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Background: Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI because of the nonphysiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of a once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may alter corticosteroid metabolism in vivo., Study Design and Methods: Prospective crossover study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling), cortisol activation in the liver (cortisone acetate challenge test), and subcutaneous adipose tissue (microdialysis, biopsy for gene expression analysis) in 51 patients with AI (primary and secondary) in comparison to IR-HC treatment and age- and BMI-matched controls., Results: Patients with AI receiving IR-HC had a higher median 24-hour urinary excretion of cortisol compared with healthy controls (72.1 µg/24 hours [IQR 43.6-124.2] vs 51.9 µg/24 hours [35.5-72.3], P = .02), with lower global activity of 11β-HSD2 and higher 5-alpha reductase activity. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary cortisol and total GC metabolite excretion, which was most significant in the evening. There was an increase in 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered after switching to DR-HC, but there was a significant reduction in the expression and activity of 11β-HSD1 in subcutaneous adipose tissue., Conclusion: Using comprehensive in vivo techniques, we have demonstrated abnormalities in corticosteroid metabolism in patients with primary and secondary AI receiving IR-HC. This dysregulation of pre-receptor glucocorticoid metabolism results in enhanced glucocorticoid activation in adipose tissue, which was ameliorated by treatment with DR-HC., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Adrenal haemorrhage (AH) is an uncommon, usually incidental imaging finding in acutely unwell patients. AH has been reported during coronavirus disease 2019 (COVID-19) infection and following ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccination. The Society for Endocrinology (SfE) established a task force to describe the UK experience of COVID-19-related AH., Design: A systematic literature review was undertaken. A survey was conducted through the SfE clinical membership to identify patients with COVID-19-related AH using a standardized data collection tool., Results: The literature search yielded 25 cases of COVID-19-related AH (19 bilateral; 13 infection-related, and 12 vaccine-related). Eight UK centres responded to the survey with at least one case. A total of 18 cases were included in the descriptive study, including 11 from the survey and 7 UK-based patients from the systematic review. Seven patients (4 males; median age 53 (range 26-70) years), had infection-related AH (four bilateral). Median time from positive COVID-19 test to AH detection was 8 (range 1-30) days. Eleven cases of vaccine-related AH (eight bilateral) were captured (3 males; median age 47 (range 23-78) years). Median time between vaccination (nine Oxford-AstraZeneca and two Pfizer-BioNTech) and AH was 9 (range 2-27) days; 9/11 AH occurred after the first vaccine dose. Acute abdominal pain was the commonest presentation (72%) in AH of any cause. All 12 patients with bilateral AH and one patient with unilateral AH required glucocorticoid replacement., Conclusion: Adrenal haemorrhage with consequential adrenal insufficiency can be a complication of COVID-19 infection and vaccination. Adrenal function assessment is mandatory to avoid the potentially fatal consequences of unrecognized adrenal insufficiency., (© 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Objective: Patients with rheumatic diseases are often treated with prolonged, high-dose systemic glucocorticoids which can cause hypothalamic-pituitary-adrenal (HPA) axis suppression and development of tertiary adrenal insufficiency. Adrenal insufficiency carries the risk of serious, potentially life-threatening adrenal crisis. Our study evaluated the prevalence, characteristics and recovery of patients with underlying rheumatology conditions who had received prolonged glucocorticoid treatment., Design and Patients: Retrospective, cross-sectional study. We evaluated 238 patients seen in outpatient rheumatology clinic, managed in accordance with current nationally and internationally accepted clinical guidelines., Measurements: Data collected included patient demographics, historical steroid data, 09.00 h cortisol/short synacthen test (SST) results and follow-up data on those with repeat assessments., Results: Overall, 65% of our cohort had a 09.00 h cortisol <350 nmol/L. On SST, 43% of patients demonstrated evidence of possible tertiary adrenal insufficiency. Prednisolone equivalent dose at time of SST was significantly higher in the group who failed SST vs. those who passed; mean of 5.57 mg vs. 3.59mg (p = .005). 09.00 h cortisol result correlated with 30-min cortisol on SST (R 2  = .20, p = .002). 0-min cortisol on SST correlated more strongly with 30-min cortisol than 09.00 h cortisol (R 2  = .59, p-value < .001). Patients with 0-min cortisol >350 nmol/L, all passed their SST. Patients who remained on prednisolone were more likely to recover (71%) vs. those switched to hydrocortisone (27%), P = .02. Peak steroid dose was predictive of recovery; significantly lower in those who recovered (mean of 22.3 mg vs. 33.8 mg, P = .03). Steroid duration was not found to be a predictor of recovery [recovery (64.2 months) vs. non-recovery (55.6 months), P = .58]. There was no correlation found to outcome on SST with age, sex, peak steroid dose, steroid duration, underlying rheumatological condition, additional exogenous steroid use or serum sodium., Conclusions: Forty three percent of our patients demonstrated sub-optimal adrenal function on SST. Steroid dose at the time of SST was the only significant predictive risk factor for tertiary adrenal insufficiency. 09.00 h cortisol demonstrated good correlation with outcome on SST and could represent a valid screening test to reduce need for SST if 09.00 h >350 nmol/L. Further prospective data are required to further characterize risk factors, predictive features of recovery and establish optimal management strategy of steroids (prednisolone vs hydrocortisone) to encourage adrenal recovery., (© 2021 John Wiley & Sons Ltd.)

Background: Glucocorticoid therapy is the most common cause of iatrogenic osteoporosis. Less is known regarding the effect of glucocorticoids when used as replacement therapy on bone remodelling in patients with adrenal insufficiency. Enhanced intracellular conversion of inactive cortisone to active cortisol, by 11 beta-hydroxysteroid dehydrogenase type 1(11β-HSD1) and other enzymes leading to alterations in glucocorticoid metabolism, may contribute to a deleterious effect on bone health in this patient group., Methods: Study design: An open crossover prospective study randomizing ten hypopituitary men, with severe ACTH deficiency, to three commonly used hydrocortisone dose regimens., Measurements: Following 6 weeks of each regimen, patients underwent 24-h serum cortisol/cortisone sampling, measurement of bone turnover markers, and a 24-h urine collection for measurement of urinary steroid metabolites by gas chromatography-mass spectrometry (GC-MS). Serum cortisone and cortisol were analysed by liquid chromatography-mass spectrometry (LC-MS)., Results: Dose-related and circadian variations in serum cortisone were seen to parallel those for cortisol, indicating conversion of ingested hydrocortisone to cortisone. The median area under the curve (AUC) of serum cortisone was significantly higher in patients on dose A (20 mg/10 mg) [670.5 (IQR 621-809.2)] compared to those on dose C (10 mg/5 mg) [562.8 (IQR 520.1-619.6), p = 0.01]. A negative correlation was observed between serum cortisone and bone formation markers, OC [1-49] (r = - 0.42, p = 0.03), and PINP (r = - 0.49, p = 0.01). There was a negative correlation between the AUC of night-time serum cortisone levels with the bone formation marker, OC [1-49] (r = - 0.41, p = 0.03) but there were no significant correlations between day-time serum cortisone or cortisol with bone turnover markers. There was a negative correlation between total urinary cortisol metabolites and the bone formation markers, PINP (r = - 0.39, p = 0.04), and OC [1-49] (r = - 0.35, p = 0.06)., Conclusion: Serum cortisol and cortisone and total urinary corticosteroid metabolites are negatively associated with bone turnover markers in patients receiving replacement doses of hydrocortisone, with nocturnal glucocorticoid exposure having a potentially greater influence on bone turnover., Trial Registration: Irish Medicines Board Clinical Trial Number - CT900/459/1 and EudraCT Number - 2007-005018-37 . Registration date: 07-09-2007.

Glucocorticoids (GCs) are steroid hormones, which are essential for life. They are secreted by the adrenal cortex under the control of the hypothalamic-pituitary-adrenal (HPA) axis. Glucocorticoids are essential for the normal function of most organ systems and, in both, excess and deficiency can lead to significant adverse consequences. Adrenal insufficiency (AI) is a rare, life-threatening disorder characterized by insufficient production of corticosteroid hormones. Primary AI is defined by the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids despite normal or increased adrenocorticotropin hormone (ACTH). Secondary AI is adrenal hypofunction due to insufficient amount of ACTH produced by the pituitary gland. Conventional treatment of both primary and secondary adrenal insufficiencies involves lifelong glucocorticoid replacement therapy. The role of cortisol deficiency and the impact of hydrocortisone replacement on morbidity and mortality in this patient group are under increasing scrutiny. Established glucocorticoid replacement regimens do not completely mirror endogenous hormonal production, and their monitoring to ensure optimum therapy is hampered by the lack of reliable biomarkers of hormone sufficiency. A further confounding issue is the tissue-specific regulation of glucocorticoid through the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) with research focusing on the role of this prereceptor regulation in the development of adverse metabolic features in patients. This review defines the factors influencing glucocorticoid action in patients with adrenal insufficiency receiving glucocorticoid therapy., (© 2018 John Wiley & Sons Ltd.)

Context: Patients with adrenal insufficiency (AI) (primary AI [PAI], secondary AI due to a pituitary disorder [PIT] and congenital adrenal hyperplasia [CAH]) have reduced life expectancy; however, the underlying explanation remains unknown., Objective: To evaluate characteristics, comorbidities, and hospitalizations in AI patients., Design: Retrospective observational., Setting and Population: Using a United States-based national payer database comprising of more than 108 million members, strict inclusion criteria including diagnostic codes and steroid prescription records were used to identify 10 383 adults with AI; 1014 with PAI, 8818 with PIT, and 551 with CAH. Patients were matched 1:1 to controls, based on age (±5 y), gender, insurance, and region and followed for more than 12 months., Intervention: None., Main Outcome Measures: Demographic variables, comorbidities (diabetes mellitus [DM] types 1 and 2, depression, anxiety, hyperlipidemia, hypertension) and hospitalization incidence., Results: Compared with controls, patients with AI had higher odds of DM, hypertension, hyperlipidaemia, depression, and anxiety, ranging from an odds ratio (OR) of 1.51 for hyperlipidaemia in PAI to 3.85 for DM in CAH. Odds of having DM (OR, 3.85; 95% confidence interval, 2.52-5.90) or anxiety (OR, 2.99; 95% confidence interval, 2.02-4.42) compared with controls were highest in CAH, whereas depression was highest in PAI and PIT (OR, 2.40 and 2.55). ORs of hyperlipidaemia and hypertension (OR, 1.98 and 2.24) were highest in the PIT cohort. Inpatient admissions were more frequent in PAI (4.64:1; P < .0001) and PIT (4.00:1; P < .0001) than controls; infection was the most common cause for admission., Conclusion: Patients with AI carry a significant metabolic and psychiatric burden, with higher risk of comorbidities and hospital admissions than matched controls.

Context: Up to 3% of US and UK populations are prescribed glucocorticoids (GC). Suppression of the hypothalamo-pituitary-adrenal axis with the potential risk of adrenal crisis is a recognized complication of therapy. The 250 μg short Synacthen stimulation test (SST) is the most commonly used dynamic assessment to diagnose adrenal insufficiency. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost., Methods: We performed a retrospective analysis to determine the prevalence of adrenal suppression due to prescribed GCs and the utility of a morning serum cortisol for rapid assessment of adrenal reserve in the routine clinical setting., Results: In total, 2773 patients underwent 3603 SSTs in a large secondary/tertiary centre between 2008 and 2013 and 17.9% (n=496) failed the SST. Of 404 patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, 33.2% (n=134) had a subnormal SST response. In patients taking inhaled GCs without additional GC therapy, 20.5% (34/166) failed an SST and suppression of adrenal function increased in a dose-dependent fashion. Using receiver operating characteristic curve analysis in patients currently taking inhaled GCs, a basal cortisol ≥348 nmol/l provided 100% specificity for passing the SST; a cortisol value <34 nmol/l had 100% sensitivity for SST failure. Using these cut-offs, 50% (n=83) of SSTs performed on patients prescribed inhaled GCs were unnecessary., Conclusion: Adrenal suppression due to GC treatment, particularly inhaled GCs, is common. A basal serum cortisol concentration has utility in helping determine which patients should undergo dynamic assessment of adrenal function., (© 2015 The authors.)

Glucocorticoid replacement therapy in patients with adrenal insufficiency (AI), whether primary (Addison's disease) or secondary (due to hypopituitarism), has been established for some 50 years. The current standard treatment regimen involves twice- or thrice-daily dosing with a glucocorticoid, most commonly oral hydrocortisone. Based on previous small-scale studies and clinical perception, life expectancy with conventional glucocorticoid replacement therapy has been considered normal, with a low incidence of adverse events. Data from the past 10-15 years, however, have shown that morbidity remains high and life expectancy is reduced. The increased morbidity and decreased life expectancy appear to be due to both increased exposure to cortisol and insufficient cortisol coverage during infections and other stress-related events. This is thought to reflect a failure of treatment to replicate the natural circadian rhythm of cortisol release, together with a failure to identify and deliver individualized cortisol exposure and to manage patients adequately when increased doses are required. The resulting over- or under-treatment may result in Cushing-like symptoms or adrenal crisis, respectively. This review summarizes the morbidity and mortality seen in patients receiving the current standard of care for AI and suggests areas for improvement in glucocorticoid replacement therapy., (© 2014 John Wiley & Sons Ltd.)

Introduction: Adrenal insufficiency is a rare but life-threatening disease. Conventional therapy consists of glucocorticoid replacement using hydrocortisone administered two or three times daily. Although such therapy extends life expectancy, mortality is not normalized, and quality of life remains poor. This failure to restore normal health is thought to be due to the inability of conventional glucocorticoid replacement therapy to normalize total cortisol exposure and to respond to the increased need for glucocorticoids during illness and stress. Also, current management regimens do not restore or replicate the intrinsic circadian rhythm of cortisol secretion., Areas Covered: This narrative review was based on a PubMed and Medline search of all English-language articles on the safety and efficacy of glucocorticoid replacement therapy in patients with adrenal insufficiency. Based on this search we discuss current treatment strategies in terms of the failure to maintain or normalize metabolism and quality of life in patients with adrenal insufficiency. The rationale for, and technology behind, the development of modified-release preparations of hydrocortisone are described, together with the evidence suggesting that hydrocortisone preparations that mimic the physiological circadian pattern of cortisol release are more effective than conventional glucocorticoid replacement therapies., Conclusions: Modified-release hydrocortisone treatments for patients with adrenal insufficiency more closely mimic the physiological circadian pattern of cortisol secretion than conventional twice or thrice daily treatment. The available evidence suggests that these modified-release preparations should improve metabolic outcomes and quality of life.

One of the more controversial areas in critical care in recent decades relates to the issue of adrenal insufficiency and its treatment in critically ill patients. There is no consensus on which patients to test for adrenal insufficiency, which tests to use and how to interpret them, whether to use corticosteroids, and, if so, who to treat and with what dose. This review illustrates the complexity and diversity of pathophysiological changes in glucocorticoid secretion, metabolism, and action and how these are affected by various types of illness. It will review adrenal function testing and give guidance on corticosteroid replacement regimens based on current published literature. There remain inherent difficulties in interpreting the effects of glucocorticoid replacement during critical illness because of the diversity of effects of glucocorticoids on various tissues. Investigation and treatment will depend on whether the likely cause of corticosteroid insufficiency is adrenal or central in origin.

Objective Mitotane induces hepatic CYP3A4 activity, resulting in accelerated cortisol inactivation, and also increases cortisol binding globulin ( CBG). Therefore, higher hydrocortisone doses are required in patients with adrenocortical cancer ( ACC) on mitotane treatment. Modified release hydrocortisone has not been used in mitotane-treated ACC patients yet. Aim Case series to compare serum cortisol, calculated free serum cortisol and ACTH levels in ACC patients on mitotane treatment with immediate and modified release hydrocortisone. Design Pharmacokinetics of immediate and modified release hydrocortisone, each administered at a dose of 40-20-0 mg, in nine patients with ACC and adjuvant mitotane treatment. For comparison, ten patients with secondary adrenal insufficiency ( SAI) on three different hydrocortisone regimens and ten healthy males were included. Methods Serum cortisol and plasma ACTH were measured by chemiluminescent enzyme immunoassay, and CBG by RIA, followed by calculation of free cortisol. Results Calculated free serum cortisol levels after 40 mg immediate release hydrocortisone in ACC patients (46 ± 14 nmol/l) were similar to those after 10 mg immediate release hydrocortisone intake in men with SAI (64 ± 16 nmol/l) or to the physiological morning free cortisol levels in healthy subjects (31 ± 5 nmol/l). Compared to immediate release hydrocortisone, free cortisol levels after 40 mg modified release hydrocortisone in ACC patients were significantly lower (12 ± 3 nmol/l; P = 0·03) resulting in a generally lower AUC (98 ± 21 vs 149 ± 37 nmol h/l; P = 0·02). Conclusions 40-20-0 mg immediate release, but not modified release hydrocortisone, resulted in sufficient glucocorticoid coverage in patients with ACC receiving mitotane treatment. The use of equivalent doses of modified release hydrocortisone preparation should be avoided in patients on mitotane treatment. [ABSTRACT FROM AUTHOR]