Side Effect of Cortikotseroid

Pharmacology & Therapeutics 96 (2002) 23 43
Mechanisms involved in the side effects of glucocorticoids

Heike Schacke, Wolf-Dietrich Docke, Khusru Asadullah*
Research Business Area Dermatology, Schering AG, D-13342 Berlin, Germany
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 . . . . . . . . . . . . .
* Corresponding author. Tel.: +49-30-468-15971; fax: +49-30-468-18054.

E-mail address: khusru.asadullah@schering.de (K. Asadullah).
0163-7258/02/$ see front matter D 2002 Elsevier Science Inc. All rights reserved.
PII: S 0 1 6 3 - 7 2 5 8 ( 0 2 ) 0 0 2 9 7 - 8
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
24
24
26
27
28
28
28
29
30
30
31
24
H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343
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 . . . . . . . . . . . . . . . . . . .
.
.
.
.
.
.
.
.
.
.
.
.
.
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).
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
31
32
32
32
33
33
34
35
36
36
36
38
38
The biological effects of GCs are mediated via the GC

receptor (GR). The relevant molecular mechanisms are
described in detail in Section 1.2. The resulting biological
effects can be summarized as anti-inflammatory/immunosuppressive, metabolic, and toxic. The anti-inflammatory
and immunosuppressive GC effects include changes in the
circulation/migration of leukocytes (e.g., neutrophilia, lymphopenia, and monocytopenia) and alterations in specific
cellular functions (e.g., inhibition of lymphokine synthesis,
monocyte function) (Winkelstein, 1994). Whereas the antiinflammatory and immunosuppressive effects are usually
desired (Winkelstein, 1994), the metabolic and toxic effects
are usually undesired. Exceptions are the use of GCs for
substitution (e.g., in the case of suprarenal insufficiency
Addisons disease) or in tumor therapy (e.g., for breast
cancer and plasmocytoma) (Ihle et al., 1989).
In dermatology, GCs are the most widely used therapy.
The introduction of topical hydrocortisone in the early
1950s represented a great advance over previously available
therapies, but it was the first of the halogenated GCs,
triamcinolone acetonide, that started a revolution, cumulating in the appearance of the very potent agents available
now. The enthusiasm for these highly effective agents was at
its peak during the 1960s and 1970s, and perhaps inevitably,
the more potent GCs were often used inappropriately and
indiscriminately. Adverse effects became apparent, and the
subsequent backlash of opinion against topical GCs has
created confusion and prejudice against all steroid-containing preparations. In its extreme form as steroid phobia, it
is still of considerable concern today (Maibach & Surber,
1992). Recently, a questionnaire-based study of 200 dermatology outpatients with atopic eczema assessed the prevalence of topical GC phobia in Great Britain. Overall,
72.5% of those questioned worried about using topical GCs
on their own or their childs skin. Twenty-four percent of the
people admitted to having been non-compliant with topical
corticosteroid treatment because of these worries. The most
frequent cause for concern was the perceived risk of skin
thinning (34.5%). In addition, 9.5% of the patients worried
about systemic absorption, leading to effects on growth and
development. This indicates that a considerable number of
25
patients today do worry about using their prescribed GCs

(Charman et al., 2000).
Duration, dosage, and dosing regime and choice of the
appropriate GC (a classification has been established based
on their potency) and its mode of application depend on the
clinical situation and take account of the risk/benefit ratio.
These factors, together with an individual susceptibility of
unknown reason, determine the occurrence and severity of
the adverse effects (Goodwin, 1994). Overall, it can be
stated that prolonged application is a high-risk factor,
whereas total dose is of secondary importance. Side effects
are usually more severe after systemic than after topical
application. Even topical therapy, however, can induce not
only local, but also systemic adverse effects, as observed
after cutaneous therapy for inflammatory dermatoses (Robertson & Maibach, 1982) and pulmonary therapy for asthma
(Mygind & Dahl, 1996). The side effects (summarized in
Table 1) occur with different prevalence, in different organs,
and after different durations of therapy. The severity ranges
from more cosmetic aspects (e.g., teleangiectasia, hypertrichosis) to serious disabling and even life threatening
situations (e.g., gastric hemorrhage) (Goodwin, 1994). Single or multiple side effects can occur. A typical combination
Table 1
GC typical side effects ordered by the affected organs
Skin
Atrophy, striae rubrae distensae
Delayed wound healing
Steroid acne, perioral dermatitis
Erythema, teleangiectasia, petechia, hypertrichosis
Skeleton and muscle
Muscle atrophy/myopathy
Osteoporosis
Bone necrosis
Eye
Glaucoma
Cataract
CNS
Disturbances in mood, behavior, memory, and cognition
Steroid psychoses, steroid dependence
Cerebral atrophy
Electrolytes, metabolism, endocrine system
Cushings syndrome
Diabetes mellitus
Adrenal atrophy
Growth retardation
Hypogonadism, delayed puberty
Increased Na + retention and K + excretion
Cardiovascular system
Hypertension
Dyslipidemia
Thrombosis
Vasculitis
Immune system
Increased risk of infection (e.g., Candida)
Re-activation of latent viruses (e.g., CMV)
Gastrointestinal
Peptic ulcer
Gastrointestinal bleeding
Pancreatitis
Fig. 1. Morbus Cushing (Nies, 1993). A patient with Cushings syndrome

(moon face, buffalo hump, central obesity, striae rubrae distensae) is shown.
This syndrome can result from excessive endogenous GC production or GC
administration (iatrogenic Cushings syndrome).
26
is evident in the case of Cushings syndrome, characterized

by a moon face, buffalo hump, central obesity, hirsutism,
osteoporosis, growth retardation, and glucose intolerance
(Fig. 1).
Taken together, the side effects of GC therapy are the
limiting factor for the use of these valuable agents today.
Thus, there is a strong need to develop substances with the
anti-inflammatory potency of classical GCs, but with
reduced side effects compared with the common GCs. The
basis for the development of such new compounds is a
deeper understanding of the molecular and cellular actions
of GCs.
1.2. Mechanisms of glucocorticoid receptor action
The effects of GCs are mediated by two distinct nuclear
receptors, the GR and the mineralocorticoid receptor (MR).
The MR binds GCs with a higher affinity than the GR.
While the GR is widely expressed in most cell types of the
organism, the expression of the MR is restricted to epithelial
cells in the kidney, colon, and salivary glands and nonepithelial cells in the brain and heart (Reichardt & Schutz,
1998). Activation of the MR leads to Na + retention via an
increased activity of epithelial Na + channels (EnaCs), and
subsequently induces an increase in blood pressure (Lifton
et al., 2001). Modern synthetic GCs, however, are GRselective.
The GR is a ligand-activated transcription factor. In the
absence of the ligand, the receptor is localized in the
cytoplasm as a protein complex together with heat shock
proteins (HSPs)-90, p60/Hop, HSP-70, and HSP-40 and
other chaperone molecules (Dittmar & Pratt, 1997; Schneikert et al., 1999). Upon ligand binding, the complex
dissociates and the receptor translocates into the nucleus
and binds as a homodimer to regulatory elements in promoter regions of GC-responsive genes, resulting in a modulated gene transcription.
Different modes of transcription regulation by the GRligand complex have been described. The positive regulation of target genes is mediated by a specific binding of
the activated GR-DNA to GC-response elements (GREs) in
the promoter or enhancer region of responsive genes (Beato
et al., 1989), followed by an induction or increase of gene
transcription (Fig. 2A). This transactivation mechanism has
been identified in a large variety of genes, including those
encoding the gluconeogenic enzymes tyrosine aminotransferase (TAT) (Hargrove & Granner, 1985) and phosphoenolpyruvate carboxykinase (PEPCK) (Ruppert et al., 1990).
The negative regulation by the GR is more variable. Firstly,
the activated GR can bind to negative GREs, leading to a
repression of gene transcription, possibly due to interference
with the binding of essential transcription factors (Fig. 2B).
This mechanism was described for the regulation of the
osteocalcin (Stromstedt et al., 1991; Meyer et al., 1997) and
pro-opiomelanocortin (POMC) gene promoters (Drouin et
al., 1993). Secondly, the GR may interact via protein-protein
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.
interaction with other transcription factors, e.g., activator

protein (AP)-1, nuclear factor-kB (NF-kB), Smad3, preventing an activation of transcription by these factors (Fig. 2C)
(Schule et al., 1990; Tuckermann et al., 1999; De Bosscher
et al., 2000). In this case, the gene expression is controlled
by the GR without binding to DNA.
When the full-length cDNA of the human GR was
obtained (Hollenberg et al., 1985), two forms of the human
GR were described: a steroid-binding form of 777 residues
(GRa) and a non-steroid-binding truncated form of 742
residues, which differed in the 15 C-terminal residues
(GRb). The human GRb does not bind GCs or anti-GCs,
and is transcriptionally inactive on GRE-containing

enhancers (Hollenberg et al., 1985; Giguere et al., 1986;
Oakly et al., 1996; Vottero & Chrousos, 1999). There is
some controversy concerning the relative levels of GR
isoforms, as well as the putative function of the GRb
isoform, and whether or not it acts as a dominant negative
modulator of the GRa isoform (Carlstedt-Duke, 1999). In
the peripheral blood of patients with GC-resistant asthma,
however, significantly higher numbers of human GRb
positive cells were found, suggesting such a dominant
negative function of the human GRb (Leung et al., 1997).
The first evidence for a physiologic role of the GRb isoform
in neutrophils was described recently by Strickland and coworkers (2001). They compared the GC sensitivity of
human neutrophils and peripheral blood mononuclear cells
and observed the existence of GRa/GRb heterodimers in
neutrophils only. They also demonstrated that the transfection of neutrophils from mice with a functional human
GRb, in whom no GRb isoform has been identified (Otto et
al., 1997), leads to an inhibition of GC-induced apoptosis.
In T-cells, it is thought that cell death is mediated through
GRa homodimers acting on GREs of GC-sensitive genes. A
similar mechanism of GC-induced apoptosis is assumed for
neutrophils. This suggests that the GRa/GRb heterodimers
in human neutrophils are functionally inactive, but that their
expression might limit the responsiveness towards GC
effects mediated via the GRa homodimer.
2. Mechanisms of glucocorticoid receptor-mediated

therapeutic effects
The general molecular mechanisms after GR binding
have been described in the previous section. The therapeutic,
anti-inflammatory, and immunosuppressive effects of the
GR/ligand complex are mediated by transrepression and by
transactivation, as well as by other mechanisms that may
affect several signal transduction pathways. Genes that code
for anti-inflammatory proteins are induced by the GR via a
GR-DNA interaction. Thus, the expression of, e.g., lipocortin-1, interleukin (IL)-1 receptor antagonist, secretory leukocyte protease inhibitor, mitogen-activated protein kinase
phosphatase-1 (Kassel et al., 2001), and IL-10 can be
increased by the GR (Barnes, 2001). On the other hand,
the majority of the pro-inflammatory genes coding for
cytokines, chemokines, and adhesion molecules are regulated by the transcription factors NF-kB and AP-1, as well as
in T-cells, by the nuclear factor of activated T-cells (for a
review, see Barnes, 2001). In these cases, the GR interacts as
a monomer with the subunits of the respective transcription
factor, inhibiting its activity and, thus, repressing the expression of the respective pro-inflammatory proteins. Based on
the large number of genes that are regulated in this way, the
hypothesis that the transrepression mechanism mediated by
the GR via a GR-protein interaction is sufficient to achieve
anti-inflammatory effects has gained support over the years
27
(Cato & Wade, 1996; Karin, 1998; Barnes, 1998). Moreover,

a number of side effects seem to be mediated predominantly
via the transactivation mechanism (Reichardt & Schutz,
1998; Kellendonk et al., 1999; Reichardt et al., 2000).
Therefore, the identification of novel selective GR ligands,
which cause a receptor conformation that prefers a GRprotein interaction, and not a GR-DNA binding-dependent
mechanism, seems to be attractive. Such partial agonists may
have widely similar anti-inflammatory effects, while they
should clearly induce less side effects. One precondition for
such a concept is that the DNA-independent GR effects alone
are sufficient for the anti-inflammatory actions. Recently,
proof has been found for this presumption through the
investigation of GC responsiveness in GR mutated mice
(GRdim/dim mice). A mutation in the GR of these mice
prevents the dimerization of the receptor and, thereby, the
capability of DNA binding. As a consequence, all DNAdependent regulatory mechanisms of the GR are disturbed in
these mice. Remarkably, however, the classical GC-mediated
anti-inflammatory effects were also observed in GRdim/dim
mice (Reichardt et al., 2001). So, phorbol 12-myristate 13acetate (PMA)-induced ear edema in mice was reduced by
dexamethasone in wild-type, as well as in mutant, mice. In
addition, the investigators demonstrated a suppression of
serum IL-6 and serum tumor necrosis factor (TNF)-a in both
wild-type and mutant animals. Lipopolysaccharide-induced
mRNA expression for TNF-a, IL-6, IL-1b, and cyclo-oxygenase-2 could be efficiently blocked by dexamethasone,
regardless of the genotype (Reichardt et al., 2001).
Consequently, mechanisms exclusively mediated by GRprotein interactions seem to be sufficient to mediate the antiinflammatory effects (Reichardt & Schutz, 1998; Kellendonk et al., 1999; Reichardt et al., 2000).
Several companies recently have claimed the development of GR-binding compounds with a dissociated profile (strong transrepression/low transactivation). Belvisi et
al. (2001) reported that such a compound, although dissociated in vitro, does not show a separation between antiinflammatory and side effects in vivo in animal experiments. However, this is more likely to result from an
insufficient dissociation of the particular compound or the
generation of an active metabolite, rather than disproving
the concept. In addition, Coghlan and co-workers (2001)
reported non-steroidal compounds that bind selectively and
with high affinity to the GR. In an asthma model, they
demonstrated anti-inflammatory activity of an in vitro dissociated compound similar to that of prednisolone. However, in this publication, they did not investigate the
potential of in vivo side effect induction by compounds of
this class.
When using a stringent in vitro screening system, we
recently identified compounds with a dissociated in vitro
profile that show anti-inflammatory activity. This confirms
the suggestion that indeed DNA binding-independent mechanisms are sufficient to mediate anti-inflammatory effects.
Remarkably, when using these compounds, certain side
28
effects in rats are significantly reduced. Thus, we found a

clear dissociation with regard to TAT and glucose, two
surrogate parameters for transactivation-induced side effects
(Schacke et al., manuscript in preparation). However, it has
to be determined which particular side effects can be
avoided using such compounds (those that are preferentially
mediated via transactivation) and which not (those that are
preferentially mediated via transrepression). To predict this,
the detailed molecular mechanisms of the particular GCmediated side effects have to be known. Moreover, the most
important GR-mediated side effects must be determined to
fully address potential advantages in early clinical trials.
3. Mechanisms of glucocorticoid-mediated side effects

3.1. Skin
Topical, as well as systemic, GC therapy can induce
numerous cutaneous side effects. The potency and in
particular the duration of therapy determine their occurrence
and severity. The most important side effects include
atrophy of the epidermis and the dermis (Fig. 3B), or even
the subcutis, which can result in the irreversible striae rubrae
distensae (Fig. 3A), and disturbed wound healing. A less,
but not unimportant, side effect is the hypertrichosis
(enhanced hair growth), which facially could be particularly
problematic for women. However, hypertrichosis is usually
reversible and disappears after cessation of therapy. The
induction of the so-called steroid acne is predominantly
seen in younger patients (Fig. 3C). Perioral dermatitis is
frequently found after abuse of topical GCs on the face (Fig.
3D). Disturbance of skin pigmentation is rare, whereas
Fig. 3. Cutaneous side effects of GC therapy. GCs can induce cutaneous

side effects after systemic, as well as topical, treatment. A: Striae rubrae
distensae. B: Skin atrophy. C: Steroid acne. D: Perioral dermatitis.
induction of erythema and teleangiectasia (together with

the atrophy leading to persistent rubeosis steroidica) is
frequently seen in patients using topical GCs on the face
over long periods. In the following sections, we will focus in
more detail on the molecular mechanisms of skin atrophy
and disturbed wound healing as the most important cutaneous side effects of GC treatment.
3.1.1. Skin atrophy
In GC-induced atrophy, the skin becomes thin and
fragile, with all parts of the skin involved, including
epidermis as well as dermis (Oikarinen & Autio, 1991).
Additionally, thinning of the horny layer barrier results in
increased permeability, which accounts for an increased
transepidermal water loss (Kolbe et al., 2001). Women seem
to be more susceptible to skin thinning effects than men
(Katz et al., 1989).
Skin atrophy is the most frequent side effect of long-term
topical corticosteroid therapy. However, by measuring the
skin thickness every day, it has been shown that even a
single topical application of the highly potent GC clobetasol
propionate may lead to a skin-thinning process lasting for 3
days. Moreover, a skin thinning of 15% has been observed
after topical application of clobetasol propionate twice daily
for 16 days (Lubach et al., 1995). However, GCs with lower
local atrophogenic potential have been developed. Thus, in
clinical trials with methylprednisolone aceponate, skin
atrophy incidences of 1/1145 and 2/673 have been observed
in patients suffering from various types of eczema (Ortonne,
1994).
Remarkably, an atrophogenic potential has also been
demonstrated for systemic and inhalative GC treatment.
Even low doses of inhaled corticosteroids repress skin
collagen synthesis within a relatively short period. Thus,
in a study that used concentrations of procollagen propeptides in suction blister fluid for the in vivo assessment of
skin collagen synthesis, a 39 63% reduction of both types I
and III procollagen peptides has been observed after 6
weeks inhalative treatment with budesonide (Autio et al.,
1996).
Suppressive effects on cutaneous cell proliferation and
protein synthesis are mainly responsible for skin atrophy.
GCs reduce the proliferative activity of keratinocytes and
dermal fibroblasts (Pe rez et al., 2001). Additionally,
decreased protein synthesis by fibroblasts was observed.
Dermal alterations caused by GCs are mainly due to an
effect on the collagen turnover, a major component of the
extracellular matrix (ECM) of the skin. However, regulation
of other ECM proteins seems also to be involved in the
development of atrophy. Indeed, decreases of tenascin-C
gene expression (Ekblom et al., 1993; Fassler et al., 1996),
as well as production of hyaluronic acid and sulfated
glycosaminoglycans (Sarnstrand et al., 1982), have been
described under treatment with GCs. Similarly, elastin
synthesis was significantly down-regulated by hydrocortisone in vitro (Russell et al., 1995). Even though functional
GREs in the promoter of the elastin gene have been

identified by Del Monaco and co-workers (1997), a decrease
of elastin synthesis was observed in GC-treated cultivated
fibroblasts (Russell et al., 1995).
Molecular investigations on skin atrophy regulation have
been focused mainly on the synthesis of Type I collagen, the
major component of skin collagen fibrils, forming 80% of
the skin collagen. The minor components are types III (10
15%), V (5%), and IV collagens (basement membrane).
Type I collagen is a heterodimer composed of 3 a chains
encoded by the tightly controlled COL1A1 and COL1A2
genes (Vuorio & Crombrugghe, 1990). After topical treatment with GCs, a decrease of collagen I and III synthesis
has been demonstrated at both mRNA and protein levels
(Oikarinen et al., 1992, 1998). It is known that transforming
growth factor (TGF)-b enhances collagen I transcription, but
the underlying mechanisms are not completely understood.
It has been shown that in addition to other transcription
factor-binding sites, there is a consensus sequence for
Smad3 binding within the COL1A2 gene promoter (Dennler
et al., 1998). This binding site is required for full transcriptional induction of COL1A2 by TGF-b, and Smad proteins
have been shown to be essential for this response (Chen et
al., 2000). Interestingly, Song and co-workers (1999)
described a negative regulatory effect of the GR to Smadactivated gene transcription. They demonstrated that the GR
interacts with the activation domain of Smad3 in vitro and in
vivo, suggesting that a direct protein-protein interaction
between GR and Smad3 may mediate the negative regulation of the COL1A2 gene by the GR. Table 2 summarizes
the effects of GCs on cutaneous gene expression. In addition, several studies suggest that a1(I)-procollagen mRNA
stability is decreased by GC treatment (Mahonen et al.,
1998; Raghow et al., 1986), while others indicate that
regulation takes place at the translational level. Interestingly,
the dexamethasone-mediated down-regulation of a1(I)-procollagen mRNA appears to be associated with the induction
of a mediator protein (Maatta & Penttinen, 1993).
Taken together, a broad spectrum of different mechanisms seems to contribute to the development of skin
atrophy after GC treatment.
Further effects of GCs on the skin are a decreased
synthesis of epidermal lipids, as well as an increased transepidermal water loss (Kolbe et al., 2001). The mechanisms
of these effects are not well understood so far.
3.1.2. Disturbed wound healing
Wound healing disorders following systemic GC treatment are a commonly observed and experimentally proven
phenomenon (Sandberg, 1964; Ehrlich & Hunt, 1968; Reed
& Clark, 1985; Wahl, 1989; Beer et al., 2000). Surprisingly,
however, no detrimental effects of GC application on wound
healing, epithelial healing after keratoplasty, and other procedures have been described in clinical studies (Sugar et al.,
1984 1985; Rendina et al., 1992; Schulze et al., 1997;
Ulman & Mutaf, 1998). This obvious bias may be caused
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.
Hubner et al., 1996

Hubner et al., 1996
Hubner et al., 1996
Brauchle et al., 1995
Fassler et al., 1996
Beer et al., 1997
Beer et al., 1997
Beer et al., 1997
Frank et al., 1996
Frank et al., 1996
Frank et al., 1996
Frank et al., 1998
Frank et al., 1996
Madlener et al., 1998
Frank et al., 1998
Oikarinen et al., 1998
Oikarinen et al., 1998
Ekblom et al., 1993;
Fassler, et al., 1996
Russell et al., 1995
Up-regulation of genes occurs due to the GR-DNA interaction-dependent

transactivation mechanism, while the down-regulation, especially of the
cytokines, happens via transrepression, a GR-protein interaction. iNOS,
inducible nitric oxide synthase; KGF, keratinocyte growth factor; MME,
macrophage metalloelastase; N.D., not done; PDGF, platelet-derived
growth factor; PDGF-RA, platelet-derived growth factor receptor antagonist; TGF-bR, TGF-b receptor. Modified from Beer et al. (2000).
(1) by the short-term application of GCs, in most cases in

clinical studies, and (2) just by the incidental occurrence of
surgery and wounding in long-term GC-treated patients,
which are not reflected in well-documented studies.
Interestingly, a distinct suppressive effect of topical GCs
on scar formation has been found after keloid excision and
is used in therapeutic regimens (Sclafani et al., 1996).
Immediate GC injection into the wound bed suppresses
type I collagen expression, and can prevent recurrent keloid
growth. In this setting also, however, the wound healing
seems not to be affected, despite the depressed type I
collagen synthesis (Kauh et al., 1997).
GC-mediated effects are multifactorial and prevent the
early inflammatory phase, which is essential for efficient
wound repair (Leibovich & Ross, 1975). Markedly
decreased infiltration and activation of inflammatory cells
appear to result from GC administration prior to wounding.
Additionally, GCs intervene in the regulation of pro-inflammatory cytokines, growth factors, matrix proteins, and
matrix proteases, which seems to have impact on wound
healing also (Table 2). In addition, it has been shown that
dexamethasone inhibits COL7A1 gene expression (Gras et
al., 2001). Collagen VII represents the major collagenous
component of the anchoring fibrils. These are attachment
structures stabilizing the association of the cutaneous basement membrane to the underlying dermis. Interference in this
attachment structure may lead to deteriorated wound healing.
Gras and co-workers (2001) were able to demonstrate that,
after dexamethasone treatment, the activated GR binds to the
30
COL7A1 promoter region containing GRE half sites, thus

interfering with the TGF-b signaling. However, the antagonization of TGF-b activation is not dependent on inhibition
of Smads. Therefore, this repression mechanism could be a
DNA-dependent one, and should be avoided by selective GR
agonists (SEGRAs).
3.2. Skeleton and muscle
Growth failure and delayed puberty are commonly
experienced by children receiving long-term systemic GC
therapy. A direct relationship exists between the dose of GC
used and growth inhibition. As little as 2.5- to 5.0-mg
prednisolone daily can cause retardation in statural growth
(Wolthers & Pedersen, 1990; Avioli, 1993). Remarkably,
growth retardation can even occur in children using intranasal or inhalative GC treatment for allergic rhinitis and
asthma (Skoner et al., 2000; Wolthers, 1996; Allen, 1998).
Besides causing a delay in bone aging and growth (Bircan et
al., 1997), GCs may also affect the final adult height. A
meta-analysis revealed a small, but significant, association
of corticosteroid therapy, generally with diminished final
height (Allen et al., 1994).
3.2.1. Osteoporosis
Patients who are subjected to long-term GC treatment
develop an increased risk for osteoporosis, which is associated with a high risk of bone fracture. It has been
documented that bone loss occurs in two phases, with a
rapid initial phase of 12% during the first few months,
followed by a slower phase of 2 5% annually (Manolagas & Weinstein, 1999). Today, there is strong evidence of
the under-diagnosis of GC-induced osteoporosis in the
clinical setting. It has been reported that more than 50%
of patients receiving chronic high-dose oral GCs were not
evaluated for osteoporosis (Bell et al., 1997). Recent evidence, however, suggests that even oral dosages as low as
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).
tion and activity. (2) GCs induce decreased gastrointestinal

Ca2 + absorption and increased urinary Ca2 + excretion. In
order to maintain the serum Ca2 + level, parathormone
release is counter-regulatorily increased, leading to increased osteoclastic bone resorption. (3) Reduced levels of
adrenal sex hormones caused by GC-induced adrenal suppression are involved in the manifestation of osteoporosis
(Lane et al., 1998). (4) GCs reduce the number of bone cells
by an increase in apoptosis of osteoblasts and osteocytes, as
shown in vivo (Silvestrini et al., 2000) and in vitro (Weinstein et al., 1998). (5) GCs exert suppressive effects on
growth hormone, insulin-like growth factor-1, and TGF-b.
These mediators, however, are of critical importance for
bone homeostasis.
The distinct underlying molecular mechanisms are only
partly understood. The expression of osteocalcin, representing the main non-collagenous protein of the ECM of the
bone, is repressed via an action of the GR on negative GREs
in the promoter of this gene (Stromstedt et al., 1991; Meyer
et al., 1997). Synthesis of type I collagen is repressed by
GCs, as explained for the skin effects in Section 3.1.1. The
molecular mechanisms of osteoclast differentiation and
activation have been illuminated recently. Two factors that
are very important for osteoclast development were discovered. Osteoprotegerin ligand (OPG-L) stimulates osteoclast
differentiation, enhances the capacity of mature osteoclasts,
and inhibits osteoclast apoptosis, thus expanding the pool of
activated osteoclasts. GCs up-regulate the OPG-L mRNA
levels via a transactivation mechanism. In contrast, OPG
mRNA and protein levels are decreased by GCs via transrepression. OPG acts as a soluble secreted receptor for
OPG-L that prevents it from binding to and activating its
receptor on osteoclast cell surfaces. Thus, the biologic
effects of OPG on bone cells are the opposite of that of
OPG-L. Consequently, GCs enhance the OPG-L/OPG ratio
this way, favoring bone resorption via an enhancement of
mature and activated osteoclasts (Simonet et al., 1997;
Yasuda et al., 1998a, 1998b; Lacey et al., 1998).
Taken together, the loss of bone is complex and results
from a number of additive effects, such as reduction of bone
formation cells by apoptosis, reduced synthesis of boneforming ECM proteins by osteoblasts, and enhanced bone
resorption (see also Kousteni et al., 2001). From the
molecular point of view, there is evidence that DNAdependent mechanisms (repression of osteocalcin gene/
transactivation of OPG-L gene) are involved in at least
some of the mentioned effects. However, some effects of
GC treatment on the bone are mediated via a different
receptor (mineralocorticoid effects) or by GR-mediated
DNA-independent transrepression (collagen type I).
3.2.2. Muscle atrophy/myopathy
GCs exert catabolic effects on skeletal muscle that at
higher doses may lead to steroid myopathy (Price et al.,
2001). Proximal muscles are usually involved, quadriceps
and other pelvic girdle muscles being more severely affec-
31
ted. Fast-twitch glycolytic type IIB fibers are particularly

susceptible. Physical exercise is effective in preventing
steroid myopathy (Bielefeld, 1996). The recovery from
severe generalized weakness may last up to 6 weeks (Shee,
1990). Whereas frequencies of up to 60% myopathy and
steroid-induced weakness have been described in several
patient populations (Batchelor et al., 1997), most reports
deal with the adverse effects in asthmatic patients. Elevated
creatinine kinase levels were found in almost all ventilated
patients in status asthmaticus; about one-third of these
patients developed symptomatic weakness (Blackie et al.,
1993). Hip flexor weakness have been observed in 64% of
asthmatic patients taking more than 40 mg/day of prednisolone (Bowyer et al., 1985). Recent investigations suggest
that GCs may even directly affect the clinical status of
asthma patients by contributing to inspiratory muscle weakness (Akkoca et al., 1999).
The catabolic effects of GCs on skeletal muscle are
mediated via several cellular mechanisms. GCs inhibit the
glucose uptake in skeletal muscles. This may contribute to
the breakdown of muscle proteins. GCs directly affect the
muscle protein content by both stimulation of protein
degradation and inhibition of protein synthesis. One of the
genes responsible for these phenomena encodes the glutamine synthetase, which catalyzes the formation of glutamine
that is then exported from skeletal muscles in catabolic
conditions. During GC-induced muscle atrophy, the glutamine efflux accounts for 25 30% of the total protein export
from skeletal muscles (LaPier, 1997). In rats, an increase in
glutamine synthetase protein and mRNA levels were found
after GC administration (Falduto et al., 1989). In addition, it
was shown that GCs increase the transcription of genes
encoding components of the ubiquitin-proteasome pathway,
thereby increasing the proteolytic capacity of muscle cells
(Price et al., 2001).
There is evidence that transactivation of several genes by
the GR is involved in generating muscle atrophy. Even if
transactivation is probably not the only mechanism causing
muscle atrophy, SEGRAs might have a good chance of
being better tolerated with regard to this serious unwanted
effect.
3.3. Eye
After systemic and topical GC application (either by
application to the eye or the lung via inhalation or systemic
therapy, regardless of the indication), adverse effects on the
eyes have been demonstrated. These include the development of cataract and glaucoma, as well as more rare
complications, such as retinal emboli and maculopathy and,
especially after topical treatment, infection (Carnahan &
Goldstein, 2000). GCs belong to the most frequently topically used pharmacons in ophthalmology. Indications
include conjunctivitis, keratitis, and scleritis, as well as
post-operative management, e.g., after cataract extraction
and cornea transplantation.
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
alterations in ECM composition. For example, GCs induce

increased accumulation of polymerized glycosaminoglycans, possibly due to decreased availability of catabolic
enzymes (Tripathi et al., 1999). In addition, the ECM excess
seems to result from an increased production of fibronectin
and collagen type IV (Zhou et al., 1998). In the organ
culture of TM cells, collagen type I is also increased after
dexamethasone incubation. This observation is in contrast to
the known negative effect of GCs on collagen synthesis in
dermal fibroblasts. In fact, Zhou and co-workers have not
obtained any inhibition of collagen synthesis in TM cells by
dexamethasone. These observations provide evidence that
GC-mediated events in TM cells causing glaucoma are cell
type-specific. After prolonged GC treatment of human TM
cells, the highest increase was obtained for the 55-kDa TMinduced GC response/myocillin (TIGR/MYOC) gene product (Lutjen-Drecoll et al., 1998). In conjunction with the
findings of other ECM proteins, this induction was not
found in fibroblasts from skin, sclera, or cornea (Zhou et
al., 1998). Interestingly, in the promoter sequence of the
TIGR/MYOC gene, several GREs have been identified.
There is a genetic predisposition for developing primary
open-angle glaucoma in patients with mutations in the
TIGR/MYOC gene (Zimmerman et al., 1999; Zhou &
Vollrath, 1999). It might be that the transactivation-mediated
increase of TIGR/MYOC is responsible for the GC-mediated increase of the intraocular pressure. Since transactivation of gene transcription seems to be at least partially
involved, novel SEGRAs might be safer with regard to
glaucoma induction.
3.4. Central nervous system
Existing psychiatric problems can be aggravated by GC
treatment. However, mood swings, euphoria, depression,
and suicide attempts may all also occur in previously stable
persons (Carpenter & Gruen, 1982). Steroid psychoses
(i.e., mania, hallucinations, and delusions) have been
reported (Hall et al., 1979). Psychiatric symptoms are more
common in women and usually develop within 2 weeks of
beginning treatment, particularly with doses of > 40 mg/day
prednisolone (Brown et al., 1999). In some patients, abuse
of corticosteroids for their euphoric effects and corticosteroid dependence has been observed (Goldberg & Wise,
1986 1987; Brown, 1997). Moreover, patients undergoing
acute and long-term administration of GCs may develop
psychiatric withdrawal symptoms, including depression and
fatigue (Fricchione et al., 1989; Dixon & Christy, 1980).
GCs have direct and reversible adverse effects on memory
and cognition that are at least partly mediated through the
hippocampus (Wolkowitz et al., 1997). Several studies
indicated that chronic GC treatment may dose dependently
cause cerebral atrophy (Bentson et al., 1978; Zanardi et al.,
2001). The reported incidence is 60% for depression and
30% for manic symptoms in endogenous hypercortisolism
(Haskett, 1985). In a meta-analysis of the literature (Brown
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
production and in increasing glucose uptake in muscle and

fatty tissue (Andrews & Walker, 1999). Persons who have a
diminished b-cell function or are low-insulin responders are
predisposed to develop overt diabetes during GC therapy
(Henriksen et al., 1997; Wajngot et al., 1992). The effects of
GCs on hyperglycemia usually remit within 48 hr of
discontinuation of oral administration. The treatment of
GC-induced diabetes resembles essentially the treatment
of Type 2 diabetes.
In patients with hypercortisolism due to Cushings
syndrome or acromegaly, the incidence of diabetes mellitus
is 30 40% (Biering et al., 2000). An enhanced incidence for gestational diabetes mellitus (23.8% vs. 4% in
controls) was demonstrated in women receiving GCs for
threatened preterm delivery (Fisher et al., 1997). In rheumatic patients, a strong association between the cumulated
prednisone dose and the development of steroid-induced
diabetes has been shown (odds ratio, 6:35) (Raul ArizaAndraca et al., 1998). GCs as part of the standard therapy
after organ transplantation are considered to be responsible
mainly for the development of post-transplant diabetes
mellitus (PTDM). Thus, prednisolone-treated renal transplant patients were found to develop PTDM in up to 40%
of the cases (Onwubalili & Obineche, 1992). In heart and
liver transplant patients, cumulative PTDM incidences of
15.7% and 19.1%, respectively, were observed (Depczynski
et al., 2000; Gonzalez-Quintela et al., 1995). Although no
clear relationship to GC dosage had been found in either
study, the impact of GCs is verified by investigations
showing a reduced rate of PTDM and improved control
of diabetes after steroid withdrawal. This was accompanied
by lowered total cholesterol levels, obesity, and hypertension rates (Everson et al., 1999). Taken together, GCinduced diabetes represents a frequent and severe medical
problem.
GCs restore carbohydrates from amino acids by stimulating enzymes of gluconeogenesis in the liver, by mobilization and degradation of proteins, and by support of
glycogen deposition in the liver.
At the molecular level, synthesis and activity of enzymes
of gluconeogenesis are subjected to a very complex regulatory mechanism (Schweizer-Groyer et al., 1997). This
mechanism involves tissue-specific factors, as well as hormonal signals. For example, the promoter of the TAT gene,
encoding a hepatic enzyme of gluconeogenesis, contains
regulatory sequences enabling activation by GCs (Rigaud et
al., 1991; Granner & Hargrove, 1983; Jantzen et al., 1987).
These so-called GC-responsive units or composite GREs
comprise binding sites for the GR and other transcription
factors (Grange et al., 1991; Roux et al., 1995; Sassi et al.,
1998). This arrangement confers tissue specificity to the
response of GCs and allows positive synergism between GC
and glucagon pathways and negative synergism with the
insulin pathway. Genes encoding other enzymes of gluconeogenesis are regulated in a similar manner. Aspartate
aminotransferase (AAT) plays a major role in amino acid
34
metabolism and in the malate-aspartate shuttle, an essential

pathway for the survival of all cells. Two isoenzymes of
AAT exist, one cytoplasmic and one mitochondrial. GCs
stimulate the cytoplasmic enzyme activity in the liver and
the kidney (Beurton et al., 1999). Glucose-6-phosphatase
(G6Pase) catalyses another important step of gluconeogenesis. The promoter of the G6Pase gene contains a GRE,
suggesting an activation of gene transcription by activated
GRs, leading to an increased rate of gluconeogenesis
(Yoshiuchi et al., 1998). GCs interfere with gluconeogenesis
also by inducing the rate-limiting enzyme PEPCK. Besides
increasing the transcription rate of the gene encoding
PEPCK, GCs further promote the stability of its mRNA.
This takes place through a transactivation mechanism via
binding of the activated GR to specific binding sites in the
promoter. Thus, enhanced glucose synthesis occurs, followed by increased glycogen storage in the liver. Glycogen
storage involved glycogen synthase, which is tightly controlled by a reversible phosphorylation of serine residues.
The main physiologic stimuli of this enzyme are glucose and
glucagon. GCs inactivate glycogen phosphorylase and activate glycogen synthase. These effects are dependent on
protein synthesis (OBrien et al., 1995; Friedman et al.,
1997; Scott et al., 1998; Crosson & Roesler, 2000).
Taken together, transactivation seems to be the determining mechanism in influencing glucose metabolism and
glycogen storage. GCs induce an increase in the synthesis
of glucose. Most of the effects leading to enhanced glucose
synthesis are mediated by increased gene transcription of
enzymes involved in gluconeogenesis. Therefore, it is likely
that these side effects can be reduced by applying dissociated GR agonists. In fact, this hypothesis is supported by
our own observations that SEGRAs do not induce an
increase in the level of blood glucose at anti-inflammatory
effective concentrations in rodents (Schacke et al., manuscript in preparation).
3.5.2. Adrenal insufficiency
The most common effects of long-term GC treatment
affect the HPA axis and cause disorders, such as iatrogenic
Cushings syndrome (moon face, buffalo hump, central
obesity), adrenal insufficiency, and growth inhibition (Fig.
1). The appearance of a cushingoid habitus is extremely
variable; some patients seem able to tolerate 30 mg/day
prednisolone, while others become cushingoid on less than
one-half of this dose (Stanbury & Graham, 1998). An
additional problem of suppression of the HPA axis represents reduced general steroid-hormone production due to a
decreased adrenocorticotropic hormone (ACTH) level,
favoring further side effects, such as hypogonadism and
osteoporosis, as outlined in Section 3.2.1.
Several studies dealt with the incidence of GC-induced
adrenal insufficiency and its duration after cessation of GC
treatment. After long-term systemic GC therapy (more than
1 year), adrenal insufficiency has to be expected in 100% of
the patients (Hummel et al., 1991). After high-dose dex-
amethasone therapy for 28 days, adrenal insufficiency

lasting for more than 4 weeks has been demonstrated
(Felner et al., 2000). Moreover, even after shorter GC
treatment (median 8 days), in 45% of the patients, adrenal
insufficiency has been observed that was sustained between
2 days and more than 3 months. The lack of correlation
between duration as well as daily and cumulative doses of
GC treatment and adrenal suppression in this study underlines the poorly predictable risk for the development of a
GC-withdrawal syndrome (Henzen et al., 2000). Remarkably, even high-dose inhalative treatment with GCs may
result in adrenal insufficiency with a threshold dose that for
beclomethasone dipropionate may lie between 800 and 1200
mg/day (Hasegawa et al., 1996; Gupta et al., 2000). In fact,
prolonged GC treatment is considered to be the main cause
of adrenal insufficiency (Goichot et al., 2000).
Corticosteroid administration results in a negative feedback effect via GRs in the anterior hypothalamus, which, in
turn, suppresses the production of corticotrophin-releasing
hormone (CRH) and POMC/ACTH (Fig. 5).
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.
The prolonged suppression of adrenocorticotropin levels

leads to atrophy of the adrenal cortex and secondary adrenal
insufficiency. GCs mediate these effects via both DNA
binding-dependent and DNA binding-independent mechanisms (Fig. 5). The GC-related adrenal insufficiency
becomes only clinically relevant (hypotonia) if exogenous
GC therapy is withdrawn too rapidly (Bell, 1984; Kountz &
Clark, 1997) or, in the case of stressful situations (e.g.,
surgery), when higher GC levels may be required (Glowniak
& Loriaux, 1997). It is noteworthy, however, that sufficient
exogenous GC supplementation also depresses the synthesis
of adrenal androgens, and in females, this way may lead to
nullification of the androgen-dependent anabolism, e.g., of
the bones (Robinzon & Cutolo, 1999).
In contrast to the regulation of POMC mRNA expression, the regulation of CRH expression by the GR is
independent of DNA binding, as shown in GRdim/dim mice
(Reichardt & Schutz, 1998; Reichardt et al., 2000). Since
the release of ACTH is mainly controlled by CRH, transrepression is without doubt the dominating molecular mechanism. Indeed, SEGRAs showed ACTH suppression in
rodents similar to classical GCs (Schacke et al., in preparation).
3.6. Cardiovascular system
Hypertension, dyslipidemia, and a reduced fibrinolytic
potential have been identified as the main adverse effects of
GCs on the cardiovascular system (Sholter & Armstrong,
2000; Sartori et al., 1999). A hypertension incidence of 88%
recently has been observed in 163 children with severe
asthma receiving chronic oral or inhalative GC therapy
(Covar et al., 2000). In long-term stable renal and liver
transplant patients, the prednisolone dose was found to be the
only independent variable, predicting increased serum cholesterol levels (Fernandez-Miranda et al., 1998). A hypofibrinolytic state due to increased plasminogen activator
inhibitor-1 activity was observed in 69% of the steroidtreated heart transplant recipients in comparison with 35%
in the non-steroid-treated group. In 24% of the patients,
myocardial microthrombi were found (Sartori et al., 1999).
Hypertension, dyslipidemia, and reduced fibrinolytic potential may predispose GC-treated patients to atherosclerosis,
coronary artery disease, and to a high cardiovascular morbidity and mortality (Nashel, 1986). The hypertensive effect
of the natural GC cortisol has been well established by
experiments demonstrating a dose-dependent increase of
blood pressure after cortisol infusion and by the high
prevalence (80%) of hypertension in Cushings syndrome
(Kelly et al., 1998). Hypertension induced by therapeutic
GCs is more prevalent in patients with high doses of GCs and
occurs often in elderly patients with a positive family history
of essential hypertension (Sholter & Armstrong, 2000; Sato
et al., 1995).
The mechanisms of GC-induced hypertension include
increased systemic vascular resistance, increased extracel-
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
under discussion, the main molecular mechanisms seem to

be transactivation of gene expression either via the GR or
the MR and changing of activity status of a protein via
phosphorylation.
The generation of synthetic GCs with high selectivity for
the GR in the 1960s and 1970s fairly excluded mineralocorticoid effects in GC therapy. It might be possible that the
introduction of SEGRAs will lead to a further reduction of
GR-typical cardiovascular side effects.
3.7. Gastrointestinal system
Adverse effects on the gastrointestinal system caused by
GCs include peptic ulcers, upper gastrointestinal bleeding,
pancreatitis (Di Fazano et al., 1999), and, especially after
inhalative usage, oral candidiasis (Kennedy et al., 2000).
Carson et al. (1991) investigated the incidence of upper
gastrointestinal bleeding in a cohort of 19,880 ambulant
patients with dermatitis or asthma systemically treated with
GCs. Whereas in patients without a history of upper gastrointestinal bleeding the incidence was low (2.8 cases per
10,000 person-months), it was notably higher in patients
receiving anticoagulants and those with a history of upper
gastrointestinal bleeding (23.0 and 15.9 cases per 10,000
person-months, respectively). In this study, however, the
concomitant use of nonsteroidal anti-inflammatory drugs
(NSAIDs) was not evaluated.
The literature on the gastrointestinal safety of oral
steroids in humans is controversial. Results from clinical
trials and epidemiological studies have been heterogeneous,
either indicating a dose-dependent increased risk of peptic
ulcers in the groups treated with GCs or no difference to
controls. The pooled relative risk for peptic ulcers in 3 metaanalyses of the literature had been 2.3, 1.7, and 1.3,
respectively (Tox et al., 2001; Rodriguez & HernandezDiaz, 2001). Remarkably, however, clear data exist regarding the enhancement of risk associated with NSAIDs by
concomitant GC therapy. So, in a study from 1991, in
comparison with patients receiving NSAIDs without GCs,
the relative risk for peptic ulcers increased with simultaneous GC therapy by a factor of 14.6 (95% confidential
interval, 6.7 32.0), whereas GC therapy alone had a relative risk of only 1.1 compared with control probands (Piper
et al., 1991). Moreover, a recent study from Wolfe and
Hawley (2000) suggests that in distinct patient populations,
such as in patients with rheumatoid arthritis, GC therapy
(relative risk, 2.9) may represent an even more important
risk factor for gastrointestinal complications than NSAIDs
(relative risk, 1.4).
Experimentally, GCs have been shown to increase gastric
acid secretion, to reduce gastric mucus, to cause gastrin and
parietal cell hyperplasia, and to delay the healing of ulcers in
animal studies (Richardson, 1985). These events, which on
a molecular basis are not fully understood yet, are considered to be responsible for the gastrointestinal side effects of
GCs.
3.8. Immune system

The inhibition of the inflammatory and specific immune
systems represents a central target of pharmacological GC
treatment, and the molecular mechanisms of how this is
achieved have been described in Section 1.2. Consequently,
adverse effects of GC therapy [and also of endogenous
hypercortisolism (Kloehn et al., 1997)] include an increased
risk for all kinds of infection (in particular, during oversuppression). Moreover, due to the immunosuppression, a
masking of infection symptoms may occur, preventing early
clinical recognition.
In a retrospective analysis of 71 controlled clinical trials
(Stuck et al., 1989), a relative risk of 1.6 (95% confidence
interval, 1.3 1.9) with respect to infectious complications
was found in patients with systemic GC therapy. The
infection rate was not increased in patients given a daily
dose of < 10-mg prednisolone. Whereas the infection risk
may not be strikingly enhanced by moderate doses of GCs
in general, there is, however, evidence for more frequent
opportunistic and complicated infections. Thus, increased
incidences of active tuberculosis, oral candidiasis and even
aspergillosis, and complicated varicella infection have been
described (Senderovitz & Viskum, 1994; Cline & Davis,
1997; Kennedy et al., 2000; Dowell & Bresee, 1993).
Moreover, GC treatment may significantly enhance the
infection risk in situations already characterized by a diminished immunocapacity. One example is the increased neonatal and maternal infection risk after antenatal GC
treatment for the prevention of chronic lung disease (Walfisch et al., 2001).
Reactivation of cytomegalovirus (CMV) under GC therapy is a serious problem, e.g., in transplant patients. It was
thought that this was just a consequence of the immunosuppression, leading to a diminished antiviral immune
response as an intrinsic side effect. Very recently, however,
evidence for a dual mechanism of GC-enhanced CMV
replication was found. So GREs were discovered in the
CMV IE1/2 enhancer, and direct stimulation of replication
by classical GCs was demonstrated. Thus, direct transactivation of virus gene expression is mediated by classical
GCs via DNA binding (Prosch et al., manuscript submitted). Based on our preliminary data indicating that SEGRAs
do not have this property in vitro, it might be speculated
that they promote herpes virus replication to a lesser extent
only.
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
the molecular mechanisms that mediate the GC effects.

Research efforts, however, were focussed mainly on the
desired GC effects, their anti-inflammatory and immunosuppressant properties. From a molecular point of view, it
turned out that the anti-inflammatory effects are mediated
predominantly via transrepression and are DNA bindingindependent.
Recent investigations have led to considerable advances
also in the understanding of the molecular mechanisms for
the GC-induced side effects. Table 3 gives a summary of
these very heterogeneous and complex mechanisms. For a
number of side effects, the underlying precise molecular
mechanisms are still unknown or several mechanisms seem
to be involved, and it is not clear which is the dominating
one (e.g., osteoporosis). It has been demonstrated, however,
that some side effects are mediated predominantly via
transrepression (skin atrophy, suppression of HPA axis),
whereas others are predominantly mediated via transactivation (diabetes mellitus, glaucoma).
37
The observation that therapeutic effects are mediated

predominately via transrepression, whereas at least certain
side effects are mediated mainly via transactivation, led to
drug-finding programs, with the aim of discovering SEGRAs with weakened transactivation activity. Such compounds are appearing on the horizon now.
Although it is hard to reliably predict the full clinical
profile of SEGRAs today, the information currently available argues for a superiority of SEGRAs with regard to
induction/severity of diabetes mellitus and glaucoma. Since
these are serious side effects limiting the clinical value of
GC therapy, it can be speculated that the development of
SEGRAs will represent a considerable advantage in antiinflammatory therapy. Appropriate in vitro and, in particular, in vivo experiments with SEGRAs will be designed to
further support this hypothesis by experimental data. Further
investigations on the mechanisms of GC-mediated effects
and, in particular, side effects are necessary. Analyzing side
effects of classical GCs in GRdim/dim mice will help in the
Table 3
Side effect-associated proteins: regulation by GCs and molecular mechanisms
Side effect
Primary targeted molecule
Mechanism
DNA-dependent
Activation
Skin atrophy
Type I collagen
Type III collagen
Tenscin C
Sulfated glycosaminoglycans
Decreased wound healing
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
TIGR/MYOC gene product

Fibronectin
Type IV collagen
Type I collagen
X
(X)
(X)
(X)
Psyche
5-HT1A receptor
Suppression of HPA axis
CRH
POMC/ACTH
Repression
(X)
(X)
(X)
(X)
(X)
(X)
(X)
X
(X)
X
(X)
(X)
X
X
X
Diabetes mellitus induction
TAT
AAT
G6Pase
PEPCK
X
X
X
X
Hypertension
aEnaC
sgk
X
X
X, mechanism that mediates GR effect; (X), possible mechanism of GR effect.
DNA-independent
Repression
38
better understanding of the molecular mechanisms of side

effect induction and in making further predictions for
SEGRAs. In vivo investigations and first clinical trials will
finally indicate the safety/efficacy profile of SEGRAs and
will contribute to a better understanding of the molecular
basis of GC-mediated effects.
Acknowledgements
We would like to thank Professor Andrew Cato
(Forschungszentrum Karlsruhe, Germany) and Professor
Guenther Schuetz (DKFZ, Heldelberg, Germany) for critical
reading of the manuscript, Professor Stephen Katz (NIH,
Bethesda, USA) for helpful discussions, Professor Wolfram
Sterry (Charite, Berlin, Germany) and Dr. Christoph Niels
(University Marburg, Germany) for providing the clinical
figures (Figs. 3A D and Fig. 1, respectively), and Stefanie
Schoepe for editing the manuscript.
References
Adachi, J. D., Bensen, W. G., Brown, J., Hanley, D., Hodsman, A., Josse,
R., Kendler, D. L., Lentle, B., Olszynski, W., Ste-Marie, L. G., Tenenhouse, A., & Chines, A. A. (1997). Intermittent etidronate therapy to
prevent corticosteroid-induced osteoporosis. N Engl J Med 337,
382 387.
Akkoca, O., Mungan, D., Karabiyikoglu, G., & Misirligil, Z. (1999). Inhaled and systemic corticosteroid therapies: do they contribute to
inspiratory muscle weakness in asthma? Respiration 66, 332 337.
Allen, D. B. (1998). Influence of inhaled corticosteroids on growth: a
pediatric endocrinologists perspective. Acta Paediatr 87, 123 129.
Allen, D. B., Mullen, M. L., & Mullen, B. (1994). A meta-analysis of the
effect of oral and inhaled corticosteroids on growth. J Allergy Clin
Immunol 93, 967 976.
Andrews, R. C., & Walker, B. R. (1999). Glucocorticoids and insulin
resistance: old hormones, new targets. Clin Sci 96, 513 523.
Armaly, M. F. (1963). Effects of corticosteroids on intraocular pressure and
fluid dynamics. I. The effect of dexamethasone in the normal eye. Arch
Ophthalmol 70, 98 103.
Asher, C., Wald, H., Rossier, B. C., & Garty, H. (1996). Aldosteroneinduced increase in the abundance of Na+ channel subunits. Am J
Physiol 271, C605 C611.
Autio, P., Karjalainen, J., Risteli, L., Risteli, J., Kiistala, U., & Oikarinen,
A. (1996). Effects of an inhaled steroid (budesonide) on skin collagen
synthesis of asthma patients in vivo. Am J Resp Crit Care Med 153,
1172 1175.
Avioli, L. V. (1993). Glucocorticoid effects on statural growth. Br J Rheumatol 32(suppl. 2), 27 30.
Barnes, P. J. (1998). Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci (Lond) 94, 557 572.
Barnes, P. J. (2001). Molecular mechanisms of corticosteroids in allergic
diseases. Allergy 56, 928 936.
Batchelor, T. T., Taylor, L. P., Thaler, H. T., Posner, J. B., & DeAngelis, L. M.
(1997). Steroid myopathy in cancer patients. Neurology 48, 1234 1238.
Beato, M., Chalepakis, G., Schauer, M., & Slater, E. P. (1989). DNA
regulatory elements of steroid hormones. J Steroid Biochem 32,
737 747.
Beer, H. D., Longaker, M. T., & Werner, S. (1997). Reduced expression of
PDGF and PDGF receptors during impaired wound healing. J Invest
Dermatol 109, 132 138.
Beer, H. D., Fassler, R., & Werner, S. (2000). Gluocorticoid-regulated gene
expression during cutaneous wound repair. Vitam Horm 59, 217 239.
Bell, N. H. (1984). The glucocorticoid withdrawal syndrome. Adv Exp Med

Biol 171, 293 299.
Bell, R., Carr, A., & Thompson, P. (1997). Managing corticosteroid-induced osteoporosis in medical outpatients. J R Coll Physicians Lond
31, 158 161.
Belvisi, M. G., Wicks, S. L., Battram, C. H., Bottoms, S. E. W., Redford, J. E.,
Woodman, P., Brown, T. J., Webber, S. E., & Foster, M. L. (2001).
Therapeutic benefit of a dissociated glucocorticoid and the relevance of
an in vivo separation of transrepression from transactivation activity.
J Immunol 166, 1975 1982.
Bentson, J., Reza, M., Winter, J., & Wilson, G. (1978). Steroids and apparent cerebral atrophy on computed tomography scans. J Comput Assist
Tomogr 2, 16 23.
Beurton, F., Bandyopadhyay, U., Dieumegard, B., Barouki, R., & Aggerbeck, M. (1999). Delineation of insulin-responsive sequence in rat cytosolic aspartate aminotransferase gene: binding sites for hepatocyte
nuclear factor-3 and nuclear factor I. Biochem J 343, 687 695.
Bielefeld, P. (1996). Present status of cortisone myopathy. Rev Med Interne
17, 255 261.
Biering, H., Knappe, G., Gerl, H., & Lochs, H. (2000). Prevalence of
diabetes in acromegaly and Cushing syndrome. Acta Med Austriaca
27, 27 31.
Bircan, Z., Soran, M., Yildirim, I., Dogan, M., Sahin, A., Bilici, A., &
Danaci, M. (1997). The effect of alternate-day low dose prednisolone
on bone age in children with steroid dependent nephrotic syndrome. Int
Urol Nephrol 29, 357 361.
Black, R. L., Oglesby, R. B., von Sallmann, L., & Bunim, J. J. (1960).
Posterior subcapsular cataracts induced by corticosteroids in patients
with rheumatoid arthritis. JAMA 1174, 166 171.
Blackie, J. D., Gibson, P., Murree-Allen, K., & Saul, W. P. (1993). Acute
myopathy in status asthmaticus. Clin Exp Neurol 30, 72 81.
Bowyer, S. L., LaMothe, M. P., & Hollister, J. R. (1985). Steroid myopathy:
incidence and detection in a population with asthma. J Allergy Clin
Immunol 76, 234 242.
Brauchle, M., Fassler, R., & Werner, S. (1995). Suppression of keratinocyte
growth factor expression by GCs in vitro and during wound healing.
J Invest Dermatol 105, 579 584.
Brennan, F. E., & Fuller, P. J. (2000). Rapid upregulation of sgk gene
expression by corticosteroid in vivo. Mol Cell Endocrinol 166,
129 136.
Brown, E. S. (1997). Chemical dependence involving glucocorticoids. Ann
Clin Psychiatry 9, 185 187.
Brown, E. S., Khan, D. A., & Nejtek, V. A. (1999). The psychiatric side
effects of corticosteroids. Ann Allergy Asthma Immunol 83, 495 504.
Carlstedt-Duke, J. (1999). GC receptor b: view II. Trends Endocrinol Metab
10, 339 342.
Carnahan, M. C., & Goldstein, D. A. (2000). Ocular complications of topical, peri-ocular, and systemic corticosteroids. Curr Opin Ophthalmol
11, 478 483.
Carpenter, W. T., Jr., & Gruen, P. H. (1982). Cortisols effects on human
mental functioning. J Clin Psychopharmacol 2, 91 101.
Carson, J. L., Strom, B. L., Schinnar, R., Duff, A., & Sim, E. (1991). The
low risk of upper gastroinstestinal bleeding in patients dispensed corticosteroids. Am J Med 91, 223 228.
Cato, A. C., & Wade, E. (1996). Molecular mechanisms of anti-inflammatory action of glucocorticoids. Bioessays 18, 371 378.
Charman, C. R., Morris, A. D., & Williams, H. C. (2000). Topical corticosteroid phobia in patients with atopic eczema. Br J Dermatol 142,
931 936.
Chen, S. J., Yuan, W., Lo, S., Trojanowska, M., & Varga, J. (2000). Interaction of Smad3 with a proximal Smad-binding element of the human
a2(I) procollagen gene promoter required for transcriptional activation
by TGF-b. J Cell Physiol 183, 381 392.
Chen, S. Y., Bhargava, A., Mastroberardino, L., Meijer, O. C., Wang, J.,
Buse, P., Firestone, G. L., Verrey, F., & Pearce, D. (1999). Epithelial
sodium channel regulated by aldosterone-induced protein sgk. Proc
Natl Acad Sci USA 96, 2514 2519.

Chiu, M. Y., Sprague, S. M., Bruce, D. S., Woodle, E. S., Thistlethwaite,
J. R., Jr., & Josephson, M. A. (1998). Analysis of fracture prevalence
in kidney-pancreas allograft recipients. J Am Soc Nephrol 9,
677 683.
Cline, J. C., & Davis, S. M. (1997). Risks of infection or reactivation of
tuberculosis associated with chronic corticosteroid therapy. Ann Pharmacother 31, 775 776.
Coghlan, M. J., Kym, P. R., Elmore, S. W., Wang, A. X., Luly, J. R.,
Wilcox, D., Stashko, M., Lin, C. W., Miner, J., Tyree, C., Nakane,
M., Jacobson, P., & Lane, B. C. (2001). Synthesis and characterization
of non-steroidal ligands for the glucocorticoid receptor: selective quinoline derivatives with prednisolone-equivalent functional activity. J
Med Chem 44, 2879 2885.
Cooper, C., Coupland, C., & Michell, M. (1995). Rheumatoid arthritis,
corticosteroid therapy and hip fracture. Ann Rheum Dis 54, 49 52.
Covar, R. A., Leung, D. Y., McCormick, D., Steelman, J., Zeitler, P., &
Spahn, J. D. (2000). Risk factors associated with glucocorticoid-induced adverse effects in children with severe asthma. J Allergy Clin
Immunol 106, 651 659.
Crosson, S. M., & Roesler, W. J. (2000). Hormonal regulation of the phosphoenolpyruvate carboxykinase gene. Role of specific CCAAT/enhancer-binding protein isoforms. J Biol Chem 275, 5804 5809.
De Bosscher, K., Vanden Berghe, W., Vermeulen, L., Plaisance, S., Boone,
E., & Haegeman, G. (2000). GCs repress NF-kB-driven genes by disturbing the interaction of p65 with the basal transcription machinery,
irrespective of coactivator levels in the cell. Proc Natl Acad Sci
USA 97, 3919 3924.
Del Monaco, M., Covello, S. P., Kennedy, S. H., Gilinger, G., Litwack, G.,
& Uitto, J. (1997). Identification of novel GC-response elements in
human elastin promoter and demonstration of nucleotide sequence specificity of the receptor binding. J Invest Dermatol 108, 938 942.
Dennler, S., Itoh, S., Vivien, D., ten Dijke, P., Huet, S., & Gauthier, J. M.
(1998). Direct binding of Smad3 and Smad4 to critical TGFb-inducible
elements in the promoter of human plasminogen activator inhibitortype 1 gene. EMBO J 17, 3091 3100.
Depczynski, B., Daly, B., Campbell, L. V., Chisholm, D. J., & Keogh, A.
(2000). Predicting the occurence of diabetes mellitus in recipients of
heart transplants. Diabetes Med 17, 15 19.
Derby, L., & Maier, W. C. (2000). Risk of cataract among users of intranasal corticosteroids. J Allergy Clin Immunol 105, 912 916.
Di Fazano, C. S., Messica, O., Quennesson, S., Quennesson, E. R.,
Inaoui, R., Vergne, P., Bonnet, C., Bertin, P., & Treves, R. (1999).
Two new cases of glucocorticoid-induced pancreatitis. Rev Rheum
Engl Ed 66, 235.
Dittmar, K. D., & Pratt, W. B. (1997). Folding of the GC receptor by
reconstituted hsp90-based chaperone machinery. The initial hsp90.p60.
hsp70-dependent step is sufficient for creating the steroid binding conformation. J Biol Chem 272, 13047 13054.
Dixon, R. B., & Christy, N. P. (1980). On the various forms of corticosteroid withdrawal syndrome. Am J Med 68, 224 230.
Dowell, S. F., & Bresee, J. S. (1993). Severe varicella associated with
steroid use. Pediatrics 92, 223 228.
Drouin, J., Sun, Y. L., Chamberland, M., Gauthier, Y., De, L. A., Nemer,
M., & Schmidt, T. J. (1993). Novel GC receptor complex with DNA
element of the hormone-repressed POMC gene. EMBO J 12, 145 156.
Eaton, D. C., Becchetti, A., Ma, H., & Ling, B. N. (1995). Renal sodium
channels: regulation and single channel properties. Kidney Int 48,
941 949.
Ehrlich, H. P., & Hunt, T. K. (1968). Effects of cortisone and vitamin A on
wound healing. Ann Surg 167, 324 328.
Ekblom, M., Fassler, R., Tomasini-Johannson, B., Nilsson, K., & Ekblom,
P. (1993). Downregulation of tenascin expression by GCs in bone marrow stromal cells and in fibroblasts. J Cell Biol 123, 1037 1045.
Escoubet, B., Coureau, C., Bonvalet, J. P., & Farman, N. (1997). Noncoordinate regulation of epithelial Na channel and Na pump subunit
mRNAs in kidney and colon by aldosterone. Am J Physiol 272,
C1482 C1491.
39
Ettinger, B., Chidambaran, P., & Pressman, A. (2001). Prevalence and determinants of osteoporosis drug prescription among patients with high exposure to glucocorticoid drugs. Am J Manag Care 7, 597 605.
Everson, G. T., Trouillot, T., Wachs, M., Bak, T., Steinberg, T., Kam, I.,
Shrestha, R., & Stegall, M. (1999). Early steroid withdrawal in liver
transplantation is safe and beneficial. Liver Transpl Surg 5(4 suppl. 1),
S48 S57.
Falduto, M. T., Hickson, R. C., & Young, A. P. (1989). Antagonism by
glucocorticoids and exercise on expression of glutamine synthetase in
skeletal muscle. FASEB J 3, 2623 2628.
Fassler, R., Sasaki, T., Timpl, R., Chu, M. L., & Werner, S. (1996). Differential regulation of fibulin, tenascin-C, and nidogen expression during
wound healing of normal and GC-treated mice. Exp Cell Res 222,
111 116.
Felner, E. I., Thompson, M. T., Ratliff, A. F., White, P. C., & Dickson,
B. A. (2000). Time course of recovery of adrenal function in children treated for leukemia. J Pediatr 137, 21 24.
Fernandez-Miranda, C., de la Calle, A., Morales, J. M., Guijarro, C.,
Aranda, J. L., Gomez-Sanz, R., Gomez-Izquierdo, T., Larumbe, S.,
Moreno, E., Rodicio, J. L., & del Palacio, A. (1998). Lipoprotein
abnormalities in long-term stable liver and renal transplanted patients. A comparative study. Clin Transplant 12, 136 141.
Fisher, J. E., Smith, R. S., Lagrandeur, R., & Loren, R. P. (1997). Gestational
diabetes mellitus in women receiving beta-adrenergics and corticosteroids for threatened preterm delivery. Obstet Gynecol 90, 880 883.
Frank, S., Madlener, M., & Werner, S. (1996). Transforming growth factors
b1, b2 and b3 and their receptors are differentially regulated during normal and impaired wound healing. J Biol Chem 271, 10188 10193.
Frank, S., Madlener, M., Pfeilschifter, J., & Werner, S. (1998). Induction of
inducible nitric oxide synthase and its corresponding tetrahydrobiopterin-cofactor-synthesizing enzyme GTP-cyclohydrolase I during cutaneous repair. J Invest Dermatol 262, 16300 16304.
Fricchione, G., Ayyala, M., & Holmes, V. F. (1989). Steroid withdrawal
psychiatric syndromes. Ann Clin Psychiatry 1, 99 108.
Friedman, J. E., Sun, Y., Ishizuka, T., Farrell, C. J., McCormack, S. E.,
Herron, L. M., Hakimi, P., Lechner, P., & Yun, J. S. (1997). Phosphoenolpyruvate carboxykinase (GTP) gene transcription and hypoglycemia
are regulated by GCs in genetically obese db/db transgenic mice.
J Biol Chem 272, 31475 31481.
Garbe, E., LeLorier, J., Boivin, J. F., & Suissa, S. (1997a). Risk of ocular
hypertension or open-angle glaucoma in elderly patients on oral glucocorticoids. Lancet 350, 979 982.
Garbe, E., LeLorier, J., Boivin, J. F., & Suissa, S. (1997b). Inhaled and
nasal glucocorticoids and the risks of ocular hypertension or open-angle
glaucoma. JAMA 277, 722 727.
Garbe, E., Suissa, S., & LeLorier, J. (1998). Association of inhaled
corticosteroid use with cataract extraction in elderly patients. JAMA
280, 539 543.
Giguere, V., Hollenberg, S. M., Rosenfeld, M. G., & Evans, R. M. (1986).
Functional domains of the human GC receptor. Cell 46, 645 652.
Glowniak, J. V., & Loriaux, D. L. (1997). A double-blind study of perioperative steroid requirements in secondary adrenal insufficiency. Surgery 121, 123 129.
Goichot, B., Wicky, C., Grunenberger, F., & Schlienger, J. L. (2000). Hypothalamo-pituitary-adrenocortical function during and after steroid
therapy: recent data and critical review. Ann Endocrinol (Paris) 61,
452 458.
Goldberg, R. L., & Wise, T. N. (1986 1987). Corticosteroid abuse revisited. Int J Psychiatry Med 16, 145 149.
Goldstein, M. F., Fallon, J. J., Jr., & Harning, R. (1999). Chronic glucocorticoid therapy-induced osteoporosis in patients with obstructive lung
disease. Chest 116, 1733 1749.
Gonzalez-Quintela, A., De la Mata, M., Varo, E., Fraga, E., Montero, J. L.,
Lopez-Cillero, P., Mino, G., & Pera, C. (1995). Incidence of new onset
diabetes mellitus in liver transplant recipients immunopressed with deflazacort. TANSE 6, 107 115.
Goodwin, J. S. (1994). Antiinflammatory drugs. In D. P. Stites, A. I. Terr,
40
T. G. Parslow (Eds.), Basic and Clinical Immunology 8th edn.

(pp. 786 795). East Norwalk: Appleton and Lange.
Gould, E., Tanapat, P., McEwen, B. S., Flugge, G., & Fuchs, E. (1998).
Proliferation of granule cell precursors in the dentate gyrus of adult
monkeys is diminished by stress. Proc Natl Acad Sci USA 95,
3168 3171.
Grange, T., Roux, J., Rigaud, G., & Pictet, R. (1991). Cell-type specific
activity of two GC responsive units of rat tyrosine aminotransferase
gene is associated with multiple binding sites for C/EBP and a novel
liver-specific nuclear factor. Nucleic Acids Res 19, 131 139.
Granner, D. K., & Hargrove, J. L. (1983). Regulation of the synthesis of
tyrosine aminotransferase: the relationship to mRNATAT. Mol Cell Biochem 53 54, 113 128.
Gras, M. P., Verrecchia, F., Uitto, J., & Mauviel, A. (2001). Downregulation
of human type VII collagen (COL7A1) promoter activity by dexamethasone. Exp Dermatol 10, 28 34.
Gupta, D., Behera, D., Lalrinmawia, H., & Dash, R. J. (2000). Hypothalamo-pituitary-adrenal axis function in asthmatics taking low dose inhaled beclomethasone dipropionate. J Assoc Physicians India 48,
682 684.
Hall, R. C., Popkin, M. K., Stickney, S. K., & Gardner, E. R. (1979).
Presentation of the steroid psychosis. J Nerv Ment Dis 167, 229 236.
Hargrove, J. L., & Granner, D. K. (1985). Biosynthesis and intracellular
processing of tyrosine aminotransferase. In P. Christen, & D. E. Metzler
(Eds.), Transaminases (pp. 511 532). New York: John Wiley and Sons.
Hasegawa, T., Ishihara, K., Fujii, H., Hajiro, T., Watanabe, I., Nishimura,
T., Okazaki, M., Katakami, N., & Umeda, B. (1996). Influence of high
dose inhaled steroids on hypothalamo-pituitary-adrenal axis function in
Japanese patients with asthma: a comparison over the course of time.
Intern Med 35, 362 366.
Haskett, R. F. (1985). Diagnostic characterization of psychiatric disability
in Cushings syndrome. Am J Psychiatry 142, 911 916.
Henriksen, J. E., Alford, F., Ward, G. M., & Beck-Nielsen, H. (1997). Risk
and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients. Diabetologia 40, 1439 1448.
Henzen, C., Suter, A., Lerch, E., Urbinelli, R., Schorno, X. H., & Briner,
V. A. (2000). Suppression and recovery of adrenal response after
short-term, high-dose glucocorticoid treatment. Lancet 355, 542 545.
Hollenberg, S. M., Weinberger, C., Ong, E. S., Cerelli, G., Oro, A., Lebo,
R., Thompson, E. B., Rosenfeld, M. G., & Evans, R. M. (1985). Primary structure and expression of a functional human GC receptor
cDNA. Nature 318, 635 641.
Hoyer, D., & Martin, G. R. (1996). Classification and nomenclature of 5-HT
receptors: a comment on current issues. Behav Brain Res 73, 263 268.
Hubner, G., Brauchle, M., Smola, H., Madlener, M., Fassler, R., & Werner,
S. (1996). Differential regulation of pro-inflammatory cytokines during
wound healing in normal and GC-treated mice. Cytokine 8, 548 556.
Hummel, M., Warnecke, H., Schuler, S., Luding, K., & Hetzer, R. (1991).
Risiko der Nebennierenrindeninsuffizienz nach Herztransplantation.
Klin Wochenschr 69, 269 273.
Ihle, R., Stobbe, H., & Heinrich, H. G. (1989). Therapeutische Grundlagen.
In F. H. Schulz, & H. Stobbe (Eds.), Grundlagen und Klinik innerer
Erkrankungen (pp. 42 81). Berlin: Volk und Gesundheit.
Jantzen, H. M., Strahle, U., Gloss, B., Stewart, F., Schmid, W., Boshart, M.,
Miksicek, R., & Schutz, G. (1987). Cooperativity of GC response elements located far upstream of the tyrosine aminotransferase gene. Cell
49, 29 38.
Julius, D. (1991). Molecular biology of serotonin receptors. Annu Rev
Neurosci 14, 335 360.
Karin, M. (1998). New twists in gene regulation by glucocorticoid receptor:
is DNA binding dispensable? Cell 93, 487 490.
Kassel, O., Sancono, A., Kratzschmar, J., Kreft, B., Stassen, M., Cato,
A. C. (2001). Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1. EMBO J 20, 7108 7116.
Katz, H. I., Prawer, S. E., Mooney, J. J., & Samson, C. R. (1989). Preatrophy:
covert sign of thinned skin. J Am Acad Dermatol 20, 731 735.
Kauh, Y. C., Rouda, S., Mondragon, G., Tokarek, R., diLeonardo, M.,
Tuan, R. S., & Tan, E. M. (1997). Major suppression of pro-alpha1(I)
type I collagen gene expression in the dermis after keloid excision and
immediate intrawound injection of triamcinolone acetonide. J Am Acad
Dermatol 37, 586 589.
Kellendonk, C., Tronche, F., Reichardt, H. M., & Schutz, G. (1999). Mutagenesis of the glucocorticoid receptor in mice. J Steroid Biochem Mol
Biol 69, 253 259.
Kelly, J. J., Mangos, G., Williamson, P. M., & Whitworth, J. A. (1998).
Cortisol and hypertension. Clin Exp Pharmacol Physiol 25 (suppl.),
S51 S56.
Kennedy, W. A., Laurier, C., Gautrin, D., Ghezzo, H., Pare, M., Malo, J. L.,
& Contandriopopoulos, A. P. (2000). Occurrence and risk factors of oral
candidiasis treated with oral antifungals in seniors using inhaled steroids. J Clin Epidemiol 53, 696 701.
Kloehn, S., Arendt, T., Reinecke-Luthge, A., Klomp, H. J., & Monig, H.
(1997). Cushing syndrome with life-threatening infectious complications. Dtsch Med Wochenschr 122, 1547 1552.
Kojima, M., Shui, Y. B., & Sasaki, K. (1995). Topographic distribution of
prednisolone in the lens after organ culture. Ophthalmic Res 27(suppl. 1),
25 33.
Kolbe, L., Kligman, A. M., Schreiner, V., & Stoudenmayer, T. (2001).
Corticosteroid-induced atrophy and barrier impairment measured by
non-invasive methods in human skin. Skin Res Technol 7, 73 77.
Kountz, D. S., & Clark, C. L. (1997). Safely withdrawing patients from
chronic glucocorticoid therapy. Am Fam Physician 55, 521 525.
Kousteni, S., Bellido, T., Plotkin, L. I., OBrien, C. A., Bodenner, D. L.,
Han, K., DiGregorio, G. B., Katzenellenbogen, J. A., Katzenellenbogen, B. S., Roberson, P. K., Weinstein, R. S., Jilka, R. L., & Manolagas,
S. C. (2001). Nongeotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity.
Cell 104, 719 730.
Lacey, D. L., Timms, E., Tan, H. L., Kelley, M. J., Dunstan, C. R., Burgess,
T., Elliott, R., Colombero, A., Elliott, G., Scully, S., Hsu, H., Sullivan,
J., Hawkins, N., Davy, E., Capparelli, C., Eli, A., Qian, Y. X., Kaufman,
S., Sarosi, I., Shalhoub, V., Senaldi, G., Guo, J., Delaney, J., & Boyle,
W. J. (1998). Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165 176.
Lane, N. E., & Lukert, B. (1998). The science and therapy of GC-induced
bone loss. Endocrinol Metab Clin North Am 27, 465 483.
LaPier, T. K. (1997). GC-induced muscle atrophy. The role of exercise in
treatment and prevention. J Cardiopulm Rehabil 17, 76 84.
Lawrence, M. S., & Sapolsky, R. M. (1994). Glucocorticoids accelerate
ATP loss following metabolic insults in cultured hippocampal neurons.
Brain Res 646, 303 306.
Leibovich, S. J., & Ross, R. (1975). The role of macrophage in wound
repair. A study with hydrocortisone and antimacrophage serum. Am J
Pathol 78, 71 100.
Leung, D. Y., Hamid, Q., Vottero, A., Szefler, S., Surs, W., Minshall, E.,
Chrousos, G. P., & Klemm, D. J. (1997). Association of GC insensitivity with increased expression of GC receptor b. J Exp Med 186,
1567 1574.
Lifton, R. P., Gharavi, A. G., & Geller, D. S. (2001). Molecular mechanisms of human hypertension. Cell 104, 545 556.
Lopez, J. F., Chalmers, D. T., Little, K. Y., & Watson, S. J. (1998). Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptor in
rat and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry 43, 547 573.
Lubach, D., Rath, J., & Kietzmann, M. (1995). Skin atrophy induced by
initial continuous topical application of clobetasol followed by intermittent application. Dermatology 190, 51 55.
Lutjen-Drecoll, E., May, C. A., Polansky, J. R., Johnson, D. H., Bloemendal, H., & Nguyen, T. D. (1998). Localization of the stress proteins
alpha B-crystallin and trabecular meshwork inducible glucocorticoid
response protein in normal and glaucomatous trabecular meshwork.
Invest Ophthalmol Vis Sci 39, 517 525.
Maatta, A., & Penttinen, R. P. (1993). A fibroblast protein binds the 30-

untranslated region of pro-alpha 1(I) collagen mRNA. Biochem J 295,
691 698.
Madlener, M., Parks, W. C., & Werner, S. (1998). Matrix metalloproteinases (MMPs) and their physiological inhibitors (TIMPs) are differentially expressed during excisional skin wound repair in mice. Exp Cell
Res 242, 201 210.
Magarinos, A. M., Verdugo, J. M., & McEwen, B. S. (1997). Chronic stress
alters synaptic terminal structure in hippocampus. Proc Natl Acad Sci
USA 94, 14002 14008.
Mahonen, A., Jukkola, A., Risteli, L., Risteli, J., & Maenpaa, P. H. (1998).
Type I procollagen synthesis is regulated by steroids and related hormones in human osteosarcoma cells. J Cell Biochem 68, 151 163.
Maibach, H.I., & Surber, C. (1992). Topical Corticosteroids. Basel, Munchen, Paris, London, New York, New Dehli, Bangkok, Singapore,
Tokyo and Sydney: Karger.
Manabe, S., Bucala, R., & Cerami, A. (1984). Nonenzymatic addition of
GCs to lens proteins in steroid-induced cataracts. J Clin Invest 74,
1803 1810.
Manolagas, S. C., & Weinstein, R. S. (1999). New developments in the
pathogenesis and treatment of steroid-induced osteoporosis. J Bone
Miner Res 14, 1061 1066.
McEvoy, C. E., Ensrud, K. E., Bender, E., Genant, H. K., Yu, W., Griffith,
J. M., & Niewoehner, D. E. (1998). Association between corticosteroid
use and vertebral fractures in older men with chronic obstructive pulmonary disease. Am J Resp Crit Care Med 157, 704 709.
Meyer, T., Carlstedt-Duke, J., & Starr, D. B. (1997). A weak TATA box is a
prerequisite for gluocorticoid-dependent repression of the osteocalcin
gene. J Biol Chem 272, 30709 30714.
Mitchell, P., Cumming, R. G., & Mackey, D. A. (1999). Inhaled corticosteroids, family history, and risk of glaucoma. Ophthalmology 106,
2301 2306.
Mygind, N., & Dahl, R. (1996). The rationale for use of topical corticosteroids in allergic rhinitis. Clin Exp Allergy 26(suppl. 3), 2 10.
Nashel, D. J. (1986). Is atherosclerosis a complication of long-term corticosteroid treatment? Am J Med 80, 925 929.
Nies, C. (1993). http://www.nebenniere.de/cushing.JPG; http://www.
nebenniere.de/infopatient-erkrankungen.htm.
Oakly, R. H., Sar, M., & Cidlowsky, J. A. (1996). The human GC receptor b
isoform. Expression, biochemical properties, and putative function. J
Biol Chem 271, 9550 9559.
OBrien, R. M., Noisin, E. L., Suwanichkul, A., Yamasaki, T., Lucas, P. C.,
Wang, J. C., Powell, D. R., & Granner, D. K. (1995). Hepatic nuclear
factor 3- and hormone-regulated expression of the phosphoenolpyruvate
carboxykinase and insulin-like growth factor-binding protein-1 genes.
Mol Cell Biol 15, 1747 1758.
Oikarinen, A., & Autio, P. (1991). New aspects of the mechanism of corticosteroid-induced dermal atrophy. Clin Exp Dermatol 16, 416 419.
Oikarinen, A., Autio, P., Kiistala, U., Risteli, L., & Risteli, J. (1992). A new
method to measure type I and III collagen synthesis in human skin in
vivo: demonstration of decreased collagen synthesis after topical GC
treatment. J Invest Dermatol 98, 220 225.
Oikarinen, A., Haapasaari, K. M., Sutinen, M., & Tasanen, K. (1998). The
molecular basis of GC-induced skin atrophy: topical GC apparently
decreases both collagen synthesis and corresponding collagen mRNA
level in human skin in vivo. Br J Dermatol 139, 1106 1110.
Onwubalili, J. K., & Obineche, E. N. (1992). High incidence of post-transplant diabetes mellitus in a single-centre study. Nephrol Dial Transplant
7, 346 349.
Ortonne, J. P. (1994). Skin atrophogenic potential of methylprednisolone
aceponate (MPA). J Eur Acad Dermatol Venereol 3, S13 S18l.
Otto, C., Reichardt, H. M., & Schutz, G. (1997). Absence of GC receptor-b
in mice. J Biol Chem 272, 26665 26668.
Pearce, G., Ryan, P. F., Delmas, P. D., Tabensky, D. A., & Seeman, E. (1998).
The deleterious effects of low-dose corticosteroids on bone density in
patients with polymyalgia rheumatica. Br J Rheumatol 37, 292 299.
Perez, P., Page, A., Brano, A., Del Rio, M., Gimenez-Conti, I., Budunova,
I., Slaga, T. J., & Jorcano, J. L. (2001). Altered skin development and
41
impaired proliferative and inflammatory responses in transgenic mice

overexpressing the glucocorticoid receptor. FASEB J 15, 2030 2032.
Piper, J. M., Ray, W. A., Daugherty, J. R., & Griffin, M. R. (1991). Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann Intern Med 114, 735 740.
Price, S. R., Du, J. D., Bailey, J. L., & Mitch, W. E. (2001). Molecular
mechanisms regulating protein turnover in muscle. Am J Kidney Dis 37
(1 suppl. 2), S112 S114.
Raghow, R., Gossage, D., & Kang, A. H. (1986). Pretranslational regulation
of type I collagen, fibronectin, and a 50-kilodalton noncollagenous
extracellular protein by dexamethasone in rat fibroblasts. J Biol Chem
261, 4677 4684.
Raul Ariza-Andraca, C., Barile-Fabris, L. A., Frati-Munari, A. C., & Baltazar-Montufar, P. (1998). Risk factors for steroid diabetes in rheumatic
patients. Arch Med Res 29, 259 262.
Reed, B. R., & Clark, R. A. (1985). Cutaneous tissue repair: practical implications of current knowledge II. Am Acad Dermatol 13, 919 941.
Reichardt, H. M., & Schutz, G. (1998). GC signallingmultiple variations
of a common theme. Mol Cell Endocrinol 146, 1 6.
Reichardt, H. M., Kaestner, K. H., Tuckermann, J., Kretz, O., Wessely, O.,
Bock, R., Gass, P., Schmid, W., Herrlich, P., Angel, P., & Schutz, G.
(1998). DNA binding of the glucocorticoid receptor is not essential for
survival. Cell 93, 531 541.
Reichardt, H. M., Tronche, F., Berger, S., Kellendonk, C., & Schutz, G.
(2000). New insights into GC and mineralocorticoid signaling: lessons
from gene targeting. Adv Pharmacol 47, 1 21.
Reichardt, H. M., Tuckermann, J. P., Gottlicher, M., Vujic, M., Weih, F.,
Angel, P., Herrlich, P., & Schutz, G. (2001). Repression of inflammatory responses in the absence of DNA-binding by the glucocorticoid
receptor. EMBO J 20, 7168 7173.
Reid, I. R. (2000). Glucocorticoid-induced osteoporosis. Baillieres Clin
Endocrinol Metab 14, 279 298.
Rendina, E. A., Venuta, F., & Ricci, C. (1992). Effects of low-dose steroids
on bronchial healing after sleeve resection. A clinical study. J Thorac
Cardiovasc Surg 104, 888 891.
Richardson, C. T. (1985). Pathogenetic factors in peptic ulcer disease. Am J
Med 79, 1 7.
Rigaud, G., Roux, J., Pictet, R., & Grange, T. (1991). In vivo footprinting
of rat TAT gene: dynamic interplay between the GC receptor and a
liver-specific factor. Cell 67, 977 986.
Robertson, D. B., & Maibach, H. I. (1982). Topical corticosteroids. Int J
Dermatol 21, 59 67.
Robinzon, B., & Cutolo, M. (1999). Should dehydroepiandrosterone replacement therapy be provided with glucocorticoids? Rheumatology
38, 488 495.
Rodriguez, L. A. G., & Hernandez-Diaz, S. (2001). The risk of upper
gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs, glucocorticoids, acetaminophen, and combinations of
these agents. Arthritis Res 3, 98 101.
Roux, J., Pictet, R., & Grange, T. (1995). Hepatocyte nuclear factor 3
determines the amplitude of the GC response of the rat tyrosine aminotransferase gene. DNA Cell Biol 14, 385 396.
Ruppert, S., Boshart, M., Bosch, F. X., Schmid, W., Fournier, R. E., &
Schutz, G. (1990). Two genetically defined trans-acting loci coordinately
regulate overlapping sets of liver-specific genes. Cell 61, 895 904.
Russell, S. B., Trupin, J. S., Kennedy, R. Z., Russell, J. D., & Davidson,
J. M. (1995). GC regulation of elastin synthesis in human fibroblasts:
down-regulation in fibroblasts from normal dermis but not from
keloids. J Invest Dermatol 104, 241 245.
Sandberg, N. (1964). Time relationship between administration of cortisone
and wound healing in rats. Acta Chir Scand 127, 446 450.
Sanders, B. P., Portman, R. J., Ramey, R. A., Hill, M., & Strunk, R. C.
(1992). Hypertension during reduction of long-term steroid therapy in
young subjects with asthma. J Allergy Clin Immunol 89, 816 821.
Sapolsky, R. M., Packan, D. R., & Vale, W. W. (1988). Glucocorticoid
toxicity in the hippocampus: in vitro demonstration. Brain Res 453,
367 371.
42
Sapolsky, R. M., Uno, H., Rebert, C. S., & Finch, C. E. (1990). Hippocampal damage associated with prolonged glucocorticoid exposure in
primates. J Neurosci 10, 2897 2902.
Sarnstrand, B., Brattsand, R., & Malmstrom, A. (1982). Effect of GCs
on glycosaminoglycan metabolism in cultured human skin fibroblasts.
J Invest Dermatol 79, 412 417.
Sartori, T. M., Maurizio, P. G., Sara, P., Ugolino, L., Annalisa, A., Panagiotis, T., Massimo, F., & Anonio, G. (1999). Relation between longterm steroid treatment after heart transplantation, hypofibrinolysis and
myocardial microthrombi generation. J Heart Lung Transplant 18,
693 700.
Sassi, H., Pictet, R., & Grange, T. (1998). GCs are insufficient for neonatal
gene induction in the liver. Proc Natl Acad Sci USA 95, 5621 5625.
Satel, S. L. (1990). Mental status changes in children receiving glucocorticoids. Review of the literature. Clin Pediatr 29, 383 388.
Sato, A., Funder, J. W., Okubo, M., Kubota, E., & Saruta, T. (1995).
Glucocorticoid-induced hypertension in the elderly. Relation to serum
calcium and family history of essential hypertension. Am J Hypertens 8,
823 828.
Sayegh, R., Auerbach, S. D., Li, X., Loftus, R. W., Husted, R. F., Stokes,
J. B., & Thomas, C. P. (1999). GC induction of epithelial sodium
channel expression in lung and renal epithelia occurs via trans-activation of a hormone response element in the 50-flanking region of the
human epithelial sodium channel a subunit gene. J Biol Chem 274,
12431 12437.
Schneikert, J., Hubner, S., Martin, E., & Cato, A. C. (1999). A nuclear
action of the eukaryotic cochaperone RAP46 in downregulation of GC
receptor activity. J Cell Biol 146, 929 940.
Schule, R., Rangarajan, P., Kliewer, S., Ransone, L. J., Bolado, J., Yang, N.,
Verma, I. M., & Evans, R. M. (1990). Functional antagonism between
oncoprotein c-Jun and the GC receptor. Cell 62, 1217 1226.
Schulze, S., Andersen, J., Overgaard, H., Norgard, P., Nielsen, H. J., Aasen,
A., Gottrup, F., & Kehlet, H. (1997). Effect of prednisolone on the
systemic response and wound healing after colonic surgery. Arch Surg
132, 129 135.
Schwabe, U. (1996). Corticosteroide. In P. Schwabe (Ed.), Arzneiverordnungs-Report 1996 (pp. 184 188). Stuttgart: Fischer.
Schweizer-Groyer, G., Cadepond, F., Jibard, N., Neau, E., Segard-Maurel,
I., Baulieu, E. E., & Groyer, A. (1997). Stimulation of transcription in
vitro from a liver-specific promoter by human glucocorticoid receptor
(hGRalpha). Biochem J 324, 823 831.
Sclafani, A. P., Gordon, L., Chadha, M., & Romo, T., 3rd (1996). Prevention of earlobe keloid recurrence with postoperative corticosteroid injections versus radiation therapy: a randomized, prospective study and
review of the literature. Dermatol Surg 22, 569 574.
Scott, D. K., Stromstedt, P. E., Wang, J. C., & Granner, D. K. (1998).
Further characterization of the GC response unit in the phosphoenolpyruvate carboxykinase gene. The role of the GC receptor-binding sites.
Mol Endocrinol 12, 482 491.
Senderovitz, T., & Viskum, K. (1994). Corticosteroid and tuberculosis.
Respir Med 88, 561 565.
Shee, C. D. (1990). Risk factors for hydrocortisone myopathy in acute
severe asthma. Respir Med 84, 229 233.
Sholter, D. E., & Armstrong, P. W. (2000). Adverse effects of corticosteroids on the cardiovascular system. Can J Cardiol 16, 505 511.
Silvestrini, G., Ballanti, P., Patacchioli, F. R., Mocetti, P., Di Grezia, R.,
Wedard, B., Angelucci, L., & Bonucci, E. (2000). Evaluation of apoptosis and the GC receptor in the cartilage growth plate and metaphyseal
bone cells of rats after high-dose treatment with corticosterone. Bone
26, 33 42.
Simonet, W. S., Lacey, D. L., Dunstan, C. R., Kelley, M., Chang, M. S.,
Luthy, R., Nguyen, H. Q., Wooden, S., Bennett, L., Boone, T., Shimamoto, G., DeRose, M., Elliott, R., Colombero, A., Tan, H. L., Trail, G.,
Sullivan, J., Davy, E., Bucay, N., Renshaw-Gegg, L., Hughes, T. M.,
Hill, D., Pattison, W., Campbell, P., & Boyle, W. J. (1997). Osteoprotegerin: a novel secreted protein involved in the regulation of bone
density. Cell 89, 309 319.
Simons, F. E. R., Persaud, M. P., Gillespie, C. A., Cheang, M., & Shuckett,
E. P. (1993). Absence of posterior subcapsular cataracts in young patients treated with glucocorticoids. Lancet 342, 776 778.
Skoner, D. P., Rachelefsky, G. S., Meltzer, E. O., Chervinsky, P., Morris,
R. M., Seltzer, J. M., Storms, W. W., & Wood, R. A. (2000). Detection of growth supression in children during treatment with intranasal
beclomethasone dipropionate. Pediatrics 105, E23.
Song, C. Z., Tian, X., & Gelehrter, T. D. (1999). GC receptor inhibits
transforming growth factor-b signaling by directly targeting the transcriptional activation function of Smad3. Proc Natl Acad Sci USA 96,
11776 11781.
Stanbury, R. M., & Graham, E. M. (1998). Systemic corticosteroid therapyside effect and their management. Br J Ophthamol 82, 704 708.
Stein-Behrens, B. A., Lin, W. J., & Sapolsky, R. M. (1994). Physiological
elevations of glucocorticoids potentiate glutamate accumulation in the
hippocampus. J Neurochem 63, 596 602.
Stewart, P. M., Wallace, A. M., Valentino, R., Burt, D., Shackleton, C. H.,
& Edwards, C. R. (1987). Mineralocorticoid activity of liquorice: 11beta-hydroxysteroid dehydrogenase deficiency comes of age. Lancet 2,
821 824.
Stokes, J. B., & Sigmund, R. D. (1998). Regulation of rENaC mRNA by
dietary NaCl and steroids: organ, tissue, and steroid heterogeneity. Am J
Physiol 274, C1699 C1707.
Strickland, I., Kisich, K., Hauk, P. J., Vottero, A., Chrousos, G. P., Klemm,
D. J., & Leung, D. Y. M. (2001). High constitutive glucocorticoid
receptor b in human neutrophils enables them to reduce their spontaneous rate of cell death in response to corticosteroids. J Exp Med 193,
585 593.
Stromstedt, P. E., Poellinger, L., Gustafsson, J. A., & Carlstedt, D. J.
(1991). The GC receptor binds to the TATA box of human osteocalcin
promoter: a potential mechanism of negative regulation. Mol Cell Biol
11, 3379 3383.
Stuck, A. E., Minder, C. E., & Frey, F. J. (1989). Risk of infectious complications in patients taking glucocorticoids. Rev Infect Dis 11, 954 963.
Sugar, A., Bokosky, J. E., & Meyer, R. F. (1984 1985). A randomized trial
of topical corticosteroids in epithelial healing after keratoplasty. Cornea
3, 268 271.
Tox, U., Goeser, T., & Steffen, H. M. (2001). Ulkusprophylaxe bei Dauertherapie mit Glukokortikoiden? Dtsch Med Wochenschr 126, 766 768.
Tripathi, R. C., Parapuram, S. K., Tripathi, B. J., Zhong, Y., & Chalam, K. V.
(1999). Corticosteroids and glaucoma risk. Drugs Aging 15, 439 450.
Tuckermann, J. P., Reichardt, H. M., Arribas, R., Richter, K. H., Schutz, G.,
& Angel, P. (1999). The DNA binding-independent function of the GC
receptor mediates repression of AP-1-dependent genes in skin. J Cell
Biol 147, 1365 1370.
Ulman, I., & Mutaf, O. (1998). A critique of systemic steroids in the
management of caustic esophageal burns in children. Eur J Pediatr
Surg 8, 71 74.
Uno, H., Lohmiller, L., Thieme, C., Kemnitz, J. W., Engle, M. J., Roecker,
E. B., & Farrell, P. M. (1990). Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. I. Hippocampus.
Brain Res Dev Brain Res 53, 157 167.
Venkatesh, V. C., & Katzberg, H. D. (1997). GC regulation of epithelial
sodium channel genes in human fetal lung. Am J Physiol 273,
L227 L233.
Virgin, C. E., Jr., Ha, T. P., Packan, D. R., Tombaugh, G. C., Yang, S. H.,
Horner, H. C., & Sapolsky, R. M. (1991). Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: implications for glucocorticoid neurotoxicity. J Neurochem 57, 1422 1428.
Vottero, A., & Chrousos, G. P. (1999). GC receptor b: view I. Trends
Endocrinol Metab 10, 333 338.
Vuorio, E., & Crombrugghe, B. (1990). The family of collagen genes. Annu
Rev Biochem 59, 837 872.
Wahl, S. M. (1989). GCs and wound healing. In: Schleimer R. P., Claman
H. N., & Oronsky A. L. (Eds.), Anti-inflammatory steroid action. Basic
and clinical aspects (pp. 280 302). San Diego: Academic Press.
Wajngot, A., Giacca, A., Grill, V., Vranic, M., & Efendic, S. (1992). The

diabetogenic effects of glucocorticoids are more pronounced in low- than
in high-insulin responders. Proc Natl Acad Sci USA 89, 6035 6039.
Walfisch, A., Hallak, M., & Mazor, M. (2001). Multiple courses of antenatal steroids: risks and benefits. Obstet Gynecol 98, 491 497.
Walsh, L. J., Wong, C. A., Pringle, M., & Tattersfield, A. E. (1996). Use of
oral corticosteroids in the community and the prevention of secondary
osteoporosis: a cross sectional study. Br Med J 313, 344 346.
Watanabe, Y., Gould, E., Daniels, D. C., Cameron, H., & McEwen, B. S.
(1992). Tianeptine attenuates stress-induced morphological changes in
the hippocampus. Eur J Pharmacol 222, 157 162.
Weinstein, R. S., Jilka, R. L., Parfitt, A. M., & Manolagas, S. C. (1998).
Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by GCs. Potential mechanisms of their deleterious
effects on bone. J Clin Invest 102, 274 282.
Winkelstein, A. (1994). Immunosuppressive therapy. In D. P. Stites,
A. T. Terr, & T. G. Parslow (Eds.), Basic and Clinical Immunology
(8th edn.) (pp. 767 780). San Mateo: Appleton and Lange.
Wissink, S., Meijer, O., Pearce, D., van Der Burg, B., & van Der Saag, P. T.
(2000). Regulation of the rat serotonin-1A receptor gene by corticosteroids. J Biol Chem 275, 1321 1326.
Wolfe, F., & Hawley, D. J. (2000). The comparative risk and predictors of
adverse gastrointestinal events in rheumatoid arthritis and osteoarthritis: a
prospective 13 year study of 2131 patients. J Rheumatol 27, 1668 1673.
Wolkowitz, O. M., Reus, V. I., Canick, J., Levin, B., & Lupien, S. (1997).
Glucocorticoid medication, memory and steroid psychosis in medical
illness. Ann N Y Acad Sci 823, 81 96.
Wolthers, O. D. (1996). Long-, intermediate- and short-term growth studies
in asthmatic children treated with inhaled glucocorticosteroids. Eur
Respir J 9, 821 827.
Wolthers, O. D., & Pedersen, S. (1990). Short term linear growth in asthmatic
children during treatment with prednisolone. Br Med J 301, 145 148.
43
Yasuda, H., Shima, N., Nakagawa, N., Mochizuki, S. I., Yano, K., Fujise,
N., Sato, Y., Goto, M., Yamaguchi, K., Kuriyama, M., Kanno, T.,
Murakami, A., Tsuda, E., Morinaga, T., & Higashio, K. (1998a). Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin
(OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis
in vitro. Endocrinology 139, 1329 1337.
Yasuda, H., Shima, N., Nakagawa, N., Yamaguchi, K., Kinosaki, M., Mochizuki, S. I., Tomoyasu, A., Yano, K., Goto, M., Murakami, A., Tsuda,
E., Morinaga, T., Higashio, K., Udagawa, N., Takahashi, N., & Suda, T.
(1998b). Osteoclast differentiation factor is a ligand for osteoprotegerin/
osteoclastogenesis inhibitory factor and is identical to TRANCE/
RANKL. Proc Natl Acad Sci USA 95, 3597 3602.
Yoshiuchi, I., Shingu, R., Nakajima, H., Hamaguchi, T., Horikawa, Y.,
Yamasaki, T., Oue, T., Ono, A., Miyagawa, J. I., Namba, M., Hanfusa,
T., & Matsuzawa, Y. (1998). Mutation/polymorphism scanning of glucose-6-phosphatase gene promoter in noninsulin-dependent diabetes
mellitus patients. J Clin Metab 83, 1016 1019.
Zanardi, V. A., Magna, L. A., & Costallat, L. T. (2001). Cerebral atrophy
related to corticotherapy in systemic lupus erythematosus (SLE). Clin
Rheumatol 20, 245 250.
Zhou, L., Li, Y., & You, B. Y. (1998). Glucocorticoid effects on extracellular matrix proteins and integrins in bovine trabecular meshwork cells
in relation to glaucoma. Int J Mol Med 2, 339 346.
Zhou, Z., & Vollrath, D. (1999). A cellular assay distinguishes normal and
mutant TIGR/myocilin protein. Hum Mol Genet 8, 2221 2228.
Ziegler, R., & Kasperk, C. (1998). Glucocorticoid-induced osteoporosis:
prevention and treatment. Steroids 63, 344 348.
Zimmerman, C. C., Lingappa, V. R., Richards, J. E., Rozsa, F. W., Lichter,
P. R., & Polansky, J. R. (1999). A trabecular meshwork GC response
(TIGR) gene mutation affects translocational processing. Mol Vis 5,
19 24.

Side Effect of Cortikotseroid

Transféré par

Informations du document

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

Side Effect of Cortikotseroid

Transféré par

Droits d'auteur :

Formats disponibles

Pharmacology & Therapeutics 96 (2002) 23 43

Mechanisms involved in the side effects of glucocorticoids

* Corresponding author. Tel.: +49-30-468-15971; fax: +49-30-468-18054.

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

The biological effects of GCs are mediated via the GC

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

patients today do worry about using their prescribed GCs

Fig. 1. Morbus Cushing (Nies, 1993). A patient with Cushings syndrome

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

is evident in the case of Cushings syndrome, characterized

interaction with other transcription factors, e.g., activator

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

and is transcriptionally inactive on GRE-containing

2. Mechanisms of glucocorticoid receptor-mediated

(Cato & Wade, 1996; Karin, 1998; Barnes, 1998). Moreover,

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

effects in rats are significantly reduced. Thus, we found a

3. Mechanisms of glucocorticoid-mediated side effects

Fig. 3. Cutaneous side effects of GC therapy. GCs can induce cutaneous

induction of erythema and teleangiectasia (together with

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

GREs in the promoter of the elastin gene have been

Hubner et al., 1996

Up-regulation of genes occurs due to the GR-DNA interaction-dependent

(1) by the short-term application of GCs, in most cases in

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

COL7A1 promoter region containing GRE half sites, thus

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

tion and activity. (2) GCs induce decreased gastrointestinal

ted. Fast-twitch glycolytic type IIB fibers are particularly

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

alterations in ECM composition. For example, GCs induce

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

production and in increasing glucose uptake in muscle and

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

metabolism and in the malate-aspartate shuttle, an essential

amethasone therapy for 28 days, adrenal insufficiency

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

The prolonged suppression of adrenocorticotropin levels

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

under discussion, the main molecular mechanisms seem to

3.8. Immune system

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

the molecular mechanisms that mediate the GC effects.

The observation that therapeutic effects are mediated

Primary targeted molecule

Decreased wound healing

TIGR/MYOC gene product

Suppression of HPA axis

Diabetes mellitus induction

X, mechanism that mediates GR effect; (X), possible mechanism of GR effect.

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

better understanding of the molecular mechanisms of side

Bell, N. H. (1984). The glucocorticoid withdrawal syndrome. Adv Exp Med

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

T. G. Parslow (Eds.), Basic and Clinical Immunology 8th edn.

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

impaired proliferative and inflammatory responses in transgenic mice

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

H. Schacke et al. / Pharmacology & Therapeutics 96 (2002) 2343

Vous aimerez peut-être aussi