR for aldosterone in
vivo is ensured indirectly. The enzyme 11b-hydroxysteroid
dehydrogenase protects the MR from cortisol by metabolizing it to cortisone, which does not activate the MR
(Stewart et al., 1987). Synthetic compounds that bind to
both the GR and the MR and are not metabolized by 11bhydroxysteroid dehydrogenase can, therefore, cause hypertension by regulating the EnaCs via the MR. Na + channels
are responsible for transepithelial Na + transport in the
collecting ducts of the kidney, in airway epithelia, and in
sweat and salivary glands. ENaCs are hetero-multimeric
complexes composed of three distinct, but homologous,
subunits termed a-, b-, and gENaC (Sayegh et al., 1999).
In addition to mineralocorticoids, GCs are important physiological regulators of amiloride-sensitive epithelial Na +
transport in target epithelia. In the 50-flanking region of
the human aENaC gene, imperfect and functional GREs
have been identified (Sayegh et al., 1999), suggesting a
positive regulation by GCs. Indeed, it has been demonstrated that dexamethasone increases aENaC mRNA expression without affecting the b- and gENaC gene expression
(Stokes & Sigmund, 1998; Asher et al., 1996; Escoubet et
al., 1997). Dexamethasone increases aENaC mRNA
expression in fetal and adult rat lungs too (Venkatesh &
Katzberg, 1997; Stokes & Sigmund, 1998). Besides the
direct effect of GCs on ENaC gene expression, an increase
in ENaC activity was observed after dexamethasone administration (Eaton et al., 1995; Brennan & Fuller, 2000; Chen
et al., 1999) mediated by the serum- and GC-regulated
kinase (sgk). GCs or aldosterone is able to enhance the
transcription of the sgk gene in a tissue-specific manner
(Chen et al., 1999; Brennan & Fuller, 2000). Although the
precise mechanisms of ENaC activation via sgk are still
36
4. Summary/conclusion
GC-mediated effects are very complex and tightly controlled. This strong control is necessary to ensure the
survival of the organism under several conditions, such as
stress, infections, etc. With the development of new techniques in molecular biology, biochemistry, and cell biology,
considerable progress has been achieved in the discovery of
37
Table 3
Side effect-associated proteins: regulation by GCs and molecular mechanisms
Side effect
Mechanism
DNA-dependent
Activation
Skin atrophy
Type I collagen
Type III collagen
Tenscin C
Sulfated glycosaminoglycans
Down-regulation of
pro-inflammatory genes
Osteoporosis
Osteoblast/osteocyte apoptosis
OPG-L
OPG
Osteocalcin
Type I collagen
X
X
Muscle atrophy/myopathy
Glutamine synthetase
Components of ubiquitin-proteasome pathway
(X)
(X)
Glaucoma
X
(X)
(X)
(X)
Psyche
5-HT1A receptor
CRH
POMC/ACTH
Repression
(X)
(X)
(X)
(X)
(X)
(X)
(X)
X
(X)
X
(X)
(X)
X
X
X
TAT
AAT
G6Pase
PEPCK
X
X
X
X
Hypertension
aEnaC
sgk
X
X
DNA-independent
Repression
38
39
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