Novel agents to treat adrenal insufficiency: findings of preclinical and early clinical trials.

INTRODUCTION: Adrenal insufficiency currently affects over 300/million population, with higher morbidity and mortality compared to the general population. Current glucocorticoid replacement therapy is limited by a lack of reliable biomarkers to guide dosing, inter-patient variation in metabolism and narrow therapeutic window. Increased morbidity and mortality may relate to unappreciated under- or over-exposure to glucocorticoids and impaired cortisol circadian rhythm. New agents are required to emulate physiological cortisol secretion and individualize glucocorticoid dosing. AREAS COVERED: History of glucocorticoid therapy, current limitations, and novel chronotherapeutic glucocorticoid delivery mechanisms. Literature search incorporated searches of PubMed and Embase utilizing terms such as adrenal insufficiency, Chronocort, Plenadren, continuous subcutaneous hydrocortisone infusion (CHSI), and glucocorticoid receptor modulator. EXPERT OPINION: Glucocorticoid chronotherapy is necessary to optimize glucocorticoid exposure and minimize complications. Current oral chronotherapeutics provide improved dosing functionality, but are modifiable only in specific increments and cannot accommodate ultradian cortisol variation. Current data show improvement in quality of life but not morbidity or mortality outcomes. CHSI has significant potential for individualized glucocorticoid dosing, but would require a suitable biomarker of glucocorticoid adequacy to be implementable. Avenues for future research include determining a glucocorticoid sufficiency biomarker, development of interstitial or systemic cortisol monitoring, or development of glucocorticoid receptor modulators.

Tuberculosis of Adrenal Glands-A Population-based Case-control Study.

Purpose: Adrenal tuberculosis (ATB) can cause primary adrenal insufficiency (PAI) or may be misdiagnosed as nonfunctional adrenal tumors (NFATs) in patients with tuberculosis. Very little is known about its epidemiology in a modern, high-income setting. The aim was to investigate adrenal involvement and associated mortality in patients with tuberculosis. Methods: By using national registers, patients with tuberculosis and adrenal lesions were compared with controls without adrenal tumors. To analyze mortality in individuals with ATB or possible adrenal affection (ie, tuberculosis and NFAT), a subgroup of controls with tuberculosis was selected. The study population was included from 2005 to 2019 and followed until death or 2020. In mortality adjustments were made for age and sex. Results: Eight patients with ATB, 23 232 patients with NFAT, and 144 124 controls were included. Among those with NFAT, we found 34 with tuberculosis and NFAT. Among controls, 129 individuals diagnosed with tuberculosis were identified. The risk of having an adrenal tumor was increased in tuberculosis (odds ratio, 1.64; 95% CI, 1.12-2.39). Of those with ATB, 7 (88%) had PAI. One patient (3%) with tuberculosis and NFAT and 1 (0.8%) control with tuberculosis had PAI. Compared with controls with tuberculosis, mortality was increased in patients with ATB (hazard ratio, 5.4; 95% CI, 2.2-13.2; adjusted hazard ratio, 6.2; 95% CI, 2.5-15.6), and in patients with tuberculosis and NFAT (1.3; 0.6-2.7; 2.3; 1.1-5.1). PAI was a contributing factor in 4/6 (67%) deaths in patients with ATB. Conclusions: Tuberculosis with adrenal lesions was extremely rare. Most patients with ATB had PAI and mortality was increased.

The Changing Epidemiology of Adrenal Insufficiency: Iatrogenic Factors Predominate.

Context: Adrenal insufficiency (AI)-related morbidity persists despite efforts to minimize its effect. Reasons for this are unknown and warrant examination. Objective: This work aimed to investigate trends in AI hospitalizations and glucocorticoid (GC) replacement therapy use. Methods: Data on hospitalizations for a principal diagnosis of AI and prescriptions for short-acting GCs between 2000 and 2019 were extracted from national repositories. Age-standardized admission and prescription rates were calculated using census data. Rates were compared over time overall and according to age, sex, and disease subtype. Results: AI admissions increased by 62.0%, from 36.78/million to 59.59/million (trend P < .0001). Adrenal crisis (AC) admissions also increased, by 90.1% (from 10.73/million to 20.40/million; trend, P < .00001). These increases were more pronounced in the second decade. Prescriptions for short-acting GCs also increased (by 67.2%, from 2198.36/million in 2000/2001 to 3676.00/million in 2017/2018). Females had higher average admission rates and a greater increase in admission rates than males. Increased AI admissions were found in all age groups among females but only in men aged 70+ yrs. Secondary AI (SAI) admission rates increased by 91.7%, whereas admission rates for primary AI (PAI) remained unchanged. Conclusion: The prevalence of AI and hospitalizations for this disorder (including ACs) have increased since 2000, with a greater increase occurring after 2010. Admission rates for SAI increased but PAI admissions remained stable. Possible causes include immunotherapies for malignancy, increased cranial imaging detecting pituitary tumors and their subsequent treatment, and increased use of low-dose, short-acting GC-replacement therapy.

Trends in hospital admissions for adrenal insufficiency in adolescents and young adults in the 21st century.

Background: Very little is known about the epidemiology of adrenal crises (AC) and adrenal insufficiency (AI) in adolescents and young adults. Methods: Data on all admissions to Australian hospitals between 2000/1 to 2019/20 for a principal diagnosis of AI (including AC) in 10-24 year olds were extracted from a national repository. Age and sex-specific rates and age-adjusted rates were compared. Findings: Over the study, there were 3386 admissions for a principal diagnosis of AI; 24.0% (n=812) were for an AC and 50·7% (n=1718) were for secondary AI. Age-adjusted AI admissions increased from 31·70/million in 2000/1 to 54·68/million in 2019/20 (p<0·0001). Age-adjusted AC admissions also increased, most notably in the second decade (from 5·80/million in 2010/11 to 15·75/million in 2019/20) (p<0·00001). Average AI and AC admission rates were comparable between the sexes, but rates increased significantly in females, especially in those aged 20 to 24 years, whose AC rate in 2019/20 (39·65/million) was significantly higher than the corresponding rate in 2000/1 (3·15/million) (p<0·00001). Average age-adjusted SAI admission rates were higher in males (23·92/million) than females (15·47/million) (p<0·00001). However, SAI admission rates increased only among females (from 11·81/million to 22·12/million in 2019/20), with an increase in 20-24 year old females in the second decade from 5·07/million in 2010 to 20·42/million (p<0·00001). Age adjusted admissions for congenital adrenal hyperplasia, primary AI (PAI) and drug-induced AI did not change significantly over the study. Interpretation: AC/AI admissions increased over the first two decades of this century in the emerging adult population, particularly among females who also experienced a marked increase in AC admission rates, most evident in the second decade. Although uncertain, possible explanations include: dose of glucocorticoid replacement; non-adherence to therapy; psychosocial factors; and difficulty in transition to adult services. Admissions for SAI also increased, while rates of PAI and CAH remained constant.

The effect of cognitive behavioral stress management on perceived stress, biological stress markers and weight loss/regain, from a diet-induced weight loss program: A randomized controlled trial.

Obesity and psychosocial stress are inter-related chronic conditions which lead to increased cardiovascular morbidity and mortality. The aim of this parallel randomized controlled trial was to determine whether the addition of a structured cognitive behavioral stress management (CBSM) on to a commercial online weight loss program, resulted in greater weight loss than the standard weight loss program in isolation. Eligible participants were adults between the ages 18-65, BMI 30-45 kg/m2, with no major systemic or psychiatric conditions. Seventy-four participants were assigned according to simple randomization using computer generated random numbers to either a 3-month online Weight Watchers® program (n = 36), or Weight Watchers® plus 10 weekly sessions of CBSM (n = 38). The primary outcome was weight at 3 months compared to baseline. Secondary outcomes were weight at 12 months and subjective/objective stress system measures and metabolic markers at 3 and 12 months. The study was powered at 90% to detect a 5 kg difference in weight between the two groups at 3 months. Independent sample t-tests were used to analyze the difference in weight (in kg) between the groups and paired sample t-tests were used to analyze the difference within group at different time intervals. At follow-up, there was no significant difference in weight loss between the groups (1.8 kg, 2.1 kg). However, CBSM was effective in reducing psychological measures of stress (p < 0.05) and salivary cortisol (waking, 20-min post-waking) at 3-months; with the effect on stress persisting at 12-months within the CBSM group. The reduction in PSS at 3 months was significantly greater in the CBSM group (3.84, p = 0.028) compared to WW only group at 3 months. Addition of CBSM to a standard weight loss intervention did not improve the weight loss over the standard approach on its own, but the CBSM intervention improved psychological stress parameters and cortisol secretion in participants living with obesity.

Adrenal crises in adolescents and young adults.

PURPOSE: Review the literature concerning adrenal insufficiency (AI) and adrenal crisis (AC) in adolescents and young adults. METHODS: Searches of PubMed identifying relevant reports up to March 2022. RESULTS: AI is rare disorder that requires lifelong glucocorticoid replacement therapy and is associated with substantial morbidity and occasional mortality among adolescents and young adults. Aetiologies in this age group are more commonly congenital, with acquired causes, resulting from tumours in the hypothalamic-pituitary area and autoimmune adrenalitis among others, increasing with age. All patients with AI are at risk of AC, which have an estimated incidence of 6 to 8 ACs/100 patient years. Prevention of ACs includes use of educational interventions to achieve competency in dose escalation and parenteral glucocorticoid administration during times of physiological stress, such as an intercurrent infection. While the incidence of AI/AC in young children and adults has been documented, there are few studies focussed on the AC occurrence in adolescents and young adults with AI. This is despite the range of developmental, psychosocial, and structural changes that can interfere with chronic disease management during this important period of growth and development. CONCLUSION: In this review, we examine the current state of knowledge of AC epidemiology in emerging adults; examine the causes of ACs in this age group; and suggest areas for further investigation that are aimed at reducing the incidence and health impact of ACs in these patients.

Corticosteroid-Binding Globulin Deficiency Independently Predicts Mortality in Septic Shock.

CONTEXT: Hydrocortisone administration in septic shock remains controversial. Corticosteroid-binding globulin (CBG) transports cortisol to inflammatory sites and is depleted in septic shock. OBJECTIVE: To determine whether severely deficient serum CBG < 200 nmol/L (reference range 269-641 nmol/L) independently predicts septic shock mortality. METHODS: A prospective observational study in patients with septic shock. Patients were categorized into 2 groups: mean plasma CBG concentrations <200 nmol/L and ≥200 nmol/L (day 1/2), with additional categorization by nadir CBG. Primary outcome was intensive care unit (ICU) mortality. Secondary outcomes were 28- and 90-day mortality, norepinephrine requirements, renal replacement therapy, and clinician-instituted hydrocortisone. RESULTS: 135 patients were included. Mortality rates in ICU were higher in the CBG < 200 nmol/L vs the CBG ≥ 200 nmol/L group: 32.4% vs 13.9% [odds ratio (OR) 2.97 (95% CI 1.19, 7.41); P = 0.02] with 28-day mortality OR 2.25 (95% CI 0.99, 5.11) and 90-day mortality OR 2.21 (95% CI 0.99, 4.91). Multivariate analysis revealed 4 factors independently associated with ICU mortality: CBG < 200 nmol/L (adjusted OR 3.23, 95% CI 1.06, 9.88), Acute Physiology and Chronic Health Evaluation II > 25 (adjusted OR 3.58, 95% CI 1.20, 10.68), Sequential Organ Failure Assessment (SOFA) liver score (adjusted OR 1.98, 95% CI 1.04, 3.72), and renal replacement therapy (adjusted OR 6.59, 95% CI 2.17, 20.01). Nadir CBG levels were associated with higher SOFA cardiovascular scores and norepinephrine total dose (µg; P < 0.01) and duration (days; P < 0.01). Plasma cortisol concentrations and hydrocortisone administration did not relate to ICU mortality. CONCLUSION: Septic shock patients with CBG < 200 nmol/L had higher norepinephrine requirements and 3.2-fold higher ICU mortality. CBG concentration was the only directly reversible independent mortality risk factor.

Risk assessment, diagnosis, and treatment of cancer treatment-related adrenal insufficiency.

INTRODUCTION: Adrenal insufficiency (AI) is an easily treatable, potentially life-threatening condition, which is increasingly recognized in malignancy. The recent introduction of immune checkpoint inhibitors, in particular, and increasing use of tyrosine kinase inhibitors have increased the frequency of AI in patients with malignancy. A review is therefore warranted to summarize current knowledge on the topic and guide safe clinical practices. AREAS COVERED: Malignancy may directly impact the hypothalamic-pituitary-adrenal axis and cause AI, or their treatment including surgery, radiotherapy and medication. In this narrative review, we discuss new causes of AI, recognition of suggestive clinical features, diagnosis and subsequent treatment, aiming to avoid potentially fatal adrenal crisis (AC). Standard literature searching and authors assessment of clinical applicability were used. EXPERT OPINION: Adrenal insufficiency can be easily treated once identified but life threatening if unrecognized. While use of new agents such as immune checkpoint inhibitors (ICIs) is increasing, greater understanding of the mechanism of AI is needed to target prediction tools and enhance risk stratification.

The epidemiology of primary and secondary adrenal malignancies and associated adrenal insufficiency in hospitalised patients: an analysis of hospital admission data, NSW, Australia.

BACKGROUND: Adrenal insufficiency (AI) causes considerable morbidity but may remain undiagnosed in patients with adrenal malignancy (AM). The epidemiology of AI and adrenal crises (AC) in AM is uncertain. METHODS: This was a retrospective study examining hospital admission data from 2006 to 2017. All admissions to all hospitals in NSW, Australia over this period with a principal or comorbid diagnosis of an adrenal malignancy were selected. Data were examined for trends in admissions for AM and associated AI/AC using population data from the corresponding years. RESULTS: There were 15,376 hospital admissions with a diagnosis of AM in NSW over the study period, corresponding to 1281 admissions/year. The AM admission rate increased significantly over the study period from 129.9/million to 215.7/million (p < 0.01). An AI diagnosis was recorded in 182 (1.2%) admissions, corresponding to an average of 2.1/million/year. This rate increased significantly over the years of the study from 1.2/million in 2006 to 3.4/million in 2017 (p < 0.01). An AC was identified in 24 (13.2%) admissions with an AI diagnosis. Four patients (16.7%) with an AC died during the hospitalisation. CONCLUSION: Admission with a diagnosis of AM has increased over recent years and has been accompanied by an increase in AI diagnoses. While AI is diagnosed in a small proportion of patients with AM, ACs do occur in affected patients.

Interaction between hypotension and age on adrenal crisis diagnosis.

Objective: To determine whether adrenal crisis (AC) identification may be affected by the definition of hypotension. Context: Delays in AC diagnosis can result in adverse outcomes. AC-related cardiovascular compromise may vary according to baseline blood pressure and may be associated with delayed AC detection in some patients. Design: A retrospective study of paired systolic blood pressure (sBP) measurements in hospitalized patients with primary AI (PAI). Patients: Patients with PAI and an acute illness admitted for urgent treatment between 2000 and 2017. Measurements: A comparison between sBP on hospital arrival and on discharge. Hypotension was classified as either absolute hypotension (sBP 100mg or lower) or relative hypotension (sBP over 100 mg but at least 20 mm Hg lower than discharge sBP). Results: Of 152 admissions with paired blood pressure measurements, 46 (30.3%) included a medically diagnosed AC. Absolute hypotension was found in 38 (25.0%) records, and a further 21 (13.8%) patients were classified as having relative hypotension. Patients aged 65 years and older had the lowest (14.8%, n = 8) proportion with absolute hypotension but the highest (27.8%, n = 15) with relative hypotension. Use of either absolute or relative hypotension as the criterion for AC diagnosis increased the proportion of patients with an AC by 28.3% and the proportion of patients with an AC in the oldest age group by 130%. Conclusions: Failure to detect cardiovascular compromise is common in older AI patients, may underestimate the AC rate in this group, and delay essential treatment. Relative hypotension may play a role in AC diagnosis.

Flash Glucose Monitoring Compared to Capillary Glucose Levels in Patients With Diabetic Ketoacidosis: Potential Clinical Applications.

OBJECTIVE: Frequent, finger-prick capillary blood glucose measurement is standard care, used to drive insulin infusion rates for inpatients being resuscitated from diabetic ketoacidosis (DKA). Over recent years there has been a shift toward continuous interstitial glucose monitoring, allowing monitoring of glucose without repeated invasive testing. While continuous interstitial glucose monitoring has been safely and reliably utilized in the outpatient setting, it has yet to be studied in acutely unwell patients with DKA. The aim of this study, allowing for physiologically lower interstitial compared to capillary glucose, was to determine if interstitial flash glucose monitoring (FGM) would lead to insulin infusion rates that were similar to capillary blood glucose (CapBG) in DKA. METHODS: In this study, 10 patients with diabetes mellitus, assessed to be in DKA, were enrolled. At the same time as standard DKA management commencement, simultaneous FGM measurements were obtained. Duplicate paired glucose readings were then analyzed for agreement. RESULTS: Actual (CapBG-driven) and predicted (FGM determined) insulin infusion rates were similar. Minor differences in predicted insulin infusion rates were noted in 2/10 patients at higher glucose concentrations, which may relate to the lag in change in glucose in the interstitial space. CONCLUSION: Based on our results, a trial of clinical outcomes in patients with DKA treated with insulin infusion rates driven by CapBG versus subcutaneous FGM appears justified. The FGM method of testing may improve patient comfort, obviate fatigue, improve staff time and direct patient contact, and potentially facilitate rapid discharge.

Use of medical identification jewellery in children and young adults with adrenal insufficiency in Australia.

PURPOSE: Patients with adrenal insufficiency (AI) are at risk of life-threatening illness. Medical jewellery is recommended for emergencies, but its uptake is unknown. This study assessed the use of medical jewellery among Australian AI patients aged 25 years and under. METHODS: Data on the age, sex, region, and diagnosis of subscribers to the largest medical jewellery provider in Australia were analysed. Subscription rates were calculated using 2017 Australian population data. RESULTS: There were 666 patients aged 25 years and under in the database but only 358 (53.8%) had an active (up to date) subscription, corresponding to a subscription rate of 43.67/million or approximately 14.6% of the estimated patient population. The majority (n = 238, 66.5%) had primary AI; followed by secondary AI (n = 82, 22.9%); and the remaining patients (n = 38, 10.6%) could not be classified. Congenital adrenal hyperplasia (CAH) was the most frequent diagnosis (n = 153, 42.7%), corresponding to a subscription rate of 18.67/ million or 28.9% of the estimated number of patients with CAH. The mean age of subscribers was 15.9 (SD = 5.8) years. Only 18 (5%) patients were aged under 5 years. More females (n = 199, 55.9%) than males were active subscribers and subscription rates differed significantly by geographic area. Inactive (lapsed) subscriptions increased with age and were highest in the 20-25 year age group. CONCLUSION: Subscription rates were lower than recommended; increased with age; and were more common in females. Older age was associated with higher levels of lapsed subscriptions. Factors leading to low use and discontinuation in young adults should be addressed.

The effect of patient-managed stress dosing on electrolytes and blood pressure in acute illness in children with adrenal insufficiency.

BACKGROUND: Adrenal crises (AC) are acute episodes of adrenal insufficiency (AI). Manifestations include hypotension and electrolyte disturbances. Glucocorticoid stress dosing (SD) can prevent AC progression, but its effect on physiological parameters has not been assessed in a 'real world setting'. AIMS: To assess the effect of prior self-managed glucocorticoid dose escalation on physiological markers in children with congenital adrenal hyperplasia (CAH) presenting to hospital for an acute illness. METHODS: An audit of records of all children with CAH presenting to paediatric referral hospital between 2000 and 2015. Potassium, sodium and glucose levels, and hypotension were compared between children who had and had not used SD. RESULTS: There were 321 attendances by patients with CAH and an acute illness during the study period. Any form of SD was used by 64.2% (n = 206); intramuscular (IM) hydrocortisone was used by 22.1% (n = 71) and oral only by 41.7% (n = 134). Use of SD (oral and/or IM) was associated with a significantly lower mean potassium level (4.02 ± 0.71 vs. 4.27 ± 0.79 mmol/l, P < .05). Linear regression analysis showed that age (beta: -0.04 years (95% CI -0.06, -0.02)), diarrhoea (beta: -0.41 (95% CI -0.06, -0.02)) and any form of stress dosing (oral, IM or both) (beta: -0.29 (95% CI -0.55, -0.04)) were each independently and significantly associated with potassium levels. SD was not significantly associated with sodium or glucose concentrations or with estimates of hypotension. CONCLUSION: Patient-initiated SD resulted in a significant reduction in hyperkalaemia and lowered mean potassium levels in paediatric patients with CAH but did not alter significantly sodium and glucose concentrations or incidences of hypotension.

P450 Oxidoreductase Deficiency: A Systematic Review and Meta-analysis of Genotypes, Phenotypes, and Their Relationships.

CONTEXT: P450 oxidoreductase deficiency (PORD) is a rare genetic disorder that is associated with significant morbidity. However there has been limited analysis of reported PORD cases. OBJECTIVE: To determine, based on the cohort of reported PORD cases, genotype-phenotype relationships for skeletal malformations, maternal virilisation in pregnancy, adrenal insufficiency, and disorders of sexual development (DSD). DATA SOURCES: PubMed and Web of Science from January 2004 to February 2018. STUDY SELECTION: Published case reports/series of patients with PORD. Eligible patients were unique, had biallelic mutations, and their clinical features were reported. DATA EXTRACTION: Patient data were manually extracted from the text of case reports/series. A malformation score, representing the severity of skeletal malformations, was calculated for each patient. DATA SYNTHESIS: Of the 211 patients published in the literature, 90 were eligible for inclusion. More than 60 unique mutations were identified in this cohort. Four groups of mutations were identified, through regression modeling, as having significantly different skeletal malformation scores. Maternal virilization in pregnancy, reported for 21% of patients, was most common for R457H mutations. Adrenal insufficiency occurred for the majority of patients (78%) and was typically mild, with homozygous R457H mutations being the least deficient. DSD affected most patients (72%), but were less common for males (46XY) with homozygous R457H mutations. CONCLUSIONS: PORD is a complex disorder with many possible mutations affecting a large number of enzymes. By analyzing the cohort of reported PORD cases, this study identified clear relationships between genotype and several important phenotypic features.

Impulse Control Disorders in Dopamine Agonist-Treated Hyperprolactinemia: Prevalence and Risk Factors.

CONTEXT: There are growing reports of dopamine agonist (DA)-induced impulse control disorders (ICDs) in hyperprolactinemic patients. However, the magnitude of this risk and predictive factors remain uncertain. OBJECTIVE: To determine ICD prevalence and risk factors in DA-treated hyperprolactinemic patients compared to community controls. DESIGN, SETTING AND PARTICIPANTS: Multicenter cross-sectional analysis of 113 patients and 99 healthy controls. MAIN OUTCOME MEASURES: Participants completed a neuropsychological questionnaire consisting of the Depression Anxiety Stress Scale (DASS21), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP-S), Hypersexual Behavior Inventory (HBI), Hypersexual Behavior Consequences Scale and Social Desirability Response Set Scale. Demographic and clinical data were collated to determine ICD risk factors. Patients testing positive for an ICD were offered a semistructured psychological interview. RESULTS: Patients were more likely than controls to test positive by QUIP-S for any ICD (61.1 vs 42.4%, P = .01), hypersexuality (22.1 vs 8.1%, P = .009), compulsive buying (15.9 vs 6.1%, P = .041) and punding (18.6 vs 6.1%, P = 0.012), and by HBI for hypersexuality (8.0 vs 0.0%, P = 0.004). Independent risk factors were male sex (odds ratio [OR] 13.85), eugonadism (OR 7.85), Hardy's tumor score and psychiatric comorbidity (OR 6.86) for hypersexuality, and age (OR 0.95) for compulsive buying. DASS21 subset scores were higher in patients vs controls and in patients with vs without different ICDs. Only 19/51 (37.3%) interviewed patients were aware of the relationship between DAs and ICDs before the study. CONCLUSIONS: DA therapy poses a high, previously underestimated risk of ICDs, especially in the form of hypersexuality in eugonadal men.

Prehospital Management of Acute Addison Disease: Audit of Patients Attending a Referral Hospital in a Regional Area.

CONTEXT: Adrenal crisis (AC) causes morbidity and mortality in patients with Addison disease [primary adrenal insufficiency (PAI)]. Patient-initiated stress dosing (oral or parenteral hydrocortisone) is recommended to avert ACs. Although these should be effective, the continued incidence of ACs remains largely unexplained. METHODS: Audit of all attendances between 2000 and 2017 of adult patients with treated PAI to one large regional referral center in New South Wales, Australia. Measurements were those taken on arrival at hospital. RESULTS: There were 252 attendances by 56 patients with treated PAI during the study period. Women comprised 60.7% (n = 34) of the patients. The mean age of attendees was 53.7 (19.6) years. Nearly half (45.2%, n = 114) of the patients had an infection. There were 61 (24.2%) ACs diagnosed by the treating clinician. Only 17.9% (n = 45) of the hospital presentations followed any form of stress dosing. IM hydrocortisone was used prior to presentation 7 (2.8%) attendances only. Among patients with a clinician-diagnosed AC, only 32.8% (n = 20) had used stress dosing before presentation. Vomiting was reported by 47.6% (n = 120) of the patients but only 33 (27.5%) of these attempted stress dosing and 5 patients with vomiting used IM hydrocortisone. The number of prior presentations was an independent predictor of use of stress doses [1.05 (1.01, 1.09)]. CONCLUSION: Dose-escalation strategies are not used universally or correctly by unwell patients with PAI; many patients do not use IM or subcutaneous hydrocortisone injections. Previous hospital treatment increases the likelihood of stress dosing, and hospital attendance offers the opportunity for reinforcement of prevention strategies.

Adrenal insufficiency due to bilateral adrenal metastases - A systematic review and meta-analysis.

OBJECTIVE: Bilateral adrenal metastases may cause adrenal insufficiency (AI) but it is unclear if screening for AI in patients with bilateral adrenal metastases is justified, despite the potential for adrenal crises. METHOD: A search using PubMed/Medline, ScienceDirect and Cochrane Reviews was performed to collect all original research articles and all case reports from the past 50 years that describe AI in bilateral adrenal metastases. RESULTS: Twenty studies were included with 6 original research articles, 13 case reports and one case series. The quality was generally poor. The prevalence of AI was 3-8%. Of all cases of AI (n = 25) the mean pooled baseline cortisol was 318 ± 237 nmol/L and stimulated 423 ± 238 nmol/L. Hypotension was present in 69%, hyponatremia in 9% and hyperkalemia in 100%. Lung cancer was the cause in 35%, colorectal 20%, breast cancer 15% and lymphoma 10%. The size of the adrenal metastases was 5.5 ± 2.8 cm (left) and 5.5 ± 3.1 cm (right), respectively. There was no correlation between basal cortisol, stimulated cortisol concentration or ACTH with the size of adrenal metastases. The median time to death was 5.0 months (IQR 0.6-6.5). However, two cases were alive after 12-24 months. CONCLUSION: The prevalence of AI in patients with bilateral adrenal metastases was low. Prognosis was very poor. Due to the low prevalence of AI, screening is likely only indicated in patients with symptoms and signs suggestive of hypocortisolism.