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Background: Takotsubo Cardiomyopathy (TCM) is a transient heart condition often precipitated by stress and characterized by atypical ventricular ballooning. The interplay between TCM and Adrenal Insufficiency (AI), particularly the influence of catecholamine excess and glucocorticoid deficiency on TCM's pathogenesis in individuals with AI, warrants comprehensive exploration for a better understanding of TCM pathophysiology and establishment of potential therapeutic strategies., Methods: We conducted an extensive literature search via PubMed and Google Scholar, targeting reports on AI, heart failure, and cardiomyopathy, supplemented by forward and backward citation tracing. We analyzed 46 cases from 45 reports, assessing the clinical presentation and outcomes in the context of AI categorization., Results: In patients with AI, a glucocorticoid deficit appears to exacerbate the myocardial vulnerability to catecholamine toxicity, precipitating TCM. Most conditions were reversible; however, three pre-1990 cases resulted in irreversible outcomes., Conclusions: The investigation into the AI and TCM intersection highlights the pathogenic significance of catecholamines in the absence of glucocorticoids. The data consolidates the hypothesis that glucocorticoid scarcity exacerbates the cardiac susceptibility to catecholaminergic toxicity, potentially triggering TCM. The study affirms glucocorticoids' cardioprotective roles and elucidates how catecholamine surges contribute to TCM pathogenesis, suggesting strategic clinical management adjustments for AI patients to reduce TCM incidence., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Iatrogenic adrenal insufficiency (AI) secondary to long-term treatment with exogenous glucocorticoids (GC) is common in patients with systematic rheumatic diseases, including rheumatoid arthritis (RA). Moreover, a proportion of these patients is always in need of even small doses of glucocorticoids to maintain clinical remission, despite concomitant treatment with conventional and biologic disease-modifying drugs., Methods: We conducted a literature review up to December 2020 on (a) the incidence of AI in both long-term GC-treated and GC-treatment naïve RA patients; (b) the potential effects of increased levels of circulating proinflammatory cytokines, as well as of chronic stress, in adrenocortical function in RA; (c) the circadian cortisol rhythm in RA; and (d) established and evolving methods of assessment of adrenocortical function., Results: Up to 48% of RA patients develop glucocorticoid-induced AI; however, predictors are not established, while adrenocortical dysfunction may also occur in GC-treatment naïve RA patients. Experimental and clinical data have suggested that inadequate production of endogenous cortisol relative to enhanced clinical needs associated with the systemic inflammatory response, coined as the 'disproportion principle', may operate in RA. Although the underlying mechanisms are unknown, both proinflammatory cytokines and chronic stress may contribute the most in the adrenals hyporesponsiveness and the target tissue glucocorticoid resistance that have been described, but not systematically studied. A precise longitudinal assessment of endogenous cortisol production may be needed for optimal RA management., Conclusion: Apart from iatrogenic AI, an intrinsically compromised adrenal reserve in RA may have a pathogenetic role and interfere with effective management, thus deserving further research., (© 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Glucocorticoids are, besides non-steroidal anti-inflammatory drugs, the most widely used anti-inflammatory medications. Prevalence studies indicate substantial use of both systemic and locally acting agents. A recognised adverse effect of glucocorticoid treatment is adrenal insufficiency, which is highly prevalent based on biochemical testing, but its clinical implications are poorly understood. Current evidence, including randomised trials and observational studies, indicates substantial variation among patients in both risk and course of glucocorticoid-induced adrenal insufficiency, but both are currently unpredictable. Oral and intra-articular formulations, as well as long-term and high-dose treatments, carry the highest risk of glucocorticoid-induced adrenal insufficiency defined by biochemical tests. However, no route of administration, treatment duration, or dose can be considered without risk. More research is needed to estimate the risk and temporal pattern of glucocorticoid-induced adrenal insufficiency, to investigate its clinical implications, and to identify predictors of risk and prognosis. Randomized trials are required to evaluate whether hydrocortisone replacement therapy mitigates risk and symptoms of glucocorticoid-induced adrenal insufficiency in patients discontinuing glucocorticoid treatment. This review aims to provide an overview of the available evidence, pointing to knowledge gaps and unmet needs.

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by single cortisol deficiency but normal aldosterone and renin levels. Beginning from the discovery of the disease to that of the pathogenic genes over a period of 30 years, the development of gene detection technology has identified a large number of FGD‑related genes. Despite the fact that the genetic defect underlying this disease is known for approximately 70% of the patients diagnosed with FGD, there are still several unknown factors causing it. FGD is divided into type 1, type 2 and non‑classical type according to the mutant gene. The case described in the present study reported two patients, who were siblings, having skin hyperpigmentation and undergone treatment in adulthood. The gonadal development was normal and the proband had a 10‑year‑old son. Laboratory tests suggested glucocorticoid deficiency and a mild lack of mineralocorticoid, indicating hyponatremia and hypotension in the proband. In addition, cortisol deficiency was not affected by adrenocorticotropic hormone treatment, while the adrenal glands in the two patients did not show any hyperplasia. Gene analysis revealed two compound heterozygote mutations c.533T>A (p. Leu178Gln) and c.737A>G (p. Asp246Gly) in the steroid hormone acute regulatory protein (STAR) gene in both patients, which may have been obtained from their parents and the proband passed one of the mutations to her son. The present study results revealed that STAR mutations cause non‑classic congenital lipoid adrenal hyperplasia in China.

Context: Patients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid a life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based., Objective: To identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency who are exposed to major stress., Design and Participants: Cross-sectional study: 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma [N = 83], sepsis [N = 100], and combat stress [N = 105]). Longitudinal study: 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing administration of 200 mg hydrocortisone over 24 hours in 4 different delivery modes (continuous intravenous infusion; 6-hourly oral, intramuscular or intravenous bolus administration)., Main Outcome Measure: We measured total serum cortisol and cortisone, free serum cortisol, and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modeling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress., Results: Serum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modeling identified continuous intravenous infusion of 200 mg hydrocortisone over 24 hours, preceded by an initial bolus of 50-100 mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range., Conclusions: Continuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress., (© Endocrine Society 2020.)

Glucocorticoid deficiency is the clinical state characterised by inadequate cortisol production. It may occur due to the primary failure of the adrenal cortex or to lack of stimulation of the adrenal cortex by adrenocorticotropic hormone. The aim of treatment of glucocorticoid deficiency is to mimic the normal physiological secretion of cortisol, in order to normalise quality of life and reverse pathological sequelae. However, the diurnal rhythm of cortisol secretion is difficult to reproduce with exogenous glucocorticoid therapy. There is wide inter- and intra-individual variability of in the dynamics of physiological glucocorticoid secretion, and glucocorticoid preparations that are currently available cannot reproduce physiological profiles. In addition, there are no reliable biomarkers to determine the adequacy of treatment. The treatment of acute glucocorticoid deficiency/ adrenal crisis involves prompt recognition and administration of parenteral hydrocortisone, rehydration, and management of electrolyte abnormalities. In the management of chronic glucocorticoid deficiency, the prevention of adrenal crisis must be balanced with avoidance of the long-term adverse effects of over-replacement. This requires close collaboration with the patient, for whom education and empowerment in the management of glucocorticoid deficiency, and the prevention of crises, are crucial., (Copyright © 2020 Elsevier B.V. All rights reserved.)

These guidelines aim to ensure that patients with adrenal insufficiency are identified and adequately supplemented with glucocorticoids during the peri-operative period. There are two major categories of adrenal insufficiency. Primary adrenal insufficiency is due to diseases of the adrenal gland (failure of the hormone-producing gland), and secondary adrenal insufficiency is due to deficient adrenocorticotropin hormone secretion by the pituitary gland, or deficient corticotropin-releasing hormone secretion by the hypothalamus (failure of the regulatory centres). Patients taking physiological replacement doses of corticosteroids for either primary or secondary adrenal insufficiency are at significant risk of adrenal crisis and must be given stress doses of hydrocortisone during the peri-operative period. Many more patients other than those with adrenal and hypothalamic-pituitary causes of adrenal failure are receiving glucocorticoids as treatment for other medical conditions. Daily doses of prednisolone of 5 mg or greater in adults and 10-15 mg.m -2 hydrocortisone equivalent or greater in children may result in hypothalamo-pituitary-adrenal axis suppression if administered for 1 month or more by oral, inhaled, intranasal, intra-articular or topical routes; this chronic administration of glucocorticoids is the most common cause of secondary adrenal suppression, sometimes referred to as tertiary adrenal insufficiency. A pragmatic approach to adrenal replacement during major stress is required; considering the evidence available, blanket recommendations would not be appropriate, and it is essential for the clinician to remember that adrenal replacement dosing following surgical stress or illness is in addition to usual steroid treatment. Patients with previously undiagnosed adrenal insufficiency sometimes present for the first time following the stress of surgery. Anaesthetists must be familiar with the symptoms and signs of acute adrenal insufficiency so that inadequate supplementation or undiagnosed adrenal insufficiency can be detected and treated promptly. Delays may prove fatal., (© 2020 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Objectives: Determine incidence of preoperative adrenal insufficiency in neonates >35 weeks gestation with congenital heart disease undergoing cardiothoracic surgery with bypass and effects of prophylactic methylprednisolone on postoperative hypothalamic-pituitary-adrenal function and hemodynamic stability., Design: Prospective observational study in 36 neonates with preoperative adrenocorticotrophic hormone stimulation tests and serial total cortisol and adrenocorticotrophic hormone measurements before and after surgery. Data analyses: analysis of variance and regression., Results: Baseline circulating adrenocorticotrophic hormone and cortisol were unchanged 4-20 days postnatal (P > 0.1); however, cortisol levels rose with increasing adrenocorticotrophic hormone, P = 0.02. Ten neonates (29%) demonstrated preoperative adrenal insufficiency (∆cortisol ≤9 µg/dl); one had postoperative hemodynamic instability. Growth-restricted neonates had lower baseline cortisol, but normal stimulation tests and responded well to surgical stresses. Seventy-five percent of neonates receiving perioperative methylprednisolone demonstrated postoperative hypothalamic-pituitary-adrenal inhibition., Conclusion: Adrenal insufficiency appears common in neonates >35 weeks gestation with congenital heart disease, but did not contribute to postoperative hemodynamic instability despite hypothalamic-pituitary-adrenal inhibition.

Background: Biochemical adrenal insufficiency induced by glucocorticoid treatment is prevalent, but data on the clinical implications are sparse. We investigated clinical consequences of glucocorticoid-induced adrenal insufficiency after oral glucocorticoid cessation., Methods: We conducted a Danish population-based self-controlled case series utilizing medical registries. In this design each individual serves as their own control allowing event rates to be compared as a function of time and treatment. Clinical indicators of adrenal insufficiency were defined as diagnoses of gastrointestinal symptoms, hypotension, cardiovascular collapse, syncope, hyponatremia, and hypoglycaemia. We included 286,680 persons who discontinued long-term (≥ 3 months) oral glucocorticoid treatment. We defined five risk periods and a reference period (before treatment): period 0 (on treatment), withdrawal period (1 month before and after cessation), followed by three consecutive 2 month-risk periods after withdrawal (periods 2-4)., Results: Median age at cessation was 69 years and 57% were female. Median treatment duration was 297 days and median cumulative dose was 3000 mg prednisolone equivalents. The incidence rates of hypotension, gastrointestinal symptoms, hypoglycemia and hyponatremia were increased in the withdrawal period compared to before treatment started (reference period). Incidence rate ratios comparing the withdrawal period with the reference period were 2.5 [95% confidence interval (CI): 1.4-4.3] for hypotension, 1.7 (95% CI: 1.6-1.9) for gastrointestinal symptoms, 2.2 (95% CI: 0.7-7.3) for hypoglycemia, and 1.5 (95% CI: 1.1-2.0) for hyponatremia. During 7 months of follow up, the rates of hypotension and gastrointestinal symptoms remained elevated compared to the reference period. Risk factors included use of antibiotics, increasing average daily dose of glucocorticoids, cumulative dose, and age., Conclusion: Oral glucocorticoid withdrawal was associated with adverse outcomes attributable to adrenal insufficiency. Our study underscores the need for future research to establish evidence-based clinical guidance on management of patients who discontinue oral glucocorticoids., Competing Interests: The authors have declared that no competing interests exist.

Long-term glucocorticoid therapy has improved outcomes in patients with Duchenne muscular dystrophy. However, the recommended glucocorticoid dosage suppresses the hypothalamic-pituitary-adrenal axis, leading to adrenal insufficiency that may develop during severe illness, trauma or surgery, and after discontinuation of glucocorticoid therapy. The purpose of this review is to highlight the risk of adrenal insufficiency in this patient population, and provide practical recommendations for management of adrenal insufficiency, glucocorticoid withdrawal, and adrenal function testing. Strategies to increase awareness among patients, families, and health care providers are also discussed.

Background: Cardiovascular manifestations associated with Addison's disease are previously documented. We described a case of an 11-year-old girl who developed dilated cardiomyopathy as a complication to Addison's disease. Glucocorticoid replacement therapy resulted in near-complete recovery of cardiac function. It is the first reported case of reversible cardiomyopathy as a complication of primary adrenal insufficiency in Syria., Case Presentation: An 11-year-old Caucasian girl with no significant past medical history presented with abdominal pain, vomiting after meals, and a low-grade fever. A physical examination and laboratory evaluation suggested primary adrenal insufficiency. An echocardiogram showed changes consistent with dilated cardiomyopathy. Causes of primary adrenal insufficiency other than autoimmune were excluded., Conclusions: Dilated cardiomyopathy is a rare complication of primary adrenal insufficiency. Proper treatment of adrenal insufficiency with glucocorticoid replacement therapy resulted in restoration of normal cardiac function.

Objective: Prolonged exposure to glucocorticoids lead to hypothalamic-pituitary-adrenal (HPA) axis suppression that recovers after cessation of treatment. We aimed to identify the predictive factors for HPA axis recovery after prolonged glucocorticoid use., Methods: Retrospective review of patients who had undergone first short Synacthen test (SST) to assess HPA axis recovery after prolonged use of glucocorticoids., Results: A total of 61% (20/33) of patients had adequate SST response at a median time of 2 years after diagnosis of adrenal insufficiency. Those who had adequate response during SST had higher ambulatory early morning cortisol ( P<.01), shorter duration of exposure to glucocorticoids ( P = .01), and lower final cumulative hydrocortisone replacement dose ( P = .03). Age, gender, body mass index, indications for glucocorticoid use, and basal adrenocorticotropic hormone levels were not predictive of HPA axis recovery. On multivariate analysis, ambulatory early morning cortisol was the only independent predictor of adequate SST response (odds ratio, 1.02; 95% confidence interval, 1.01 to 1.04; P = .02). Using receiver operating characteristic curve analysis, ambulatory early morning cortisol of 8.8 μg/dL predicted a positive SST response with a sensitivity of 70% and specificity of 93%., Conclusion: Early morning ambulatory cortisol could be used to decide on timely SST in order to prevent complications from unnecessary replacement with glucocorticoids., Abbreviations: ACTH = adrenocorticotropic hormone; BMI = body mass index; CV = coefficient of variation; HPA = hypothalamic-pituitary-adrenal; SST = short Synacthen test.

Steroid treatment is commonly recommended for autoimmune disorders in rheumatology practice. While adrenal crisis may occur upon existence of an inducing factor in patients with known or unknown adrenal insufficiency as well as in those with a suppressed hypothalamic-pituitary-adrenal (HPA) axis due to chronic steroid use, addisonian crisis rarely develops in patients on supraphysiological doses of steroid and, when emerged, it might be very difficult to recognize. Here, we present a patient who developed adrenal crisis while receiving high-dose methylprednisolone treatment due to retroperitoneal fibrosis and we also discuss possible mechanisms with a brief literature review.

A 73-year-old Japanese woman with untreated Graves' hyperthyroidism developed glucocorticoid-induced adrenal insufficiency (AI) after a supraphysiological dose of prednisolone therapy for bronchial asthma. Days later, she had high plasma adrenocorticotropic hormone (ACTH) levels and was expected to recover from glucocorticoid-induced AI. Her plasma ACTH levels remained high over 3 months during a physiological dose of hydrocortisone replacement. However, she suffered a further decrease in her serum cortisol level and was diagnosed with isolated adrenocorticotropin deficiency (IAD), in which bioinactive ACTH likely caused the high ACTH value. IAD should be considered as an unusual disorder associated with Graves' disease, especially in older patients.

Adrenal insufficiency (AI) is a rare disease in childhood and adolescence that results from disruption in the hypothalamic-pituitary-adrenal axis. Pediatricians should be familiar with this entity since acute adrenal crisis is a life-threatening condition that requires immediate treatment. In the early stages of AI, the clinical manifestations may be subtle and non-specific; thus, they are frequently unrecognized. The main therapeutic approach in all forms of adrenal insufficiency is glucocorticoid replacement; the dose should be titrated appropriately to avoid under or overtreatment. Patient and family education is particularly important, to enable adjustment of dosage replacement therapy during stress and to prevent crisis. This article summarizes the current knowledge of AI and provides new insights on its management in children.

Study Objective: To evaluate the effect of an epidural corticosteroid injection of 80 mg and 40 mg of methylprednisolone acetate on the hypothalamic-pituitary-adrenal axis and on back pain., Design: Randomized, single-blinded prospective study., Setting: Operating room of a university-affiliated hospital., Patients: 42 patients with low back pain due to radiculopathy., Interventions: Group 1 received an epidural corticosteroid injection of 80 mg of methylprednisolone acetate, and Group 2 received an epidural corticosteroid injection of 40 mg of methylprednisolone acetate. All study patients underwent a stimulation test of one μg of adrenocorticotropin hormone (ACTH), and their pain levels were graded just prior to and following the epidural corticosteroid injection on weeks one, 3, and 4., Measurements: Serum cortisol of the ACTH stimulation tests and back pain levels were rated using a visual analog scale (VAS). Serum cortisol levels lower than 18 ng/mL 30 minutes following the ACTH stimulation test were considered to be secondary adrenal insufficiency., Main Results: 21 patients were enrolled in each group. The rate of secondary adrenal insufficiency in Group 1 was ~86%, ~ 22%, and ~17% of patients versus ~53% (P = 0.024), 15% (P = 0.874), and ~12% (P = 0.715) of Group 2 patients at weeks one, 3, and 4, respectively. About 62%, 56%, and 39% of Group 1 patients had a favorable clinical response as opposed to ~47% (P = 0362), 35% (P = 0.21), and ~6% (P = 0.049) of Group 2 patients at weeks one, 3, and 4, respectively., Conclusions: Epidural corticosteroid injection of methylprednisolone acetate in both groups was associated with very high rates of secondary adrenal insufficiency, but significantly more so in Group 1 at week one. This suppression was transient, with recovery of the gland in most patients noted over the ensuing weeks. An epidural corticosteroid injection of 80 mg had higher rates of favorable clinical response than a 40 mg injection, but significantly more so at week 4 only. This favorable response waned over a few weeks in both groups., (© 2013 Elsevier Inc. All rights reserved.)

Glucocorticoid therapy is widely used, but withdrawal from glucocorticoids comes with a potential life-threatening risk of adrenal insufficiency. Recent case reports document that adrenal crisis after glucocorticoid withdrawal remains a serious problem in clinical practice. Partly due to difficulties in inter-study comparison the true prevalence of glucocorticoid-induced adrenal insufficiency is unknown, but it might be somewhere between 46 and 100% 24h after glucocorticoid withdrawal, 26-49% after approximately one week, and some patients show prolonged suppression lasting months to years. Adrenal insufficiency might therefore be underdiagnosed in clinical practice. Clinical data do not permit accurate estimates of a lower limit of glucocorticoid dose and duration of treatment, where adrenal insufficiency will not occur. Due to individual variation, neither the glucocorticoid dose nor the duration of treatment can be used reliably to predict adrenal function after glucocorticoid withdrawal. Also the recovery rate of the adrenal glands shows individual variation, which may be why there is currently insufficient evidence to prove the efficacy and safety of different withdrawal regimens. Whether a patient with an insufficient response to an adrenal stimulating test develops clinically significant adrenal insufficiency depends on the presence of stress and resulting glucocorticoid demand and it is thus totally unpredictable and can change relative fast. Adrenal insufficiency should therefore always be taken seriously. Individual variation in hypothalamic-pituitary-adrenal axis function might be due to differences in glucocorticoid sensitivity and might be genetic. Further awareness of the potential side effect of withdrawal of glucocorticoid and further research are urgently needed., (Copyright © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Adrenal insufficiency may be caused by the destruction or altered function of the adrenal gland with a primary deficit in cortisol secretion (primary adrenal insufficiency) or by hypothalamic-pituitary pathologies determining a deficit of ACTH (secondary adrenal insufficiency). The clinical picture is determined by the glucocorticoid deficit, which may in some conditions be accompanied by a deficit of mineralcorticoids and adrenal androgens. The substitutive treatment is aimed at reducing the signs and symptoms of the disease as well as at preventing the development of an addisonian crisis, a clinical emergency characterized by hypovolemic shock. The oral substitutive treatment should attempt at mimicking the normal circadian profile of cortisol secretion, by using the lower possible doses able to guarantee an adequate quality of life to patients. The currently available hydrocortisone or cortisone acetate preparations do not allow an accurate reproduction of the physiological secretion pattern of cortisol. A novel dual-release formulation of hydrocortisone, recently approved by EMEA, represents an advancement in the optimization of the clinical management of patients with adrenal insufficiency. Future clinical trials of immunomodulation or immunoprevention will test the possibility to delay (or prevent) the autoimmune destruction of the adrenal gland in autoimmune Addison's disease.

Patients with adrenal insufficiency (AI) receive first glucocorticoid replacement dose after waking, resulting in a 3-5 h delay compared to physiological secretion. Impaired quality of life (QoL) and fatigue might be due to this delayed dose scheme. Modified-release glucocorticoid preparations might have therapeutic advantages. Exploratory pilot study including 14 patients with AI was conducted in a single university center. Patients on morning dose prednisolone (5 mg) were included, switched to modified-release prednisone (5 mg) at 10 PM for 3 months, and then switched back on standard prednisolone. 3 standardized questionnaires (GBB-24, MFI, and AddiQoL) investigating complaints and fatigue were completed at baseline, after 3, and 6 months. Data regarding clinical and hormonal parameters were assessed. Modified-release prednisone showed significant improvement in one of 4 scales of GBB-24 and positive trends to better scores in 3 of 4 scales. The global score of discomfort improved significantly. The MFI showed also significant improvement in 3 of 5 scales and positive trend to better scores in 2 scales. Significant changes to better scores were seen in 4 out of 30 items of the AddiQoL. Modified-release prednisone showed decreased complaints and fatigue compared to standard prednisolone indicating importance of glucocorticoid increase in early morning hours before waking., (© Georg Thieme Verlag KG Stuttgart · New York.)

Patients on long-term steroid therapy are often given supplementary intravenous glucocorticosteroids during perioperative care. The reason is to minimize the risk of acute adrenal insufficiency, which is a potential life threatening condition. Based on a recent Cochrane review and the available literature on the subject a rational way in dealing with the matter is described.

A 6-year-old girl was admitted to our hospital for excessive weight gain. On presentation, she had a typical Cushingoid appearance and hypertension. Laboratory analysis was indicative for an exogenous glucocorticoid source, showing values that were low for serum cortisol and adrenocorticotropin and for 24-h urinary glucocorticoid (metabolite) excretion. Five and 2 months before presentation, she was treated with intradermal triamcinolone acetonide for keloid scars. Recovery of intrinsic cortisol production occurred 12 months after the last steroid dose. Intradermal triamcinolone acetonide for keloid scars in children should be used with care taking into account the here reported complication.

Adrenal insufficiency is caused by either primary adrenal failure, mostly due to autoimmune adrenalitis, or by hypothalamic-pituitary impairment of the corticotropic axis, predominantly by long-term pharmacodynamic glucocorticoid treatment or by pituitary tumour growth and related treatment. Despite optimized life-saving glucocorticoid and mineralocorticoid replacement therapy, health-related quality of life in adrenal insufficiency is more severely impaired than previously thought and patients with adrenal insufficiency are also threatened by an increased mortality. Optimizing hormone replacement remains one of the most challenging tasks in endocrinology. Monitoring of glucocorticoid replacement quality is hampered by lack of objective assessment tools and therefore largely based on clinical grounds. Thus, long-term management of patients with adrenal insufficiency remains a continuous challenge asking for the experienced specialist. However, diagnosis and management of suspected acute adrenal failure is an important task for all physicians. This review explains the rationale behind the current hormone replacement scheme, points to the deficits and hints at possible future therapies.

Background: Replacing glucocorticoids in primary adrenal insufficiency (AI) or Addison's disease (AD) is today based on oral replacement therapy with hydrocortisone in a conventional immediate-release tablet. It is recognised that physiological gastrointestinal factors may have a strong influence on the plasma concentration-time profile of hydrocortisone. Hydrocortisone has a sufficiently high permeability in both the small and large intestine, but in vivo dissolution from the available oral product is limited at higher doses. The short elimination half-life of hydrocortisone (approximately 1.5 h) when given in traditional immediate-release dosage forms requires two or more dose administrations per day, with high peaks and low trough values in between. The endogenous secretion of cortisol from the adrenal cortex follows a distinct diurnal pattern, with increasing and high plasma levels of cortisol early in the morning (approximately 05.00-08.00 h), intermediate levels in the afternoon, low levels in the evening and a cortisol-free interval at night. There is, therefore, a clinical need for an improved drug delivery product that more closely follows the circadian pattern of cortisol in plasma., Objective: The pharmaceutical and biopharmaceutical properties of the dosage form containing hydrocortisone will determine intestinal absorption rate and the plasma concentration-time profile of hydrocortisone (cortisol). Factors that cause or result in pharmacokinetic variability should be understood and avoided where possible., Methods: A literature search was performed with the aim of covering the field of gastrointestinal drug absorption of hydrocortisone in AD., Results/conclusion: Novel oral drug delivery principles for facilitation of once-daily dosing and providing a safe and physiologically based plasma concentration-time profile of hydrocortisone in replacement therapy are discussed. Development of new drug formulations is ongoing and will certainly lead to an improved replacement therapy of AD with hydrocortisone. Of special interest is a therapy based on once-daily treatment and less fluctuating plasma concentrations of hydrocortisone (cortisol).

The reported incidence of adrenal insufficiency varies greatly depending on the population of critically ill patients studied, the test and cutoff levels used, and the severity of illness. Several studies have shown increased mortality in patients with very low or very high baseline cortisol levels. Manifestations of adrenal insufficiency in the critically ill patient are numerous and nonspecific, so clinicians are urged to have a high index of suspicion and be alert to important diagnostic clues, such as hyponatremia, hyperkalemia, and hypotension, that are refractory to fluids and vasopressors without any clear causation. Multiple tests have been developed to diagnose adrenal insufficiency, but the most commonly used test in the intensive care unit is the adrenocorticotropic hormone (ACTH) stimulation test. The low-dose ACTH stimulation test has been shown to be more sensitive and specific than the high-dose test; however, the high-dose test is preferred since the low-dose test has not been validated. Although diagnosing adrenal insufficiency continues to be difficult in the critically ill patient, administration of high-dose corticosteroids, defined as methylprednisolone 30 mg/kg/day or more (or its equivalent), over a short period of time provides no overall benefit and may even be harmful; however, administration of low-dose corticosteroids for a longer duration decreases both the amount of the time that vasopressors are required and mortality at 28 days. Hydrocortisone 200-300 mg/day, administered in divided doses or as a continuous infusion, is the preferred corticosteroid in patients with septic shock and should be started as early as possible. For patients in whom the ACTH stimulation test cannot be given immediately, clinicians are urged to consider using dexamethasone until such time that the test can be administered, since, unlike hydrocortisone, it does not interfere with the cortisol test.

Objective: To evaluate the concept of relative adrenal insufficiency necessitating corticosteroid therapy in septic shock., Design: Retrospective study., Setting: Medical-surgical intensive care unit of a university hospital., Patients: We studied 218 consecutive patients with septic shock in a 3-yr period who underwent a short 250-microg adrenocorticotropic hormone test because of >6 hrs of hypotension requiring repeated fluid challenges and/or vasopressor/inotropic treatment., Interventions: The test was performed by intravenously injecting 250 mug of synthetic adrenocorticotropic hormone and measuring cortisol immediately before and 30 and 60 mins postinjection., Measurements and Main Results: Intensive care unit mortality until day 28 was 22%. Nonsurvivors had greater disease severity, as exemplified by higher Simplified Acute Physiology Score II and Sequential Organ Failure Assessment score, on the day of adrenocorticotropic hormone testing. Cortisol levels directly correlated with albumin levels. Simplified Acute Physiology Score II and Sequential Organ Failure Assessment score increased with higher strata of baseline cortisol/albumin or lower cortisol increases/albumin ratios as measures of free cortisol. Baseline cortisol, cortisol increases, and albumin levels did not independently contribute to mortality prediction by disease severity and absence of corticosteroid (hydrocortisone) treatment in a Cox proportional hazard model, although adrenocorticotropic hormone-induced cortisol increase <100 nmol/L (n = 53) predicted mortality (p = .007). Posttest treatment by corticosteroids (n = 161, 74%) was associated with higher survival in patients with cortisol increase <100 nmol/L (p = .0296)., Conclusions: In intensive care unit patients with septic shock, the cortisol response to adrenocorticotropic hormone inversely relates to disease severity, independent of blood cortisol binding. An adrenocorticotropic hormone-induced cortisol increase <100 nmol/L predicts mortality and beneficial effects of corticosteroid treatment. The data favor relative adrenal insufficiency.

Background: Glucocorticoids are the main drug used to control vasogenic edema in patients with brain tumor. Rapid GC tapering may not only decompensate intracranial pressure, but also unmask SAI, and some symptoms of SAI can be mistakenly attributable to increased intracranial pressure or side effects of chemotherapy and radiation therapy., Methods: The University of Virginia Neuro-Oncology Database was reviewed from February 2002 to January 2006, and 5 neuro-oncology patients with clinical and laboratory evidence of SAI were identified., Results: In our experience, 1% of neuro-oncology patients treated with GC developed SAI. Symptoms resembled increased intracranial pressure or side effects of antineoplastic treatment., Conclusion: A healthy index of suspicion for this complication and use of pharmacologic testing will help avert misattribution of symptoms of SAI and its deleterious consequences.

Objective: Evaluation of glucocorticoid replacement quality in adrenal insufficiency (AI) relies primarily on clinical judgement and thus largely depends on the physician's expertise. It is a matter of debate whether cortisol day curves are of value in assessing glucocorticoid replacement quality. Here we compared the results of a structured clinical assessment to the outcome of repeated, timed serum cortisol measurements., Design: Cross-sectional study in the outpatient department of a university teaching hospital., Patients: Forty-six patients (19 men, 27 women, age range 16-76 years) with primary (n = 23) and secondary (n = 23) AI on stable replacement with a median dose of 37.5 mg cortisone acetate (range 25-50 mg) since 10 +/- 7 years (range 1-31 years)., Measurements: Clinical performance was scored by structured assessment of signs and symptoms, physical examination and routine biochemical tests. Serum cortisol was measured on two to three separate occasions in three timed samples after the morning glucocorticoid dose. Bone mineral density was measured in 15 patients with long-standing glucocorticoid replacement., Results: Thirty-seven patients were considered well replaced, whereas clinical scores suggested over- or under-replacement in five and four, respectively. There was no correlation of the clinical score with total or body weight-adjusted glucocorticoid dose. The mean z score of serum cortisol differed significantly between under- and over-replaced patients (P < 0.05) but neither group differed significantly from well-replaced patients. Bone mineral density was normal in all patients studied., Conclusions: Our results suggest that serum cortisol day curves are of limited value in the monitoring of glucocorticoid replacement. Bone mineral density in AI is generally normal and does not require routine follow-up.

All endocrinologists would like to make glucocorticoid replacement therapy for their hypoadrenal patients as physiological as possible. Many would like the reassurance of a method of monitoring such treatment to confirm that they are achieving this aim. Advances in our knowledge of the normal physiology are relevant to our attempts to do this. The cortisol production rate in normal subjects is lower than was previously believed. The normal pattern of glucocorticoid secretion includes both a diurnal rhythm and a pulsatile ultradian rhythm. Glucocorticoid access to nuclear receptors is 'gated' by the 11-beta-hydroxysteroid dehydrogenase enzymes, which interconvert active cortisol and inactive cortisone. Such complexities make the target of physiological glucocorticoid replacement therapy hard to achieve. The available evidence suggests that conventional treatment of hypoadrenal patients may result in adverse effects on some surrogate markers of disease risk, such as a lower bone mineral density than age-sex matched controls, and increases in postprandial glucose and insulin concentrations. Although the quality of life of hypoadrenal patients may be impaired, there is no evidence of an improvement on higher doses of steroids, although quality of life is better if the hydrocortisone dose is split up, with the highest dose taken in the morning. Thus the evidence suggests that most patients may safely be treated with a low dose of glucocorticoid (e.g. 15 mg hydrocortisone daily) in two or three divided doses, with education about the appropriate action to take in the event of intercurrent illnesses.

Background: Previous meta-analyses demonstrated that high-dose glucocorticoids were not beneficial in sepsis. Recently, lower-dose glucocorticoids have been studied., Purpose: To compare recent trials of glucocorticoids for sepsis with previous glucocorticoid trials., Data Sources: Systematic MEDLINE search for studies published between 1988 and 2003., Study Selection: Randomized, controlled trials of sepsis that examined the effects of glucocorticoids on survival or vasopressor requirements., Data Extraction: Two investigators independently collected data on patient and study characteristics, treatment interventions, and outcomes., Data Synthesis: The 5 included trials revealed a consistent and beneficial effect of glucocorticoids on survival (I2 = 0%; relative benefit, 1.23, [95% CI, 1.01 to 1.50]; P = 0.036) and shock reversal (I2 = 0%; relative benefit, 1.71 [CI, 1.29 to 2.26]; P < 0.001). These effects were the same regardless of adrenal function. In contrast, 8 trials published before 1989 demonstrated a survival disadvantage with steroid treatment (I2 = 14%; relative benefit, 0.89 [CI, 0.82 to 0.97]; P = 0.008). In comparison with the earlier trials, the more recent trials administered steroids later after patients met enrollment criteria (median, 23 hours vs. <2 hours; P = 0.02), for longer courses (6 days vs. 1 day; P = 0.01), and in lower total dosages (hydrocortisone equivalents, 1209 mg vs. 23 975 mg; P = 0.01) to patients with higher control group mortality rates (mean, 57% vs. 34%; P = 0.06) who were more likely to be vasopressor-dependent (100% vs. 65%; P = 0.03). The relationship between steroid dose and survival was linear, characterized by benefit at low doses and increasing harm at higher doses (P = 0.02)., Limitations: We could not analyze time-related improvements in medical care and potential bias secondary to nonreporting of negative study results., Conclusions: Although short courses of high-dose glucocorticoids decreased survival during sepsis, a 5- to 7-day course of physiologic hydrocortisone doses with subsequent tapering increases survival rate and shock reversal in patients with vasopressor-dependent septic shock.

Objective: To describe the long-term follow-up of acute adrenal insufficiency attributable to bilateral adrenal hemorrhage., Methods: We performed a retrospective review of medical records of four patients who underwent follow-up for 6(1/2) to 19 years., Results: Despite published reports of more than 500 patients with bilateral massive adrenal hemorrhage through 2001, no long-term data assessing the continuing requirements for glucocorticoid and mineralocorticoid replacement are available. After follow-up of four patients with acute bilateral adrenal hemorrhage and glucocorticoid insufficiency for 6(1/2) to 19 years, we document the absence of need for long-term mineralocorticoid replacement on the basis of no occurrence of postural hypotension, normal electrolytes, normal baseline or cosyntropin-stimulated serum aldosterone levels, and generally, though not invariably, normal plasma renin activity levels. We further document the improvement in either or both baseline and cosyntropin-stimulated serum cortisol levels in three of the four patients and the ability of one patient to function normally without cortisol replacement for 4 years. Adrenal histologic findings in this last-mentioned patient revealed previously undescribed changes consistent with regeneration and myelolipoma. Finally, we confirm bilateral atrophic adrenal glands by computed tomography 5(1/2) to 11(1/2) years after bilateral adrenal hemorrhage in three of the four patients., Conclusion: Long-term follow-up of patients with acute adrenal insufficiency attributable to adrenal hemorrhage demonstrates, for the first time, absence of need for prolonged mineralocorticoid replacement and some improvement in endogenous glucocorticoid function in at least some of these patients.

Objective: To characterize naturally developing glucocorticoid deficiency in dogs., Design: Retrospective case series., Animals: 18 dogs with glucocorticoid deficiency defined by an inadequate response to stimulation with adrenocorticotropic hormone (ACTH), a normal Na:K ratio (> 27), and no history of receiving corticosteroids for at least 6 weeks., Procedure: Information including signalment, body weight, clinical signs on admission, historical findings, physical examination findings, results of CBC and serum biochemical analyses, results of ACTH stimulation tests and other ancillary endocrine tests, diagnostic imaging findings, findings from other procedures such as endoscopy and surgery, and information on concurrent diseases, management, and outcome were retrieved from the medical records of dogs with glucocorticoid deficiency treated between 1986 and 1995 at the University of Pennsylvania's School of Veterinary Medicine and 2 dogs from private practices., Results: Most dogs were young (< 7 years) and represented larger breeds (> 20 kg). Clinical signs were nonspecific: lethargy, weight loss, and gastrointestinal disturbances including regurgitation with radiographic evidence of megaesophagus. Hypocholesterolemia, hypoalbuminemia, hypoglycemia, and a mild, nonregenerative anemia were common. Ten of the 18 dogs responded well to glucocorticoid supplementation alone, with only 2 dogs developing electrolyte abnormalities. Four (22%) of the dogs died, with death usually occurring as a result of secondary disease processes rather than hypoadrenocorticism., Clinical Implications: An ACTH stimulation test should be considered as part of the diagnostic plan in dogs with signs of weight loss, inappetence, and intermittent vomiting and diarrhea. Glucocorticoid-deficient dogs may not require supplemental mineralocorticoids.

The cytokines tumor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1), and IL-6 are secreted at inflammatory sites in tandem and play a crucial role in the inflammatory and wound-healing processes. All three cytokines are potent activators of the hypothalamic-pituitary-adrenal axis, through which they restrain inflammation, whereas IL-6 itself plays a role in the termination of inflammation as well. To test the hypothesis that endogenous glucocorticoids exert a negative tonic effect on the secretion of these cytokines, we studied 17 patients with Cushing's disease and 2 patients with primary adrenal Cushing's syndrome before and after surgery. Plasma TNF alpha, IL-1 beta and IL-6 were measured before surgery, while the patients were hypercortisolemic; on postoperative day 4 or 5, when they were hypocortisolemic; and on postoperative day 9 or 10, when they were receiving glucocorticoid replacement. During severe hypocortisolism, on postoperative day 4 or 5, plasma IL-6 levels rose significantly, compared to the preoperative values (P < 0.001). During the same interval, TNF alpha and IL-1 beta also rose, albeit to a lesser extent. Over the same interval, patients with severe hypocortisolism experienced temperature elevation, fatigue, somnolence, flu-like symptoms, and anorexia, symptoms that have been traditionally attributed to glucocorticoid deficiency; these were also experienced by subjects that received recombinant human IL-6. There was no postoperative increase in any of the cytokines studied in the patients who were not hypocortisolemic after surgery and who also lacked the corresponding symptomatology. Plasma IL-6 concentrations decreased significantly, albeit not to normal levels, in the hypocortisolemic group of patients on postoperative day 9 or 10, when they were receiving glucocorticoid replacement. We conclude that the peripheral levels of IL-6 and to a lesser extent, those of TNF alpha and IL-1 beta are tonically inhibited by basal levels of glucocorticoids. The increased IL-6 production that occurs when cortisol levels fall might explain the symptomatology of acute glucocorticoid deficiency.

Objective: Patients with adrenal crisis are at risk of severe hypotension not responding to administration of catecholamines. As glucocorticoids may be a prerequisite for intact beta-adrenoceptor function, impaired adrenoceptor activity may explain the hypotension and reduced cardiac performance in adrenal insufficiency. The aim of our study was, therefore, to further elucidate the permissive action of glucocorticoids on adrenergic function and cardiac performance., Design: Prospective randomized controlled study., Patients: Nine patients with adrenal insufficiency were investigated before and 48 hours after glucocorticoid withdrawal. Mineralocorticoid therapy remained unchanged during the study period., Measurements: Lymphocyte beta 2-adrenoceptor density, intracellular c-AMP response to isoprenaline, platelet alpha 2-receptor density, plasma catecholamines, serum cortisol, plasma ACTH, echocardiography., Results: Glucocorticoid depletion was demonstrated by a fall in serum cortisol from mean +/- SEM 441 +/- 62 to 45 +/- 18 nmol/l. Glucocorticoid withdrawal decreased lymphocyte beta 2-receptor density from 798 +/- 111 to 498 +/- 54 binding sites/cell (P < 0.05) and the intracellular c-AMP response to isoprenaline from 15.0 +/- 4.2 to 8.2 +/- 1.7 pmol/10(6) cells (P < 0.05). Echocardiography showed impaired diastolic relaxation after glucocorticoid withdrawal with prolongation of the rapid filling period (80.3 +/- 12.5 vs 138.3 +/- 11.8 ms, P < 0.05). Plasma catecholamines, platelet alpha 2-receptor density and systolic left ventricular function were not affected by glucocorticoid deficiency., Conclusions: This study demonstrates the importance of normal glucocorticoid levels for beta 2-adrenoceptor function and helps to explain the decreased responsiveness to catecholamines and the impaired cardiac performance in adrenal crisis.

The therapeutic benefit of glucocorticoids appears to derive chiefly from their suppression of immunologic and inflammatory responses, but beyond these generalized phenomena, there are a number of tissue-specific effects. Increasing knowledge of these actions is shedding light on such issues as steroid resistance and steroid-induced adrenocortical insufficiency.

We investigated effects of corticotropin-releasing hormone (CRH), lysine vasopressin and interleukin (IL)-1 beta[1-148], a less pyrogenic analog of human IL-1 beta, on the hypothalamo-pituitary-adrenal axis in a rat model of secondary adrenocortical insufficiency. After 2 weeks of corticosterone 21-sodium succinate treatment, hypothalamic CRH, anterior pituitary adrenocorticotropic hormone (ACTH) and the adrenal weight of the rats decreased significantly and their plasma ACTH showed a significantly smaller response to ether stress, as did plasma corticosterone level. A mixed solution of CRH (10 micrograms) and lysine vasopressin (2 micrograms) or recombinant human IL-1 beta[1-148] (1 micrograms), administered to these rats for 7 days, apparently accelerated the recovery of the pituitary and adrenocortical responsiveness to ether stress and significantly increased the recovery rate of anterior pituitary ACTH contents and adrenal weight. The IL-1 beta analog also increased hypothalamic CRH. These data indicated that, in a rat model with glucocorticoid-induced adrenocortical insufficiency, synthesis and release of hypothalamic CRH, pituitary ACTH and adrenal glucocorticoid were all considerably affected. CRH combined with lysine vasopressin or a less pyrogenic IL-1 beta analog, when administered to these rats, accelerated the recovery of the pituitary and the adrenocortical functions significantly, suggesting the potential clinical usefulness of these peptides.

In male rats with a high and low blood levels of corticosterone, the activity of serotonin-, dopamine-, noradrenaline-, glycine, GABA-, and cholinergic processes was shown to depend on the glycocorticoid content in the organism and receptor binding of 3H-corticosterone in different brain structures. The formation of adequate processes of neurotransmitter adaptation to a short-term vibration is only possible at a fairly high level of glycocorticoids in the organism.