Mechanisms involved in the side effects of glucocorticoids

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Abstract

Glucocorticoids (GCs) represent the most important and frequently used class of anti-inflammatory drugs. While the therapeutic effects of GCs have been known and used for more than 50 years, major progress in discovering the underlying molecular mechanisms has only been made in the last 10–15 years. There is consensus that the desired anti-inflammatory effects of GCs are mainly mediated via repression of gene transcription. In contrast, the underlying molecular mechanisms for GC-mediated side effects are complex, distinct, and frequently only partly understood. Recent data suggest that certain side effects are predominantly mediated via transactivation (e.g., diabetes, glaucoma), whereas others are predominantly mediated via transrepression (e.g., suppression of the hypothalamic-pituitary-adrenal axis). For a considerable number of side effects, the precise molecular mode is either so far unknown or both transactivation and transrepression seem to be involved (e.g., osteoporosis). The differential molecular regulation of the major anti-inflammatory actions of GCs and their side effects is the basis for the current drug-finding programs aimed at the development of dissociated GC receptor (GR) ligands. These ligands preferentially induce transrepression by the GR, but only reduced or no transactivation. This review summarizes the current knowledge of the most important GC-mediated side effects from a clinical to a molecular perspective. The focus on the molecular aspects should be helpful in predicting the potential advantages of selective GR agonists in comparison to classical GCs.

Introduction

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).

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 anti-inflammatory 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—Addison's 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 child's 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 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 is evident in the case of Cushing's 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.

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 non-epithelial cells in the brain and heart (Reichardt & Schütz, 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 GR-selective.

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 GR-ligand 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 interaction with other transcription factors, e.g., activator protein (AP)-1, nuclear factor-κB (NF-κB), Smad3, preventing an activation of transcription by these factors (Fig. 2C) Schüle 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 (GRα) and a non-steroid-binding truncated form of 742 residues, which differed in the 15 C-terminal residues (GRβ). The human GRβ 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 GRβ isoform, and whether or not it acts as a dominant negative modulator of the GRα isoform (Carlstedt-Duke, 1999). In the peripheral blood of patients with GC-resistant asthma, however, significantly higher numbers of human GRβ positive cells were found, suggesting such a dominant negative function of the human GRβ (Leung et al., 1997). The first evidence for a physiologic role of the GRβ isoform in neutrophils was described recently by Strickland and co-workers (2001). They compared the GC sensitivity of human neutrophils and peripheral blood mononuclear cells and observed the existence of GRα/GRβ heterodimers in neutrophils only. They also demonstrated that the transfection of neutrophils from mice with a functional human GRβ, in whom no GRβ 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 GRα homodimers acting on GREs of GC-sensitive genes. A similar mechanism of GC-induced apoptosis is assumed for neutrophils. This suggests that the GRα/GRβ heterodimers in human neutrophils are functionally inactive, but that their expression might limit the responsiveness towards GC effects mediated via the GRα homodimer.

Section snippets

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

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

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

Acknowledgements

We would like to thank Professor Andrew Cato (Forschungszentrum Karlsruhe, Germany) and Professor Guenther Schuetz (DKFZ, Heldelberg, Germany) and Dr. Christoph Niels (University Marburg, Germany) for critical reading of the manuscript, Professor Stephen Katz (NIH, Bethesda, USA) for helpful discussions, Professor Wolfram Sterry (Charite, Berlin, Germany) for providing the clinical figures (Figs. 3A–D and Fig. 1, rerpectively), and Stefanie Schoepe for editing the manuscript.

References (223)

  • J.L. Carson et al.

    The low risk of upper gastroinstestinal bleeding in patients dispensed corticosteroids

    Am J Med

    (1991)
  • R.A. Covar et al.

    Risk factors associated with glucocorticoid-induced adverse effects in children with severe asthma

    J Allergy Clin Immunol

    (2000)
  • S.M. Crosson et al.

    Hormonal regulation of the phosphoenolpyruvate carboxykinase gene. Role of specific CCAAT/enhancer-binding protein isoforms

    J Biol Chem

    (2000)
  • M. Del Monaco et al.

    Identification of novel GC-response elements in human elastin promoter and demonstration of nucleotide sequence specificity of the receptor binding

    J Invest Dermatol

    (1997)
  • L. Derby et al.

    Risk of cataract among users of intranasal corticosteroids

    J Allergy Clin Immunol

    (2000)
  • K.D. Dittmar et al.

    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

    (1997)
  • R.B. Dixon et al.

    On the various forms of corticosteroid withdrawal syndrome

    Am J Med

    (1980)
  • D.C. Eaton et al.

    Renal sodium channels: regulation and single channel properties

    Kidney Int

    (1995)
  • R. Fässler et al.

    Differential regulation of fibulin, tenascin-C, and nidogen expression during wound healing of normal and GC-treated mice

    Exp Cell Res

    (1996)
  • E.I. Felner et al.

    Time course of recovery of adrenal function in children treated for leukemia

    J Pediatr

    (2000)
  • J.E. Fisher et al.

    Gestational diabetes mellitus in women receiving beta-adrenergics and corticosteroids for threatened preterm delivery

    Obstet Gynecol

    (1997)
  • S. Frank et al.

    Transforming growth factors β1, β2 and β3 and their receptors are differentially regulated during normal and impaired wound healing

    J Biol Chem

    (1996)
  • J.E. Friedman et al.

    Phosphoenolpyruvate carboxykinase (GTP) gene transcription and hypoglycemia are regulated by GCs in genetically obese db/db transgenic mice

    J Biol Chem

    (1997)
  • E. Garbe et al.

    Risk of ocular hypertension or open-angle glaucoma in elderly patients on oral glucocorticoids

    Lancet

    (1997)
  • V. Giguere et al.

    Functional domains of the human GC receptor

    Cell

    (1986)
  • J.V. Glowniak et al.

    A double-blind study of perioperative steroid requirements in secondary adrenal insufficiency

    Surgery

    (1997)
  • M.F. Goldstein et al.

    Chronic glucocorticoid therapy-induced osteoporosis in patients with obstructive lung disease

    Chest

    (1999)
  • C. Henzen et al.

    Suppression and recovery of adrenal response after short-term, high-dose glucocorticoid treatment

    Lancet

    (2000)
  • G. Hübner et al.

    Differential regulation of pro-inflammatory cytokines during wound healing in normal and GC-treated mice

    Cytokine

    (1996)
  • H.M. Jantzen et al.

    Cooperativity of GC response elements located far upstream of the tyrosine aminotransferase gene

    Cell

    (1987)
  • M. Karin

    New twists in gene regulation by glucocorticoid receptor: is DNA binding dispensable?

    Cell

    (1998)
  • J.D. Adachi et al.

    Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis

    N Engl J Med

    (1997)
  • O. Akkoca et al.

    Inhaled and systemic corticosteroid therapies: do they contribute to inspiratory muscle weakness in asthma?

    Respiration

    (1999)
  • D.B. Allen

    Influence of inhaled corticosteroids on growth: a pediatric endocrinologist's perspective

    Acta Paediatr

    (1998)
  • R.C. Andrews et al.

    Glucocorticoids and insulin resistance: old hormones, new targets

    Clin Sci

    (1999)
  • M.F. Armaly

    Effects of corticosteroids on intraocular pressure and fluid dynamics. I. The effect of dexamethasone in the normal eye

    Arch Ophthalmol

    (1963)
  • C. Asher et al.

    Aldosterone-induced increase in the abundance of Na+ channel subunits

    Am J Physiol

    (1996)
  • P. Autio et al.

    Effects of an inhaled steroid (budesonide) on skin collagen synthesis of asthma patients in vivo

    Am J Resp Crit Care Med

    (1996)
  • L.V. Avioli

    Glucocorticoid effects on statural growth

    Br J Rheumatol

    (1993)
  • P.J. Barnes

    Anti-inflammatory actions of glucocorticoids: molecular mechanisms

    Clin Sci (Lond)

    (1998)
  • P.J. Barnes

    Molecular mechanisms of corticosteroids in allergic diseases

    Allergy

    (2001)
  • T.T. Batchelor et al.

    Steroid myopathy in cancer patients

    Neurology

    (1997)
  • N.H. Bell

    The glucocorticoid withdrawal syndrome

    Adv Exp Med Biol

    (1984)
  • R. Bell et al.

    Managing corticosteroid-induced osteoporosis in medical outpatients

    J R Coll Physicians Lond

    (1997)
  • M.G. Belvisi et al.

    Therapeutic benefit of a dissociated glucocorticoid and the relevance of an in vivo separation of transrepression from transactivation activity

    J Immunol

    (2001)
  • J. Bentson et al.

    Steroids and apparent cerebral atrophy on computed tomography scans

    J Comput Assist Tomogr

    (1978)
  • F. Beurton et al.

    Delineation of insulin-responsive sequence in rat cytosolic aspartate aminotransferase gene: binding sites for hepatocyte nuclear factor-3 and nuclear factor I

    Biochem J

    (1999)
  • H. Biering et al.

    Prevalence of diabetes in acromegaly and Cushing syndrome

    Acta Med Austriaca

    (2000)
  • Z. Bircan et al.

    The effect of alternate-day low dose prednisolone on bone age in children with steroid dependent nephrotic syndrome

    Int Urol Nephrol

    (1997)
  • R.L. Black et al.

    Posterior subcapsular cataracts induced by corticosteroids in patients with rheumatoid arthritis

    JAMA

    (1960)
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