ABSTRACT

Glucocorticoids are steroid hormones produced by the adrenal cortex. They have pleiotropic effects and contribute substantially to the maintenance of resting and stress-related homeostasis. Although the molecular mechanisms of their actions are not fully understood, most of glucocorticoid effects are mediated by a ubiquitously expressed transcription factor, the glucocorticoid receptor. The latter influences the transcription rate of several glucocorticoid-target genes or interact physically with other transcription factors regulating their transcriptional activity in a positive or negative fashion. We present the molecular mechanisms of glucocorticoid action, and we discuss glucocorticoid treatment in endocrine and non-endocrine disorders, the side effects of glucocorticoids, their concomitant use and interactions with other drugs, and the risk factors for adrenal suppression. We suggest regimens for weaning patients from long-term glucocorticoid therapy, describe the glucocorticoid withdrawal syndrome, and provide some future perspectives on glucocorticoid treatment. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Glucocorticoids are steroid hormones produced by the zona fasciculata of the adrenal cortex. These molecules are secreted into the peripheral blood under the control of the hypothalamic-pituitary-adrenal (HPA) axis in an ultradian, circadian and stress-related fashion (1). Glucocorticoids influence a myriad of physiologic functions contributing substantially to the maintenance of resting and stress-related homeostasis. At the cellular level, glucocorticoids regulate proliferation, differentiation and programmed cell death (apoptosis) of various cell types and may change the methylation status of cytosine-guanine dinucleotides (CpG) located in the regulatory regions of many genes, leading to important epigenetic alterations (1, 2).

Although glucocorticoids have been introduced in the treatment of rheumatoid arthritis since 1949, their molecular mechanisms of actions remain an evolving field of molecular and cellular endocrinology. Their anti-inflammatory and immunosuppressive effects are mediated mostly by their cognate receptor, the glucocorticoid receptor (GR), a transcription factor that belongs to the steroid receptor subfamily of the nuclear receptor superfamily (3). The therapeutic applications of synthetic glucocorticoids have been greatly broadened to encompass a large number of non-endocrine and endocrine diseases. Indeed, the prevalence of long-term glucocorticoid use worldwide is estimated at between 1% and 3% of adults (4).

When glucocorticoids are used at supraphysiologic doses, glucocorticoid-induced Hypothalamic-pituitary-adrenal (HPA) axis suppression renders the adrenal glands unable to generate sufficient cortisol if glucocorticoid treatment is abruptly stopped. In addition to adrenal suppression, a growing list of glucocorticoid adverse effects have been documented.

Glucocorticoid resistance has become another limitation in the therapeutic use of glucocorticoids. Our ever-increasing and deeper understanding of the molecular mechanisms of glucocorticoid actions might provide the basis for designing selective GR agonists that will optimize the therapeutic outcome, while minimizing undesired side effects.

MOLECULAR MECHANISMS OF GLUCOCORTICOID ACTION

Within the glucocorticoid target cell, the human (h) GR interacts with heat shock proteins (HSP90, HSP70) and immunophillins (FKBP51 and FKBP52), forming a multiprotein complex. Upon glucocorticoid-binding, the hGR dissociates from its protein partners, translocates into the nucleus, and forms homo- or hetero-dimers that bind to specific DNA sequences, termed “glucocorticoid response elements” (“GREs”), influencing the transcription of several glucocorticoid target genes in a positive or negative fashion (3, 5). For additional information please see the

Endotext chapter on Glucocorticoid receptors (6). Many anti-inflammatory genes are trans-activated by glucocorticoids, while pro-inflammatory genes are trans-repressed by these hormones. Aside from the genomic actions, accumulating evidence suggests that glucocorticoids may exert some effects in a very short time frame, independently of gene transcription and/or translation (7). These nongenomic glucocorticoid effects are believed to be mediated by membrane-bound hGRs that trigger specific kinase signaling pathways (8).

In addition to the above-mentioned actions, glucocorticoids can influence gene expression independently of hGR binding to DNA. These actions are mediated by physical interaction between the monomeric hGR with other transcription factors, such as the nuclear factor κB (NF-κB), the activator protein 1 (AP-1), and the signal transducers and activators of transcription (STATs), influencing the transcription rate of target genes of the latter (3, 5, 6).

SYNTHETIC GLUCOCORTICOIDS

Since the introduction of glucocorticoids (GCs) in the treatment of rheumatoid arthritis in 1949, intense efforts have been made by science and industry to maximize the beneficial effects and minimize the side effects of glucocorticoids. Thus, many synthetic compounds with glucocorticoid activity were manufactured and tested (9). The pharmacologic differences among these chemicals result from structural alterations of their basic steroid nucleus and its side groups. These changes may affect the bioavailability of these compounds - including their gastrointestinal or parenteral absorption, plasma half-life, and metabolism in the liver, fat, or target tissues - and their abilities to interact with the glucocorticoid receptor and to modulate the transcription of glucocorticoid - responsive genes (10, 11). In addition, structural modifications diminish the natural cross-reactivity of glucocorticoids with the mineralocorticoid receptor, eliminating their undesirable salt-retaining activity. Other modifications increase glucocorticoids' water solubility for parenteral administration or decrease their water solubility to enhance topical potency (11).

Synthetic GCs' clinical efficacy depends on their pharmacokinetics and their pharmacodynamics. Pharmacokinetic parameters such as the elimination half-life and pharmacodynamic parameters such as the concentration producing the half-maximal effect determine the duration and intensity of GC effects (12). It is known that the presence of an 11β-hydroxyl group is essential for the anti-inflammatory and immunosuppressive effects of GCs and for the sodium retaining effects of the mineralocorticoids (MCs). The most important pharmacokinetic systems for GCs and MCs are the 11β- hydroxysteroid dehydrogenases (11β-HSDs) because they regulate the target cell adjustment between the active hydroxy- and the inactive oxo- form of a steroid (13, 14). 11β- hydroxysteroid dehydrogenase type 2 (11β-HSD2, oxidizing enzyme) catalyzes the conversion of cortisol to cortisone, the inactive metabolite, whereas 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD1, reductase) converts cortisone to cortisol. Thus, 11β-HSD1, which is expressed in a wide range of tissues, mainly in the liver, facilitates GC hormone action whereas the major role of 11β-HSD2 is to prevent cortisol from gaining access to high-affinity MC receptors and, therefore, the enzyme is predominantly expressed in the MC responsive cells of the kidney and other MC target tissues (colon, salivary glands) and the placenta (13).

The main structural features determining GC potency are the size and the polarity of the substituent in position 6 or 16. A hydrophobic residue increases GC activity (statistically significant enhancement with 6-α methyl and 16-methylene substitution). The more polar 16-hydroxy substitution decreases GC potency. The 6α and 9α-fluorination (such as in 6α and 9α fluorocortisol respectively) leads to increased GC and MC activity and double fluorination in the same positions augments this shift. Moreover, the Δ1-dehydro-configuration (in prednisolone) enhances GC activity but opposite to that effect it attenuates MC potency. The same effect is observed with the 16-methylene, 16α-methyl (dexamethasone) and 16β-methyl (betamethasone) groups. Thus, the more selective GC transactivation activity of GCs with a 16α-methyl or 16β-methyl group and a Δ1-dehydro-configuration, results from a significantly decreased activity via the mineralocorticoid receptor (MR) and an enhanced activity via the glucocorticoid receptor (GR) (15). Moreover, whereas GC selectivity can be improved by hydrophobic substituents in position 16 and the Δ1-dehydro-configuration, maximal GC activity needs additional fluorination in position 9α (such as in dexamethasone) (16). Figure 1 presents the chemical structures of cortisol and the most commonly used synthetic GCs.

Figure 1:

Chemical Structures of the Most Commonly Used Synthetic GCs.

Protein binding is another pharmacokinetic property that influences GCs biological activity because only the unbound GC fraction is biologically active (14). In humans, endogenous cortisol binding to cortisol binding globulin (CBG) ranges between 67% and 87%, whereas a further 7-19% of total cortisol is bound to albumin, leading to about 95% of cortisol being protein-bound in the plasma. Except for prednisolone, synthetic GCs bind predominantly to albumin and only marginally to CBG. Plasma binding e.g. of dexamethasone and betamethasone is 75% and 60% respectively, and this is quite constant across a wide concentration rate (17). Thus, CBG binding is not a major determinant of plasma and biological half-lives of synthetic GCs.

However, especially for hydrocortisone and prednisone, pharmacokinetics are non-linear due to protein binding. As a result, higher doses result in more rapid clearance rates. It has to be mentioned that prednisone itself is biologically inactive and its 11-keto group must be reduced by hepatic 11βHSD1 to form the active drug, prednisolone. Moreover, clearance rate depends on age and is more rapid in children than adults (18) and also depends upon individual variability. Finally, certain diseases may influence synthetic GCs' pharmacokinetics. Thus, clearance is reduced particularly in renal and hepatic diseases and hypothyroidism and increased in hyperthyroidism. The concomitant use of other drugs influences synthetic GCs' half-lives and, thus, their final effect in target tissues (18, 19). Classic bioassays measure synthetic GC potency by testing the ability to suppress eosinophils and inhibit inflammation and the ability to stimulate hepatic glycogen deposition. The biologic effective half-life of glucocorticoids divides them into short-, intermediate-, or long-acting, based on the duration of corticotropin suppression after a single dose of the compound. The main corticosteroids used in clinical practice together with their relative biologic potencies and their plasma and biological half-lives are listed in Table 1.

SYSTEMIC GLUCOCORTICOID ADMINISTRATION

COMPARTMENTAL GLUCOCORTICOID ADMINISTRATION

MONITORING OF PATIENTS ON GLUCOCORTICOID TREATMENT

As osteoporosis, with resultant fractures, constitutes one of the most serious morbid complications of GC use, worsening patients quality of life, recently, the American College of Rheumatology (ACR) updated the 2010 recommendations for patients receiving oral GC therapy (125). In this systematic review, the authors addressed the initial assessment in patients that began or continue glucocorticoid treatment for longer than 3 months, and discussed the advantages and disadvantages of lifestyle modification, as well as for calcium, vitamin D and pharmaceutical treatment, including bisphosphonates, raloxifene, teriparatide, and denosumab. According to the ACR guidelines, there are three categories of fracture risk. High risk criteria include patients aged over 40 years, previous osteoporotic fracture, hip or spine BMD T-score ≤ −2.5, or 10-year fracture probability of ≥20% (major osteoporotic fracture) or ≥3% (hip fracture) (125, 126). Moderate and low risk criteria are based only on FRAX-derived fracture probability (10–19% and >1 to ≤3% respectively for moderate

risk, and <10% and ≤1% respectively for low risk) (125, 126). In patients aged less than 40 years, a previous osteoporotic fracture is considered as a high-risk criterion, whereas the criteria of moderate and low risk are based on the BMD. Patients at low fracture risk are recommended to receive only calcium and vitamin D, whereas adults at moderate-to-high fracture risk should be treated with calcium and vitamin D plus an oral bisphosphonate. However, adults in whom oral bisphosphonates are not appropriate, are recommended to continue calcium plus vitamin D but switch from an oral bisphosphonate to another anti-fracture medication (125). Finally, adults who complete a planned regimen with oral bisphosphonates and continue glucocorticoid treatment, are recommended to continue oral bisphosphonate treatment or switch to another anti-fracture medication (125). Recommendations were also suggested for children, women of childbearing potential, and people with organ transplants, as well as patients receiving very high doses of glucocorticoids (125). For additional details please see the Endotext chapter on Glucocorticoid-induced osteoporosis (74).

CONCOMITANT USE OF GLUCOCORTICOIDS WITH OTHER DRUGS

Special attention is required in the concomitant use of glucocorticoids with other drugs because of potential interactions, and because some drugs may affect the metabolism of the steroids, which may lead to a decreased or increased glucocorticoid effect on their target tissues (20). Such interactions and effects are shown in Tables 3, 4 and 5.

PREDICTING GLUCOCORTICOID-INDUCED HPA AXIS SUPPRESSION

Several predictors of glucocorticoid-induced HPA axis suppression have been discussed, the major of which are the following:

WEANING PATIENTS FROM GLUCOCORTICOID THERAPY

Besides their multiple therapeutic uses, GC withdrawal is indicated when their use is no longer recommended as the maximum therapeutic benefit has been obtained or when significant side effects appear and become uncontrollable, such as GC induced psychosis, diabetes mellitus, severe hypertension, and incapacitating osteoporosis. The goal of a successful GC withdrawal regimen can be described as the rapid transition from a state of tissue hypercortisolism to a state of total exogenous GC deprivation without resurgence of the underlying disease and without adrenal insufficiency or any other GC dependency. Although there are no consensus documents, several tapering regimens have been published so far. In clinical practice, the majority of physicians develop their own withdrawal regimens. The common point is that GC withdrawal should never be abrupt (19).

A systematic review published in 2002 found 9 randomized, controlled clinical trials, 7 of which investigated bronchial asthma and chronic obstructive pulmonary disease, which compared different GC tapering regimens. According to this review there was no significant difference between rapid or slow tapering, regarding the diseases' exacerbation and relapse rates, suggesting that prolonged withdrawal may not be necessary for a better outcome of the underlying disease. However, the same review highlighted the uncertainty about the safety and efficacy of GC withdrawal in many chronic diseases, emphasizing the need for further research in this area (131).

In general, patients taking any steroid dose for less than 2 weeks are not likely to develop HPA axis suppression and can stop therapy suddenly without tapering. The possible exception to this is the patient who receives frequent "short" steroid courses e.g. in asthma. Where there has been chronic therapy, the objective is to rapidly reduce the therapeutic dose to a physiological level (equivalent to 7.5mg/d prednisolone) e.g. by reducing 2.5mg every 3-4 days over a few weeks, and then proceed with slower withdrawal in order to permit the HPA axis to recover (19, 21).

As far as patients with underlying disease are concerned it is recommended that all available clinical, biochemical and laboratory data on the activity status of the disease be collected in order to easily identify signs of recurrence. In such a case prescribed doses should be increased (19).

After the initial reduction to physiological levels, doses should be reduced by 1mg/d of prednisolone or equivalent every 2-4 weeks depending upon patient's general condition, until the medication is discontinued. Alternatively, after the initial reduction to 5-7.5mg of prednisolone, the clinician can switch the patient to HC 20mg/d and reduce by 2.5mg/d every week until the dose of 10mg/d is achieved. After 2-3 months on the same dose, the HPA axis function should be assessed through a Corticotropin (ACTH-Synachten) test or through an Insulin Tolerance test (ITT). A pass response to these tests indicates adequate function of the axis and GCs can be safely withdrawn. If the axis has not fully recovered, treatment should be continued and the axis function should be reassessed (21).

Other tapering regimens have been published some of them dealing with switching the patient to an alternate dosage of GC before discontinuation (138).

Irrespectively of the tapering regimen used, if GC withdrawal syndrome, adrenal insufficiency's symptomatology, or exacerbation of the underlying disease appears, the dose being given at the time should be elevated or maintained for a longer period of time. Moreover, in the absence of evidence of HPA axis full recovery in patients who have been treated with GCs for prolonged periods, supplementation equivalent to 100-150mg of HC is recommended during situations of severe stress such as major surgery, fractures, severe systemic infections, major burns, etc.

Finally, it has become obvious, that all patients treated long-term with GCs should be treated in a similar fashion to patients with chronic ACTH deficiency, thus, they should be instructed to carry some type of identification (worn around the neck or wrist or carried as a card) (19, 21).

ACUTE ADRENAL CRISIS

Full HPA axis recovery after cessation of GC therapy may take as long as 1 year or more (11, 139). Abrupt cessation of glucocorticoid treatment or quick tapering can precipitate an acute adrenal insufficiency crisis. The main symptoms range from anorexia, fatigue, nausea, vomiting, dyspnea, fever, arthralgia, myalgia, and orthostatic hypotension to dizziness, fainting, and circulatory collapse. Hypoglycemia is occasionally observed in children and very thin adult individuals. The diagnosis is a medical emergency, and treatment should be immediate administration of fluids, electrolytes, glucose, and parenteral glucocorticoids.

GLUCOCORTICOID WITHDRAWAL SYNDROME (GWS)

Chronic administration of high doses of GCs and also other hormones such as estrogens, progestins, androgens and growth hormone induce varying degrees of tolerance, resulting in a progressively decreased response to the effect of the drug, followed by dependence and rarely "addiction". Traditionally, the term "Endocrine Withdrawal Syndromes" has been used to describe symptoms and signs of specific hormone deficiency after discontinuation of hormonal therapy or removal of an endocrine gland. However, discontinuation of hormonal therapy frequently results in a mixed picture of two different syndromes: a typical hormone deficiency syndrome and a generic withdrawal syndrome. Four aspects of GCs withdrawal after cessation of pharmacological high-dose therapy are important: 1) relapse of the underlying disease for which the drug was prescribed 2) HPA axis suppression which can persist for a long time 3) psychological dependence 4) a non-specific withdrawal syndrome despite normal HPA axis function and even while patients are receiving physiological replacement doses of GCs (140, 141).

Amatruda et al. first defined the steroid withdrawal syndrome as a symptom complex resembling true adrenal insufficiency, with nonspecific symptoms like weakness, nausea, and arthralgias, occurring in patients who have finished a dosage reduction of glucocorticoid therapy and who respond normally to HPA axis testing (142). Thus, after cessation of GC therapy patients may develop anorexia, nausea, emesis, weight loss, fatigue, myalgias, arthralgias, weakness, headache, abdominal pain, lethargy, postural hypotension, fever, skin desquamation, tachycardia, emotional lability, and even delirium, and psychotic states even if the response of the HPA axis to stimuli has returned to normal (140). Children and adolescents may experience signs and symptoms of GWS even when GCs are still being administered in supraphysiological doses (19). Biochemical evidence related to the GWS includes hypercalcemia and hyperphosphatemia (140).

The GWS has been considered a withdrawal reaction due to established physical dependence on supraphysiological GC levels (140). It has also been described as a state of relative GC resistance in these patients, effectively rendering them hypoadrenal (141). The mechanisms responsible for GWS have not been fully elucidated. Nevertheless, several mediators should be considered and include CRH, vasopressin, POMC, several cytokines such as IL-1β, IL-6, TNF-α, prostaglandins such as E2, I2, phospholipase A2 and also alterations of the noradrenergic and dopaminergic systems (19, 140).

The severity of GWS depends on the genetics and developmental history of the patient, on his environment, and on the phase and degree of dependence the patient has reached (140). The syndrome is self-limited with a median duration of 10 months. Its management should include a temporary increase in the dose of GCs followed by gradual, slow tapering to a maintenance dose (141).

BIOCHEMICAL DIAGNOSIS OF ADRENAL INSUFFICIENCY

Glucocorticoid treatment may not suppress the HPA axis at all, or it may cause central suppression and adrenal gland atrophy of varying degrees. Several endocrine tests have been used to define progression of glucocorticoid-induced adrenal insufficiency. The insulin tolerance test and the metyrapone test have been employed in the diagnosis of adrenal suppression and are quite sensitive, however, the risks involved with both tests do not justify their use when a rapid ACTH stimulation test can distinguish clinically significant adrenal suppression.

To evaluate the adequacy of hypothalamic-pituitary-adrenal axis recovery, the rapid Synachten (or high-dose ACTH stimulation test) is mostly used. An intravenous bolus of 250 ug of corticotropin 1-24 is administered and cortisol is measured after 30 or 60 minutes or both. A plasma cortisol concentration > 18 - 20 μg/ dL at these times indicates adequate recovery of the hypothalamic-pituitary-adrenal axis (139).

The low-dose Synachten test (1ug or 500 ng ACTH(1-24)/1.73 m2) is also being used for the assessment of the HPA axis after prolonged use of GC medication (143-145). It is unclear if the low-dose test is superior to the high-dose test for the detection of secondary adrenal insufficiency. Some studies have shown that the low-dose Synachten test is more sensitive in detecting partial secondary adrenal insufficiency (as can occur in chronic use of GCs), which is not detected by the standard high-dose test because the latter provides a supraphysiologic stimulus able to stimulate a partially damaged adrenal (146-149). A meta-analysis of 28 studies evaluated the utility of the high and low-dose ACTH test. At a specificity of 95% the sensitivity of the high-dose test for primary adrenal insufficiency was 97%, greater than that for secondary adrenal insufficiency (57%). The sensitivities for secondary adrenal insufficiency were similar between the high-dose (57%) and the low-dose Synachten test (61%) (150). In contrast, a review of the literature published between 1965 and 2007 suggests that the low-dose test is the best test currently available for establishing the diagnosis of secondary AI (151). Further studies are needed to establish if the low-dose Synachten test is preferable for the diagnosis of secondary AI.

The Corticotropin Releasing Hormone (CRH) test can also be used in patients taking GC treatment for prolonged periods, as it can assess both the ACTH and cortisol responses and can distinguish between secondary and tertiary adrenal insufficiency (133, 152).

The Dexamethasone Suppression Test has been shown to predict the later development of an impaired adrenal function after a 14-day course of prednisone in healthy volunteers and this information may allow a more targeted approach for the patients after cessation of steroid therapy (153).

FUTURE PERSPECTIVES ABOUT GLUCOCORTICOID THERAPY

Although hydrocortisone (HC) is the most commonly used regimen for replacement in patients with primary and secondary adrenal insufficiency, it is evident that this conventional therapy cannot provide the physiological rhythm of cortisol release. Moreover, with current replacement therapy, the majority of patients with adrenal insufficiency report impaired health-related quality of life, early morning fatigue, socioeconomic health problems and, finally, increased mortality (154). Circadian infusions of HC delivered by a programmable pump can mimic the normal rhythm of cortisol secretion and improve biochemical control and quality of life in patients with adrenal insufficiency and congenital adrenal hyperplasia. Because such infusions are not a practical solution, new formulations of oral HC, which mimic cortisol physiology have been evaluated. A dual-release hydrocortisone tablet with an immediate-release outer layer covering a sustained-release core, has been used in patients with Addison’s disease showing improvements in cardiovascular risk factors, including body weight, hemoglobin A1C and blood pressure, as well as a significant improvement in fatigue (154-156). In the long-term, this once-daily formulation was well-tolerated with a small number of adverse effects (157). Another modified-release multiparticulate hydrocortisone capsule formulation has been developed recently (158). This formulation was well tolerated and very effective in controlling disease biomarkers of congenital adrenal hyperplasia, such as androstenedione and 17-hydroxyprogesterone, with a lower hydrocortisone dose equivalency (154).

Apart from their use for hormonal replacement, the clinical success of synthetic GCs as anti-inflammatory agents is largely attributed to their ability to reduce the expression of proinflammatory genes, via activation of the GR and the concomitant inhibition of the activity of proinflammatory transcription factors, including NF-κB and AP-1, through a mechanism called trans-repression. On the other hand, the appearance of their AEs mainly arise from their ability to activate, after induction of the GR, target genes involved in the metabolism of sugar, protein, fat, muscle and bone via a mechanism called trans-activation (159, 160). There is a plethora of recent work dealing with the characteristics of novel selective GR ligands with equal efficacy and improved side-effects profiles, in other words ligands that show an improved therapeutic index (159-162). These efforts have resulted in a number of different terminologies: Selective GR modulators, selective GR agonists, gene-selective compounds, dissociated compounds, etc. (161, 163), which have been developed and are still being developed mainly focusing on the trans-repression mechanism and stimulating the side-effect pathway to a lesser extent, at least in specific tissues. Nevertheless, the likelihood of finding a compound that actually separates all activated genes from all repressed genes is highly unlikely mainly because the transactivation vs trans-repression characteristics are highly cell-type and gene specific. Moreover, it is also unclear whether such a compound would be truly desirable, as upregulation of anti-inflammatory genes may also play a role in the treatment of many diseases (159-161). In addition, many non-steroidal dissociated GR modulators, some of which do not support trans-activation, have shown promising benefit to side-effect ratios (e.g. ZK216348, CpdA) (159).

Considering the complexity of pathways regulated by GR, it is clearly too naive to assume that an ideal exogenous GR modulator only eliciting the beneficial anti-inflammatory effects without any trace of side-effects will ever be found. Complementing genome-wide gene profiling studies and transcription factor/DNA binding patterns on various target tissues at once will become an adamant strategy for the future (159). However, recent reports of Selective GR modulators provide fertile ground for additional efforts and it is obvious that any progress in this area would be a major benefit for thousands of patients receiving GC therapy (161).

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