Steroid Drug WithdrawalAdrenal insufficiency results from inadequate adrenocortical function, which uso de anabolicos en mujeres be due to destruction of the adrenal cortex primary adrenal insufficiency; Addison's diseasedeficient pituitary ACTH secretion secondary adrenal insufficiencyor deficient hypothalamic secretion of CRH or other ACTH secretagogues tertiary adrenal insufficiency. Primary corticosteroid withdrawal syndrome dexamethasone secondary adrenal insufficiency related to natural causes is uncommon, whereas iatrogenic, tertiary adrenal insufficiency caused by suppression of Hypothalamic-Pituitary-Adrenal HPA function by corticosteroid withdrawal syndrome dexamethasone administration is common. Glucocorticoid treatment may not suppress the HPA axis at all, or it may cause central suppression or complete adrenal gland atrophy. When this inhibition lasts longer than the duration of the glucocorticoid exposure, it is called adrenal suppression. Since the introduction of glucocorticoids in the treatment of rheumatoid arthritis inthe therapeutic applications of these drugs were greatly broadened to encompass a large number of nonendocrine and endocrine diseases
Glucocorticoid Therapy and Adrenal Suppression - Endotext - NCBI Bookshelf
Adrenal insufficiency results from inadequate adrenocortical function, which may be due to destruction of the adrenal cortex primary adrenal insufficiency; Addison's disease , deficient pituitary ACTH secretion secondary adrenal insufficiency , or deficient hypothalamic secretion of CRH or other ACTH secretagogues tertiary adrenal insufficiency. Primary and secondary adrenal insufficiency related to natural causes is uncommon, whereas iatrogenic, tertiary adrenal insufficiency caused by suppression of Hypothalamic-Pituitary-Adrenal HPA function by glucocorticoid administration is common.
Glucocorticoid treatment may not suppress the HPA axis at all, or it may cause central suppression or complete adrenal gland atrophy.
When this inhibition lasts longer than the duration of the glucocorticoid exposure, it is called adrenal suppression. Since the introduction of glucocorticoids in the treatment of rheumatoid arthritis in , the therapeutic applications of these drugs were greatly broadened to encompass a large number of nonendocrine and endocrine diseases The glucocorticoid-induced adrenal suppression, when glucocorticoids are used in supraphysiologic doses, renders the adrenal glands unable to generate sufficient cortisol if glucocorticoid treatment is abruptly stopped and the patient develops glucocorticoid deficiency manifestations.
The true prevalence of clinically significant adrenal insufficiency and adrenal crisis is considered rare since physicians usually discontinue high-dose glucocorticoids gradually to allow recovery of the HPA axis, but this prevalence is likely to be underreported in clinical practice. Some of the risk factors for HPA axis suppression are clearly defined, whereas others are less certain 5, 6.
For this reason, if glucocorticoid dosage is to be reduced, it should be tapered slowly 2. Glucocorticoid treatment in endocrine and nonendocrine disorders, the side effects of these medications, their concomitant use and interactions with other drugs, the risk factors for adrenal suppression, the way for weaning from therapy, the glucocorticoid withdrawal syndrome and some future perspectives about glucocorticoid treatment are discussed in detail here. Since the introduction of glucocorticoids GCs in the treatment of rheumatoid arthritis in , intense efforts have been made by science and industry to maximize the beneficial and to minimize the side effects of glucocorticoids.
Thus, many synthetic compounds with glucocorticoid activity were manufactured and tested. 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 7.
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 1, 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 The main structural features determining GC potency are the size and the polarity of the substituent in position 6 or The more polar hydroxy substitution decreases GC potency. Protein binding is another pharmacokinetic property that influences GCs biological activity because only the unbound GC fraction is biologically active.
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. Moreover, clearance rate depends on the age and is more rapid in children than adults 18 and also depends upon individual variability 3. Finally, certain diseases may influence SGCs' pharmacokinetics. Thus, clearance is reduced particularly in renal and hepatic diseases and hypothyroidism and increased in hyperthyroidism.
The concomitant use of other drugs influences SGCs' half-lives and, thus, their final effect in target tissues 3,18, Classic bioassays measure SGC potency by testing the ability to suppress eosinophils and inhibit inflammation and the ability to stimulate hepatic glycogen deposition 3.
The biologic effect 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. View in own window. GCs are used in both endocrine and non-endocrine disorders.
First of all, they are administered as replacement therapy in patients with primary or secondary adrenal insufficiency, and as adrenal suppression therapy in congenital adrenal hyperplasia and glucocorticoid resistance 8, They are also used in patients with Grave's opthalmopathy and for some diagnostic purposes such as in establishing Cushing's syndrome 2,3.
Moreover, due to their immunosuppressive and anti-inflammatory properties they are used in a broad range of non-endocrine disorders affecting many different systems Thus, they are given to treat skin disorders such as dermatitis and pemphigus, rheumatologic diseases such as systemic lupus erythematosus, polyarteritis and rheumatoid arthritis, and also polymyalgia rheumatica and myasthenia Gravis.
In hematology, they are used, along with chemotherapy, for the treatment of lymphomas and leukemias 3, 21 and in hemolytic anemias and idiopathic thrombocytopenic purpura. In addition, they are administered in gastrointestinal diseases such as inflammatory bowel disease, in liver diseases chronic active hepatitis and in respiratory diseases angioedema, anaphylaxis, asthma, sarcoidosis, tuberculosis, obstructive airway disease.
Moreover, GCs are used in nephrotic syndrome and vasculitis and also in the suppression of the host-versus-graft and graft-versus-host reaction in cases of organ transplantation. In nervous disorders such as cerebral edema and raised intracranial pressure the use of GCs is also beneficial 3,22, Acute administration of pharmacologic doses of glucocorticoids is advocated in a small number of nonendocrine diseases, such as for patients suffering from acute traumatic spinal cord injury Moreover, steroid administration should be considered as a post-operative additional therapy for cases with severe neurological deficits even after surgery Glucocorticoids are also used for postoperative pain relief after severe bone operations Recommended treatment consisted of 2 doses of 12mg betamethasone given IM 24h apart or 4 doses of 6mg dexamethasone given 12h apart.
In the NIH Consensus Developmental Panel recommended that repeat courses should not be used routinely until insightful findings are available.
Acute administration of pharmacologic doses of glucocorticoids is also necessary in some types of acute illness. For years it is known that any type of acute illness or trauma results in loss of the diurnal variation in cortisol secretion. In the early phase of critical illness cortisol levels frequently rise and levels of CBG and albumin are substantially depleted. In the chronic phase of critical illness, however, high ACTH and cortisol levels are generally sustained and CBG levels gradually increase.
Both very high and very low cortisol levels have been associated with increased mortality from critical illness.
High cortisol levels reflect severe stress, whereas low levels reflect an inability to sufficiently respond to stress The term "critical illness-related cortisol insufficiency" CIRCI defines a state of both the inadequate production of GCs as well as a corticosteroid tissue resistance. According to the current recommendations, CIRCI should be suspected in hypotensive patients who respond poorly to fluids and vasopressor agents, particularly in the setting of sepsis.
The proven benefit of treatment with GCs at this time seems to be limited to patients with vasopressor dependent septic shock and those with early severe Acute Respiratory Distress Syndrome ARDS within 14 days of onset. For such patients, who should receive treatment, an ACTH test is not necessary to identify their adrenal insufficiency.
GCs should be tapered slowly and reinstituted with recurrence of signs of sepsis, hypotention, or worsening oxygenation As far as pediatric severe sepsis is concerned, GCs should be given only in children with suspected or proven adrenal insufficiency It should also be noted that routine cortisol assays measure the total hormone concentration rather than the biologically active, free cortisol concentration. Given the reduction of CBG levels during the early phase of critical illness, the use of total hormone levels in the diagnosis of relative adrenal insufficiency is partly invalidated.
Accordingly, appropriate levels and responses of free cortisol have been identified in patients despite abnormalities in total cortisol levels. However, the assay for free cortisol is currently impractical for clinical use. Alternative markers are the free cortisol index, free cortisol levels calculated from total cortisol and CBG and salivary cortisol levels Benefits of GCs replacement has been demonstrated in a number of other patient populations including high-risk cardiac surgery, liver failure, post-traumatic stress disorder, community acquired pneumonia and weaning from mechanical ventilation 29, Although SGCs remain an important component of therapy for many conditions, in recent years there are arguments against their use based mainly on the concern of toxicity.
Nowadays, GCs toxicity is one of the commonest causes of iatrogenic illness associated with chronic inflammatory disorders. This happens because it is in general difficult to separate the effects of GCs from the outcome of the underlying disease, other comorbidities, or the use of other medication. Moreover, toxicity reports usually concern patients using high doses of GCs, different types of GCs with different relative drug potencies, for an heterogeneous group of related diseases and for different periods of time 4,33, Only recently there has been intense effort by scientists and clinicians to explore and quantify the incidence and severity of the AEs of GC therapy 4.
Generally, it is known that GCs' toxicity is related to both the average and cumulative dose during their use However, a recent review of "the 4 extensively reviewed trials on low dose GCs in rheumatoid arthritis" led to the conclusion that definitive association of low dose GCs with many AEs such as osteoporosis, myopathy, cardiovascular disease, glaucoma, increased incidence of any kind of infection and behavior disturbances remains elusive, and that the fear of GCs toxicity is probably overestimated based on extrapolation from observations with higher dose treatment.
All AEs demonstrated a strong dose-dependent association with cumulative GC use. In conclusion, this survey adds further evidence that more GC associated AEs are dependent on both the average dose and the duration of therapy and that even low dose GC therapy could lead to serious AEs The AE rate depends both on the quality of the study and -primarily- on the disease in the study population.
Psychological and behavioral disturbances e. A recent observational study aimed to identify patterns of self reported health problems relating to dose and duration of GCs in unselected patients with RA. The study identified 2 distinct dose-related patterns of AEs. A continuous, approximately linear rising with increasing dose was found for cushingoid phenotype, ecchymosis, leg edema, mycosis, parchment-like skin, shortness of breath and sleep disturbance. The most clearly attributable adverse drug reaction to GCs, Cushing syndrome, becomes evident after at least one month of treatment and was observed in 2.
The second pattern identified describes an elevation in the frequency of health problems beyond a certain threshold value and is defined as a "threshold pattern". The threshold for the increase in glaucoma, depression and an increase in blood pressure was observed at dosages of over 7. All these associations found are in agreement with biological mechanisms and clinical observations However, more thorough research on the risk-benefit ratio of long-term GCs is needed and could help to create new targets for drug development.
Iatrogenic, tertiary adrenal insufficiency by chronic administration of high doses of GCs is the most common cause of adrenal insufficiency.
As a result, in the absence of ACTH, the adrenal cortex loses the ability to produce cortisol 6. Nevertheless, the adrenal cortex restores the ability to secrete enough amounts of cortisol for some period of time and also mineralocorticoids, as this latter function depends mainly on the renin-agiotensin system rather than on ACTH.
The association between AI and treatment with oral GCs has been recognized for decades, although the magnitude of the risk has not been determined until recently. It has also been reported that the inhibition of the HPA axis function induced by exogenous GCs may persist for 6 to 12 months after treatment is withdrawn Based on the literature the absolute risk of adrenal crisis after cessation of oral and inhaled GCs might be considered rare, but it is likely to be substantially underreported in clinical practice The first study that quantified the increased risk of AI in people prescribed oral and inhaled GCs in the general population was published in The largest increase in risk occurred in association with a recent prescription for fluticasone proprionate These findings were confirmed by more recent studies that aimed to investigate the prevalence of AI in patients treated either with inhaled 41 or with oral GCs 39, A population-based study that compared the risk for CVD in Similar associations were noted in another observational study that included However, the previous results are not confirmed by other studies Moreover, an association of GCs use and the risk for atrial fibrillation and flutter has been established by several studies The maintenance of glucose levels by GCs is multifactorial and could be explained by several potential mechanisms including the induction of enzymes involved in hepatic gluconeogenesis, the decrease in glucose uptake in peripheral tissues, the stimulation of lipolysis, the prevention of insulin production and the induction of ceramides' biosynthesis leading to insulin resistance A recent review of the existing literature published between shows that GCs-induced hyperglycemia is common among patients with and without diabetes mellitus.
The OR for new onset diabetes mellitus ranges from 1,5 to 2,5 and the induction of the disease is strongly predicted by GCs accumulative dose and duration of therapy GC therapy is associated with a risk of infectious complications, as GCs are known to have suppressive effects upon both innate and acquired immunity.