Endocrine https://doi.org/10.1007/s12020-021-02649-6 MINI REVIEW Therapy options for adrenal insufficiency and recommendations for the management of adrenal crisis Hanna Nowotny1 S. Faisal Ahmed2 Sophie Bensing3 Johan G. Beun4,5 Manuela Brösamle4 Irina Chifu6 ● ● ● ● ● ● Hedi Claahsen van der Grinten7 Maria Clemente8 Henrik Falhammar3 Stefanie Hahner6 Eystein Husebye9 ● ● ● ● ● Jette Kristensen4 Paola Loli10 Svetlana Lajic11 Nicole Reisch1 On Behalf of Endo ERN (MTG1) ● ● ● ● Received: 1 December 2020 / Accepted: 22 January 2021 © The Author(s) 2021 Abstract Adrenal insufficiency (AI) is a life-threatening condition requiring life-long glucocorticoid (GC) substitution therapy, as well as stress adaptation to prevent adrenal crises. The number of individuals with primary and secondary adrenal insufficiency in Europe is estimated to be 20–50/100.000. A growing number of AI cases are due to side effects of GC treatment used in different treatment strategies for cancer and to immunotherapy in cancer treatment. The benefit of hormone replacement 1234567890();,: 1234567890();,: therapy is evident but long-term adverse effects may arise due to the non-physiological GC doses and treatment regimens used. Given multiple GC replacement formulations available comprising short-acting, intermediate, long-acting and novel modified-release hydrocortisone as well as subcutaneous formulations, this review offers a concise summary on the latest therapeutic improvements for treatment of AI and prevention of adrenal crises. As availability of various glucocorticoid formulations and access to expert centers across Europe varies widely, European Reference Networks on rare endocrine conditions aim at harmonizing treatment and ensure access to specialized patient care for individual case-by-case treatment decisions. To improve the availability across Europe to cost effective oral and parenteral formulations of hydrocortisone will save lives. Keywords Adrenal insufficiency Congenital adrenal hyperplasia Adrenal crisis Glucocorticoid replacement ● ● ● ● Hydrocortisone Stress instructions ● These authors contributed equally: Svetlana Lajic, Nicole Reisch * Nicole Reisch 7 Amalia Children’s Hospital, Department of Pediatric nicole.reisch@med.uni-muenchen.de Endocrinology, Radboud University Medical Centre, 1 Nijmegen, The Netherlands Medizinische Klinik IV, Klinikum der Universität München, 8 Munich, Germany Pediatric Endocrinology Unit, Hospital Vall d´Hebron, 2 Autonomous University of Barcelona, CIBERER, Developmental Endocrinology Research Group, University of Barcelona, Spain Glasgow, Glasgow, Scotland, UK 9 3 Department of Clinical Science and K.G. Jebsen Center for Department of Molecular Medicine and Surgery, Karolinska Autoimmune Disorders, University of Bergen, and Department of Institutet and Department of Endocrinology, Karolinska University Medicine, Haukeland University Hospital, Bergen, Norway Hospital, Stockholm, Sweden 10 4 Division of Endocrinology, San Raffaele Vita-Salute University, European Patient Advocacy Group for Adrenal Diseases, IRCCS San Raffaele Hospital, Milan, Italy European Reference Network on Rare Endocrine Conditions 11 (Endo ERN), Endo ERN Coordinating Centre, Leiden, The Department of Women´s and Children´s Health, Division of Netherlands Pediatrics, Unit for Pediatric Endocrinology and Metabolic 5 Disorders, Karolinska Institutet/Karolinska University Hospital, AdrenalNET, Soest, The Netherlands Stockholm, Sweden 6 Division of Endocrinology and Diabetology, Department of Internal Medicine I, University Hospital of Wuerzburg, University of Wuerzburg, Wuerzburg, Germany Endocrine Introduction Current glucocorticoid replacement therapy Thomas Addison first described adrenal insufficiency in Replacement therapy for patients with AI consists of the 1855. However, it was not until 1948 that a larger application of glucocorticoids, and in PAI mostly additional quantity of cortisone (so called compound E) was syn- mineralocorticoids. Conventional therapeutic regimens include thesized as a result of the discovery and works by Ken- short-acting substances as hydrocortisone the synthetic form of dall, Sarett and Reichstein, and it could thereafter be used cortisol and cortisone acetate or synthetic intermediate or long- for treatment of the disease and prevention of adrenal acting glucocorticoids, such as prednisone, prednisolone, and crisis. Individuals with adrenal insufficiency (AI) have dexamethasone. Short-acting glucocorticoids should always be reduced or no production of glucocorticoids and in pri- used as the primary treatment option. A total of 15–25 mg mary adrenal insufficiency this is often associated with a hydrocortisone (cortisone acetate 20–35 mg) in adults in two reduction in mineralocorticoid synthesis [1]. In Western to three daily doses and 8 mg/m2 body surface/day in children countries primary adrenal insufficiency (PAI; adrenal divided in three to four doses, or appropriate equivalent dose if level) is mainly caused by an autoimmune adrenalitis (Mb using a synthetic glucocorticoid, is considered an adequate Addison) and can go in hand with other autoimmune hormone replacement dose, even though the daily production endocrine diseases (polyendocrine syndrome). PAI can of cortisol is even lower (5–6 mg/m2) [9, 10]. In CAH mostly also be due to infections, bilateral infarction, metastases, higher glucocorticoid (GC) replacement doses than in primary hemorrhages and adrenalectomy, as well as genetic syn- adrenal insufficiency due to Addison’s disease are necessary to dromes (e.g., congenital adrenal hyperplasia (CAH), adequately suppress adrenal androgen production. In children adrenoleukodystrophy) [2]. The main causes of second- with CAH, hydrocortisone in a range of 10–15 mg/m2 body ary adrenal insufficiency (SAI; pituitary level) are tumors surface/day is mostly necessary and in adults 15–25 mg/day of the pituitary gland, adrenocorticotropic hormone [11]. Practical experience shows that glucocorticoid dosing in (ACTH) deficiency, and hypophysitis due to increasing CAH often is higher than recommended [12, 13]. Miner- use of immune checkpoint inhibitors. Other causes alocorticoids in PAI are replaced by fludrocortisone at a dose include trauma due to operation, infarction such as of 0.05–0.2 mg/day [9, 11]. It is important to know that Sheehan’s syndrome or infections. Tertiary adrenal hydrocortisone exerts potent mineralocorticoid action while insufficiency (hypothalamic level) is probably the most prednisolone only has reduced mineralocorticoid activity and common cause of AI and mostly due to long-term high- dexamethasone none at all. dose synthetic glucocorticoid therapy but can also be Hormone replacement shows substantial heterogeneity caused by repressing lesions and certain drugs (opioids) across Europe, but hydrocortisone twice or thrice daily is resulting in a prolonged hypothalamic–pituitary–adrenal most widely used [14]. Chronic cortisol replacement with axis suppression [3, 4]. long-acting synthetic glucocorticoids is less desirable as Physiological cortisol secretion has a distinct diurnal it exerts unfavorable night time glucocorticoid activity as rhythm with a rise over night, a peak upon awakening and a consequence of the longer biological half-lives and has decreasing levels during the day and depends on the same limited options for dose titration. Longer-acting GC diurnal ACTH secretion. This robust pattern is controlled replacement regimen have shown to be associated with by the interaction of the suprachiasmatic nucleus (SCN) more adverse effects [13, 15–18]. in the hypothalamus as the main circadian pacemaker However, even today in many countries, including Eur- with the hypothalamus-pituitary-adrenal (HPA) axis, as opean countries, hydrocortisone is not available, but corti- well as peripheral clocks located in many organs sone acetate (e.g., Italy and Norway) or longer-acting including the adrenals via differential expression of so- synthetic GCs need to be used. In some situations long- called “canonical clock genes” [5]. Glucocorticoids acting synthetic glucocorticoids as prednisolone may be themselves are serving as transducers between these preferred over hydrocortisone, e.g., for compliance reasons, central and peripheral systems [6] and also play a key role better control or suppression of adrenal androgens in CAH. in the regulation of multiple body functions, such as Undoubtedly, excess glucocorticoid replacement affects metabolism, the stress- and immune response and cog- quality of life and causes multiple morbidities and increased nition [7]. Moreover, cortisol is secreted in a pulsatile mortality [19–22], which can only partially be explained by way with peaks approximately every 3 h, which trigger a higher incidence of adrenal crises in this group of patients pulsatile binding to the glucocorticoid receptor (GR) and [23]. Research in recent years revealed compelling evidence GR-mediated gene pulsing [8]. This rationale indicates of side effects of dysregulated glucocorticoid rhythmicity that disruptions in any part of this tightly controlled highlighting that the mode of glucocorticoid replacement system can possibly lead to detrimental effects and matters [24]. Patients with long-term supraphysiological GC pathological changes in several body functions [7]. replacement have been found to be at risk for a higher Endocrine incidence of infections, especially those of the upper air- and limits the availability. It may, however, be used in ways and gastrointestinal tract, and show an increased rate certain subgroups of patients, e.g., in patients with the of hospitalization and use of antimicrobial substances [25]. greatest risk of metabolic comorbidities and in patients with Bancos et al. [26] observed that patients with AI under poor therapeutic compliance. standard hydrocortisone therapy present with significantly Chronocort® (Diurnal, UK) is a modified-release pre- impaired NK-cell cytotoxicity along with a reduced paration, currently undergoing the approval process in expression of NK-cell-specific surface receptors. In addi- Europe for treatment of CAH in adults. The drug consists of tion, ratios of classical to non-classical monocytes were multiple micro-crystals covered by a polymer sheathing, shown to be inversed, with higher levels of classical enabling a delayed and sustained release. It is used CD14 + CD16- monocytes under traditional hydrocortisone according to a “toothbrush-regimen” (1/3 of the daily dose treatment. Further studies are required to determine whether at 7 a.m. and 2/3 of the daily dose at 11 p.m.) and results in patients with AI have an increased risk of infections. Non- nearly physiological cortisol levels throughout the entire physiological and supra-physiologic glucocorticoid sub- day including the overnight rise and the morning peak in stitution therapy may also be associated with an increase in cortisol [40]. This is especially important for patients with cardiovascular and metabolic morbidity [27–30]. A Swed- CAH as it prevents the ACTH-driven excess production of ish population-based cohort study in patients with CAH adrenal androgens and thus reduces the disease impact on showed higher incidence of cardiovascular and metabolic growth, puberty, and fertility [41]. Data from the phase III disorders compared to healthy controls [28]. Especially in trial including 122 patients with classic CAH due to 21- females with PAI the risk of ischemic heart disease and hydroxylase deficiency (21OHD) showed that both, cardiovascular disease was increased and associated with modified-release hydrocortisone and conventional gluco- higher glucocorticoid replacement doses [30]. Besides these corticoid treatment regimen, achieved improved hormonal substantial morbidities, the dysregulation of the cortisol control at 6 months. The study found better biochemical circadian profile is negatively impacting on the capability, control on Chronocort® versus conventional glucocorticoid endurance, and sleep quality resulting in impaired physical therapy, with lower 17-hydroxyprogesterone standard and mental health, as well as reduced quality of life [31, 32]. deviation score (SDS) at 4 and 12 weeks, but only between 07:00 h and 15:00 h at 6 months, thus failing its primary outcome at 6 months. Further observations included a lower New developments in glucocorticoid number of adrenal crises per year, women restarting men- replacement therapies struation and two partner pregnancies with Chronocort® therapy [42]. In attempting to prevent or minimize these detrimental Although Chronocort® appears to offer a good imitation effects caused by circadian changes on health in patients of the circadian pattern of cortisol secretion, it still misses with AI, further treatment options aiming at mimicking the pulsatile secretory pattern. Subcutaneous infusion of normal circadian cortisol rhythm have been developed. glucocorticoids via specialized pumps have been shown to Plenadren® (Takeda) was approved for treatment of AI in enable reproduction of near physiological patterns of both adults in 2011. The main pharmacological principle is a circadian and ultradian rhythmicity imitating the production dual-release system resulting from an outer layer providing of individual pulses with an interval of 80–110 min and immediate release and an inner retard formulation [33]. plasma peaks and troughs every 3 h as previously described Comparison of once-daily Plenadren® and conventional [8, 43–45]. Economic reasons and the complexity of having twice-daily hydrocortisone therapy indicated a smoother a pump as well as absent evidence for the superiority of cortisol profile up to 4 h after Plenadren® intake mimicking such treatment reserve this treatment for special cases, the physiological diurnal cortisol levels with the exception which have so far prevented its use in clinical practice. of a rise in cortisol levels prior to awakening [34], as well as A particular challenge of GC replacement is accurate an overall reduction of daily cortisol exposure [35]. A dosing in low-dose ranges for children. Until recently this switch to dual-release preparations (Plenadren®) reduced the had to be done by crushing hydrocortisone tablets or levels of monocytes to the levels found in untreated controls pharmacy compounded capsules as licensed preparations and lead to a significant reduction in body weight, body of hydrocortisone have only been available as 10 mg mass index (BMI), and HbA1c [36, 37]. It still remains tablets in Europe and 5 mg tablets in the United States. unclear whether these findings represent a better physiolo- However, up to 25% of pharmacy compounded capsules gical circadian profile or are the result of a lower daily dose have been shown not to fulfill the acceptance criteria of the of hydrocortisone equivalent [38, 39]. The economic burden European Pharmacopeia of uniformity of net mass or drug of an ~10 times higher price of Plenadren® versus con- content or showed inadequate labeling [46]. To overcome ventional hydrocortisone also needs to be taken into account this, in Europe hydrocortisone granules for children and Endocrine adolescents (Alkindi®) now have been licensed in doses of AI is a rare disease and health care professionals may not 0.5, 1, 2, and 5 mg [47]. The draw-back of these granules always be familiar with the optimal management of adrenal is the high cost compared to conventional hydrocortisone crisis in these patients [56]. Therefore, a well-trained patient tablets or compounded capsules, which may limit their (and/or relative) is the key success factor for prevention and availability in different countries. In infants it may also be management of an adrenal crisis. difficult to administer the granules since they cannot be Steroid emergency cards for children and adults already dissolved. have been successfully harmonized across Europe (Fig. 3) In May 2020 in the Netherlands, the Dutch Medicines and are available in the respective national language on Evaluation Board (CBG) has approved a registration for a one side and in English on the other (https://adrenals.eu/ new series of hydrocortisone tablets. They are covered with emergency-card/) [57]. a small film to neutralize the bad taste and all have their Patients with AI should regularly be educated on the use of own color. Currently 1 mg (white), 5 mg, and 10 mg (red) sick day rules, emergency equipment and empowerment [56]. are available. At the moment (November 2020), the other Sick day rules, e.g., include doubling or tripling of standard two tablets (2 mg and 3 mg) are being under evaluation by glucocorticoid daily doses, application of hydrocortisone every the Dutch Medicines Evaluation Board (CBG). 6 h with increasing amount upon clinical deterioration and emergency injection of hydrocortisone (e.g., Solu-Cortef®, Hydrocortisone 100-Rotexmedica®, Hydrocortisone Pan- Adrenal crisis: improving prevention of one pharma 100®, Actocortina 100 mg®) either intramuscularly or of the most significant morbidity factors in AI intravenously [49] (https://adrenals.eu/stress-instructions/). Although off-label, subcutaneous hydrocortisone application Besides daily routine hormone replacement requiring can be used in adults instead of i.m. injection, the pharmaco- improvement and the need for further research regarding kinetics during real life emergency use should be evaluated long-term health benefits potentially offered by these novel further [58]. In some European countries, a hydrocortisone therapeutic options, adrenal crisis (AC) prevention, one of solution for i.v. or i.m. injection (e.g., Solu-Cortef®/Hydro- the most significant morbidity factors in AI, is still a chal- cortisone 100-Rotexmedica®/Hydrocortisone Panpharma 100®/ lenge. With an incidence of 5–10 adrenal crises/100 patient Actocortina 100 mg®) is not available, and other glucocorti- years and a mortality rate of 0.5/100 years [48], prevention, coids have to be used instead (https://endo-ern.eu/specific- quick diagnosis, and correct treatment is essential [49]. It expertise/adrenal/existing-guidelines-consensus-statements/). should be noted that both symptoms and signs of adrenal There is thus a need for distributing and providing both oral crisis may be more difficult to interpret in the old patient and parenteral formulations of hydrocortisone at a reasonable and in young children [50]. cost across Europe. This will save lives and reduce long-term In particular, the current SARS-CoV-2 pandemic and the morbidity. risk of COVID-19 infection emphasizes the importance of It is essential that patients are equipped at any time with education on this topic. Currently, there is no evidence that an emergency card (Fig. 1) and an emergency kit for self- patients with AI are at an increased risk of acquiring injection. They should always have a supply of medication COVID-19 or are prone to a severe course of COVID-19 infections. Adrenal crises are rare events in children and when examined in children with rare conditions such as CAH, they are even rarer [51]. However, it cannot be stressed enough that there is a need to collect real-world data on adrenal crises and sick day episodes in such a way that it can be linked to changes in therapies or other events such as the COVID-19 pandemic. Registry platforms such as the I-CAH Registry (https://home.i-cah.org) have the potential to serve this purpose over the longer term. Cases of patients with AI and COVID-19 infection are currently being ascertained by a joint initiative of ESE and EndoERN through a surveillance project that is being performed on EuRRECa’s e-REC platform (https://eurreca.net) and is open to all centers worldwide (https://www.ese-hormones. org/research/rare-disease-covid-19-task-force/). The current situation also emphasizes the need for standardized patient Fig. 1 European steroid emergency card for children (left) and adults education to prevent adrenal crises in any infection [52–55]. (right) in the English version (https://adrenals.eu/emergency-card/) Endocrine Adrenal Crisis – an overview on symptoms, causes and therapies [9,48-50,59-68] Definition Other symptoms Causes Major impairment of general health with at least two of the following 8. Fatigue, lack of energy, 1. Infections (gastroenteritis) signs/symptoms: weight loss 2. Surgery 1. Hypotension (systolic 9. Hypovolaemia to 3. Pain blood pressure less than hypovolaemic shock 4. Strenuous exercise 100 mmHg) 10. Cardiomyopathy 5. Severe Emotional stress 2. Nausea or vomiting 11. Anorexia, Abdominal pain 6. Accidents 3. Severe fatigue (peritonitis) 7. Unsuitable dose adjustments 4. Fever 12. Skin abnormalities (PAI 8. No clear cause 5. Somnolence hyperpigmentation vs. SAI 6. Hyponatraemia (<132 alabaster-like paleness) Grading mmol/l) or hyperkalaemia 13. Pre-renal failure, 7. Hypoglycaemia normochromic anaemia, Grade 1: outpatient care only lymphocytosis, Grade 2: hospital care eosinophilia Grade 3: admission to ICU Grade 4: death from adrenal crisis Preventive measurements in adults and children at home See also: https://endo-ern.eu/specific-expertise/adrenal/existing-guidelines-consensus-statements/ https://adrenals.eu/how-an-emergency-injection-works/ Sick day rule illness with fever that requires bed rest and/or antibiotics Doubling or tripling oral 1 glucocorticoid dose Sick day rule prolonged vomiting or diarrhea, severe physical stress, acute i.v. or i.m. injection of 2 trauma or surgery hydrocortisone (e.g. Solu- Cortef®/Hydrocortisone 100- Rotexmedica®/Hydrocortisone Panpharma 100®/Actocortina 100mg®), consult endocrinologist, go to hospital Preventive measurements and treatment in adults during surgery and other stressful interventions Type of surgery Preoperative Treatment Postoperative treatment Surgery under anaesthesia HC 100 mg i.v., continuous i.v. infusion while nil by mouth or (general or regional) infusion of HC 200 mg/24h PONV (or HC 50 mg/6h i.m.) Caesarean section 2x enteral HC dose for 48h – 1 week (24 h if rapid recovery) Bowel procedures requiring Bowel prep under clinical resume enteral – double laxatives/enema supervision hydrocortisone doses for 24 h consider i.v. fluids and i.v. GC during preparation HC 100 mg i.v. or i.m. at start of procedure Labour and vaginal delivery HC 100 mg i.v. at onset of labour resume enteral – double continuous infusion of 200 hydrocortisone doses for 24h mg/24h or HC 50 mg/6h i.m. Dental procedure Extra morning dose 1h before double oral dose for 24h, then surgery (10 mg HC) return to normal dose Minor procedure no preop. measure required extra dose if symptoms persist Fig. 2 Overview on symptoms, causes and preventive therapies of intramuscular, i.v. intravenously, s.c. subcutaneously, PONV post- adrenal crisis. ICU intensive care unit, PAI primary adrenal insuffi- operative nausea and vomiting, HC hydrocortisone, mg milligram, ciency, SAI secondary adrenal insufficiency, GC glucocorticoid, i.m. h hour [9, 48–50, 59–68] Endocrine ults [9] https:///endo-ern.eu/sspecific-experrtise/adrenal/eexisting-guideelines- Treatment of adrenall crisis in adu consensuus-statements/ Treatment of adrenall crisis in chilldren [69-72] https://enndo-ern.eu/wp-content/uploaads/2020/11/E Emergency-regimen-ADRE ENAL-crisis-P Pediatric_2011101.pdf 1. Give stress s dose of hydrocortissone (HC) (550-100 mg/m m2) i.v. or i.m m. see chart below. b Repeaat if necessarry. Fludrocorrtisone is nott required acuutely when high h dose of HC H is given.. 2. Start m maintenance treatment with w HC i.v. 50-75-100 5 mg/m2/24h div vided q 6 h OR give the HC as ana intravenouus continuouss infusion at a dose of 2-3 mg /m2 /h. Weightt of the child d (age of thee child) H Hydrocortiso ne 50mg/mll i.v. (e.g. Sollu-Cortef®/ Hy ydrocortisone 1000-Rotexmedica®//Hydrocortisone Panpharma P 100®/Actocortina 100mg®) 1 <15 kg (0-2 years) 255 mg 15-25 kg k (2-6 yearss) 500 mg >25 kg (>6 years) 1000 mg 3. Fluidss: If the patieent is shockedd give 10-200 mL/kg 0.9% % sodium chloride i.v. boolus and repeeat as necessarry. Start onggoing mainteenance plus ddeficit for deehydration giiven as 0.9% sodium chlo oride with 5%% glucose. 4. Checkk blood glucoose hourly, iff less than 3..5 mmol/L giive 2-5 mL/k kg of 10% gllucose. 5. Checkk sodium andd potassium. Treat if neceessary. 6. Monittor blood preessure and caardiac functioon. 7. Switchh to oral regiimen dependding on cliniccal state. Starrt with HC 30-50 3 mg/m2/24h. / Graduaally reduce too maintenancce level. 8. Start m mineralocortticoid replaceement (fludroocortisone, Florinef®) F 0..05-0.1 mg daily. d Fig. 3 Summary of treatment of adrenal crisis in adults and children in CVP central venous pressure, IBP invasive blood pressure, ICU the hospital setting. i.v. intravenously, i.m. intramuscular, h hour, intensive care treatment [9, 69–72] of at least three months including a sick day package of can already now be an alternative for those with poor quality hydrocortisone tablets. Further information on prevention of life and/or metabolic comorbidities. Larger, long-term out- and treatment of adrenal crises in children and adults is come-based trials are required to assess the benefits of newer summarized in Figs. 2 and 3 or can be found by using the preparations against current treatment practice. There is still a following link (https://endo-ern.eu/specific-expertise/adrena need with regards to harmonization of treatment and patient l/existing-guidelines-consensus-statements/). education, as well as access to medications and specialized patient care across Europe. This is a dedicated aim of the European Reference Network on Rare Endocrine Conditions Conclusion (EndoERN). Conventional immediate-release hydrocortisone remains the Funding This work was supported by the European Union’s Health Program (2014–2020) on the EuRRECa project “777215/EuRRECa” gold standard glucocorticoid replacement therapy in patients (S.F.A., J.G.B., E.H., N.R.) and by the Deutsche For- with adrenal insufficiency. However, dual- and modified- schungsgemeinschaft (Heisenberg Professorship 325768017 to N.R. and release hydrocortisone and other, still experimental approaches Projektnummer: 314061271-TRR205 to N.R.). We would also like to Endocrine thank the support of the contributing authors/centers that all participate in C.A. Stratakis, D.J. Torpy, Diagnosis and treatment of primary the European Reference Network for Rare Endocrine Conditions (Endo- adrenal insufficiency: an endocrine society clinical practice ERN). Open Access funding enabled and organized by Projekt DEAL. guideline. J. Clin. Endocrinol. Metab. 101(2), 364–389 (2016). https://doi.org/10.1210/jc.2015-1710 10. N.V. Esteban, T. Loughlin, A.L. Yergey, J.K. Zawadzki, J.D. Compliance with ethical standards Booth, J.C. Winterer, D.L. Loriaux, Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J. Conflict of interest N.R. is PI of the Chronocort® Phase III and Clin. Endocrinol. Metab. 72(1), 39–45 (1991). https://doi.org/10. extension study and of the EU-AIR SHP617-400-P40012 study. The 1210/jcem-72-1-39 other authors report no conflicts of interest in this work. 11. P.W. Speiser, W. Arlt, R.J. Auchus, L.S. Baskin, G.S. Conway, D. P. Merke, H.F.L. Meyer-Bahlburg, W.L. Miller, M.H. Murad, S. Publisher’s note Springer Nature remains neutral with regard to E. Oberfield, P.C. White, Congenital adrenal hyperplasia due to jurisdictional claims in published maps and institutional affiliations. steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 103(11), 4043–4088 (2018). https://doi.org/10.1210/jc.2018-01865 Open Access This article is licensed under a Creative Commons 12. W. Arlt, D.S. Willis, S.H. Wild, N. Krone, E.J. Doherty, S. Attribution 4.0 International License, which permits use, sharing, Hahner, T.S. Han, P.V. Carroll, G.S. Conway, D.A. Rees, R.H. adaptation, distribution and reproduction in any medium or format, as Stimson, B.R. Walker, J.M. Connell, R.J. Ross; United Kingdom long as you give appropriate credit to the original author(s) and the Congenital Adrenal Hyperplasia Adult Study, E., Health status of source, provide a link to the Creative Commons license, and indicate if adults with congenital adrenal hyperplasia: a cohort study of 203 changes were made. The images or other third party material in this patients. J. Clin. Endocrinol. Metab. 95(11), 5110–5121 (2010). article are included in the article’s Creative Commons license, unless https://doi.org/10.1210/jc.2010-0917 indicated otherwise in a credit line to the material. If material is not 13. L. Paizoni, M.K. Auer, H. Schmidt, A. Hubner, M. Bidlingmaier, N. included in the article’s Creative Commons license and your intended Reisch, Effect of androgen excess and glucocorticoid exposure on use is not permitted by statutory regulation or exceeds the permitted metabolic risk profiles in patients with congenital adrenal hyperplasia use, you will need to obtain permission directly from the copyright due to 21-hydroxylase deficiency. J. Steroid Biochem Mol. Biol. holder. To view a copy of this license, visit http://creativecommons. 197, 105540 (2020). https://doi.org/10.1016/j.jsbmb.2019.105540 org/licenses/by/4.0/. 14. R.D. Murray, B. Ekman, S. Uddin, C. Marelli, M. Quinkler, P.M. Zelissen, E.U.A.I.R.I. the, Management of glucocorticoid repla- cement in adrenal insufficiency shows notable heterogeneity-data from the EU-AIR. Clin. Endocrinol. (Oxf.) 86(3), 340–346 References (2017). https://doi.org/10.1111/cen.13267 15. M.K. Auer, L. Paizoni, L.C. Hofbauer, M. Rauner, Y. Chen, H. 1. E. Charmandari, N.C. Nicolaides, G.P. Chrousos, Adrenal insuf- Schmidt, A. Huebner, M. Bidlingmaier, N. Reisch, Effects of ficiency. Lancet 383(9935), 2152–2167 (2014). https://doi.org/10. androgen excess and glucocorticoid exposure on bone health in 1016/S0140-6736(13)61684-0 adult patients with 21-hydroxylase deficiency. J. Steroid Biochem 2. W. Arlt, B. Allolio, Adrenal insufficiency. Lancet 361(9372), Mol. Biol. 204, 105734 (2020). https://doi.org/10.1016/j.jsbmb. 1881–1893 (2003). https://doi.org/10.1016/S0140-6736(03)13492-7 2020.105734 3. T. Li, J.L. Cunningham, W.P. Gilliam, L. Loukianova, D.M. 16. K.R. Frey, T. Kienitz, J. Schulz, M. Ventz, K. Zopf, M. Quinkler, Donegan, I. Bancos, Prevalence of opioid-induced adrenal insuf- Prednisolone is associated with a worse bone mineral density in ficiency in patients taking chronic opioids. J. Clin. Endocrinol. primary adrenal insufficiency. Endocr. Connect 7(6), 811–818 Metab. 105(10) (2020). https://doi.org/10.1210/clinem/dgaa499 (2018). https://doi.org/10.1530/EC-18-0160 4. F. de Vries, M. Bruin, D.J. Lobatto, O.M. Dekkers, J.W. Schoones, 17. M. Quinkler, B. Ekman, C. Marelli, S. Uddin, P. Zelissen, R.D. W.R. van Furth, A.M. Pereira, N. Karavitaki, N.R. Biermasz, A.H. Murray, E.-A. Investigators, Prednisolone is associated with a Zamanipoor Najafabadi, Opioids and their endocrine effects: a worse lipid profile than hydrocortisone in patients with adrenal systematic review and meta-analysis. J. Clin. Endocrinol. Metab. insufficiency. Endocr. Connect 6(1), 1–8 (2017). https://doi.org/ 105(3) (2020). https://doi.org/10.1210/clinem/dgz022 10.1530/EC-16-0081 5. H. Oster, E. Challet, V. Ott, E. Arvat, E.R. de Kloet, D.J. Dijk, S. 18. E. Whittle, H. Falhammar, Glucocorticoid regimens in the treat- Lightman, A. Vgontzas, E. Van Cauter, The functional and ment of congenital adrenal hyperplasia: a systematic review and clinical significance of the 24-hour rhythm of circulating glu- meta-analysis. J. Endocr. Soc. 3(6), 1227–1245 (2019). https://doi. cocorticoids. Endocr. Rev. 38(1), 3–45 (2017). https://doi.org/ org/10.1210/js.2019-00136 10.1210/er.2015-1080 19. S. Bensing, L. Brandt, F. Tabaroj, O. Sjoberg, B. Nilsson, A. 6. A.C. Moreira, S.R. Antonini, M. de Castro, Mechanisms in Ekbom, P. Blomqvist, O. Kampe, Increased death risk and altered endocrinology: a sense of time of the glucocorticoid circadian cancer incidence pattern in patients with isolated or combined clock: from the ontogeny to the diagnosis of Cushing’s syndrome. autoimmune primary adrenocortical insufficiency. Clin. Endocri- Eur. J. Endocrinol. 179(1), R1–R18 (2018). https://doi.org/10. nol. (Oxf.) 69(5), 697–704 (2008). https://doi.org/10.1111/j.1365- 1530/EJE-18-0102 2265.2008.03340.x 7. N. Nader, G.P. Chrousos, T. Kino, Interactions of the circadian 20. H. Falhammar, L. Frisen, C. Norrby, A.L. Hirschberg, C. Almq- CLOCK system and the HPA axis. Trends Endocrinol. Metab. 21 vist, A. Nordenskjold, A. Nordenstrom, Increased mortality in (5), 277–286 (2010). https://doi.org/10.1016/j.tem.2009.12.011 patients with congenital adrenal hyperplasia due to 21- 8. G.M. Russell, C. Durant, A. Ataya, C. Papastathi, R. Bhake, W. hydroxylase deficiency. J. Clin. Endocrinol. Metab. 99(12), Woltersdorf, S. Lightman, Subcutaneous pulsatile glucocorticoid E2715–2721 (2014). https://doi.org/10.1210/jc.2014-2957 replacement therapy. Clin. Endocrinol. (Oxf.) 81(2), 289–293 21. P. Burman, A.F. Mattsson, G. Johannsson, C. Hoybye, H. Hol- (2014). https://doi.org/10.1111/cen.12470 mer, P. Dahlqvist, K. Berinder, B.E. Engstrom, B. Ekman, E.M. 9. S.R. Bornstein, B. Allolio, W. Arlt, A. Barthel, A. Don-Wau- Erfurth, J. Svensson, J. Wahlberg, F.A. Karlsson, Deaths among chope, G.D. Hammer, E.S. Husebye, D.P. Merke, M.H. Murad, adult patients with hypopituitarism: hypocortisolism during acute Endocrine stress, and de novo malignant brain tumors contribute to an 34. J. Porter, J. Blair, R.J. Ross, Is physiological glucocorticoid repla- increased mortality. J. Clin. Endocrinol. Metab. 98(4), 1466–1475 cement important in children? Arch. Dis. Child 102(2), 199–205 (2013). https://doi.org/10.1210/jc.2012-4059 (2017). https://doi.org/10.1136/archdischild-2015-309538 22. R. Bergthorsdottir, M. Leonsson-Zachrisson, A. Oden, G. 35. G. Johannsson, A.G. Nilsson, R. Bergthorsdottir, P. Burman, P. Johannsson, Premature mortality in patients with Addison’s dis- Dahlqvist, B. Ekman, B.E. Engstrom, T. Olsson, O. Ragnarsson, ease: a population-based study. J. Clin. Endocrinol. Metab. 91 M. Ryberg, J. Wahlberg, B.M. Biller, J.P. Monson, P.M. Stewart, (12), 4849–4853 (2006). https://doi.org/10.1210/jc.2006-0076 H. Lennernas, S. Skrtic, Improved cortisol exposure-time profile 23. J. Martin-Grace, R. Dineen, M. Sherlock, C.J. Thompson, Adrenal and outcome in patients with adrenal insufficiency: a prospective insufficiency: physiology, clinical presentation and diagnostic randomized trial of a novel hydrocortisone dual-release formula- challenges. Clin. Chim. Acta (2020). https://doi.org/10.1016/j.cca. tion. J. Clin. Endocrinol. Metab. 97(2), 473–481 (2012). https:// 2020.01.029 doi.org/10.1210/jc.2011-1926 24. S. Hahner, M. Loeffler, M. Fassnacht, D. Weismann, A.C. 36. A.M. Isidori, M.A. Venneri, C. Graziadio, C. Simeoli, D. Fiore, Koschker, M. Quinkler, O. Decker, W. Arlt, B. Allolio, Impaired V. Hasenmajer, E. Sbardella, D. Gianfrilli, C. Pozza, P. Pasqua- subjective health status in 256 patients with adrenal insufficiency letti, S. Morrone, A. Santoni, F. Naro, A. Colao, R. Pivonello, A. on standard therapy based on cross-sectional analysis. J. Clin. Lenzi, Effect of once-daily, modified-release hydrocortisone ver- Endocrinol. Metab. 92(10), 3912–3922 (2007). https://doi.org/10. sus standard glucocorticoid therapy on metabolism and innate 1210/jc.2007-0685 immunity in patients with adrenal insufficiency (DREAM): a 25. L.C. Smans, P.C. Souverein, H.G. Leufkens, A.I. Hoepelman, P. single-blind, randomised controlled trial. Lancet Diabetes Endo- M. Zelissen, Increased use of antimicrobial agents and hospital crinol. 6(3), 173–185 (2018). https://doi.org/10.1016/S2213-8587 admission for infections in patients with primary adrenal insuffi- (17)30398-4 ciency: a cohort study. Eur. J. Endocrinol. 168(4), 609–614 37. M. Quinkler, R. Miodini Nilsen, K. Zopf, M. Ventz, M. Oksnes, (2013). https://doi.org/10.1530/EJE-12-0879 Modified-release hydrocortisone decreases BMI and HbA1c in 26. I. Bancos, J. Hazeldine, V. Chortis, P. Hampson, A.E. Taylor, J. patients with primary and secondary adrenal insufficiency. Eur. J. M. Lord, W. Arlt, Primary adrenal insufficiency is associated with Endocrinol. 172(5), 619–626 (2015). https://doi.org/10.1530/EJE- impaired natural killer cell function: a potential link to increased 14-1114 mortality. Eur. J. Endocrinol. 176(4), 471–480 (2017). https://doi. 38. P.M. Stewart, Modified-Release Hydrocortisone: Is It Time to org/10.1530/EJE-16-0969 Change Clinical Practice? J. Endocr. Soc. 3(6), 1150–1153 27. G. Johannsson, A. Falorni, S. Skrtic, H. Lennernas, M. Quinkler, (2019). https://doi.org/10.1210/js.2019-00046 J.P. Monson, P.M. Stewart, Adrenal insufficiency: review of 39. G. Johannsson, S. Skrtic, H. Lennernas, M. Quinkler, P.M. Stewart, clinical outcomes with current glucocorticoid replacement ther- Improving outcomes in patients with adrenal insufficiency: a review apy. Clin. Endocrinol. (Oxf.) 82(1), 2–11 (2015). https://doi.org/ of current and future treatments. Curr. Med Res Opin. 30(9), 10.1111/cen.12603 1833–1847 (2014). https://doi.org/10.1185/03007995.2014.925865 28. H. Falhammar, L. Frisen, A.L. Hirschberg, C. Norrby, C. Almq- 40. M. Whitaker, M. Debono, H. Huatan, D. Merke, W. Arlt, R.J. vist, A. Nordenskjold, A. Nordenstrom, Increased cardiovascular Ross, An oral multiparticulate, modified-release, hydrocortisone and metabolic morbidity in patients with 21-hydroxylase defi- replacement therapy that provides physiological cortisol exposure. ciency: A Swedish Population-Based National Cohort Study. J. Clin. Endocrinol. (Oxf.) 80(4), 554–561 (2014). https://doi.org/10. Clin. Endocrinol. Metab. 100(9), 3520–3528 (2015). https://doi. 1111/cen.12316 org/10.1210/JC.2015-2093 41. D.P. Merke, R.J. Auchus, Congenital adrenal hyperplasia due to 29. F. Dalin, G. Nordling Eriksson, P. Dahlqvist, A. Hallgren, J. 21-hydroxylase deficiency. N. Engl. J. Med 383(13), 1248–1261 Wahlberg, O. Ekwall, S. Soderberg, J. Ronnelid, P. Olcen, O. (2020). https://doi.org/10.1056/NEJMra1909786 Winqvist, S.B. Catrina, B. Kristrom, M. Laudius, M. Isaksson, 42. D. Merke, A. Mallappa, W. Arlt, A. Brac de la Perriere, A.L. M. Halldin Stenlid, J. Gustafsson, G. Gebre-Medhin, S. Bjornsdottir, Hirschberg, A. Juul, J. Newell-Price, C.G. Perry, A. Prete, A. A. Janson, A.K. Akerman, J. Aman, K. Duchen, R. Bergthorsdottir, Rees, N. Reisch, M. Stikkelbroeck, P. Touraine, K. Maltby, P. G. Johannsson, E. Lindskog, M. Landin-Olsson, M. Elfving, E. Treasure, J. Porter, R.J. Ross, A phase 3 study of a modified- Waldenstrom, A.L. Hulting, O. Kampe, S. Bensing, Clinical and release hydrocortisone in the treamtment of congenital adrenal immunological characteristics of autoimmune addison disease: a hyperplasia. J. Endocrine Soc. 4 (2020). https://doi.org/10.1210/ Nationwide Swedish Multicenter Study. J. Clin. Endocrinol. Metab. jendso/bvaa046 102(2), 379–389 (2017). https://doi.org/10.1210/jc.2016-2522 43. A. Mallappa, A.A. Nella, N. Sinaii, H. Rao, V. Gounden, A.F. 30. J. Skov, A. Sundstrom, J.F. Ludvigsson, O. Kampe, S. Bensing, Perritt, P. Kumar, A. Ling, C.Y. Liu, S.J. Soldin, D.P. Merke, Sex-Specific risk of cardiovascular disease in autoimmune addison Long-term use of continuous subcutaneous hydrocortisone infu- disease-a population-based cohort study. J. Clin. Endocrinol. Metab. sion therapy in patients with congenital adrenal hyperplasia. Clin. 104(6), 2031–2040 (2019). https://doi.org/10.1210/jc.2018-02298 Endocrinol. (Oxf.) 89(4), 399–407 (2018). https://doi.org/10. 31. T.M.M. Rönneberg,, The circadian clock and human health. Curr. 1111/cen.13813 Biol. 26, R432–443 (2016). https://doi.org/10.1016/j.cub.2016.04. 44. M. Oksnes, S. Bjornsdottir, M. Isaksson, P. Methlie, S. Carlsen, 011 R.M. Nilsen, J.E. Broman, K. Triebner, O. Kampe, A.L. Hulting, 32. C.D. Andela, S.M. Staufenbiel, S.D. Joustra, A.M. Pereira, E.F. S. Bensing, E.S. Husebye, K. Lovas, Continuous subcutaneous van Rossum, N.R. Biermasz, Quality of life in patients with hydrocortisone infusion versus oral hydrocortisone replacement adrenal insufficiency correlates stronger with hydrocortisone for treatment of addison’s disease: a randomized clinical trial. J. dosage, than with long-term systemic cortisol levels. Psycho- Clin. Endocrinol. Metab. 99(5), 1665–1674 (2014). https://doi. neuroendocrinology 72, 80–86 (2016). https://doi.org/10.1016/j. org/10.1210/jc.2013-4253 psyneuen.2016.06.015 45. L. Gagliardi, M.A. Nenke, T.R. Thynne, J. von der Borch, W.A. 33. G. Johannsson, R. Bergthorsdottir, A.G. Nilsson, H. Lennernas, T. Rankin, D.E. Henley, J. Sorbello, W.J. Inder, D.J. Torpy, Con- Hedner, S. Skrtic, Improving glucocorticoid replacement therapy tinuous subcutaneous hydrocortisone infusion therapy in Addi- using a novel modified-release hydrocortisone tablet: a pharma- son’s disease: a randomized, placebo-controlled clinical trial. J. cokinetic study. Eur. J. Endocrinol. 161(1), 119–130 (2009). Clin. Endocrinol. Metab. 99(11), 4149–4157 (2014). https://doi. https://doi.org/10.1530/EJE-09-0170 org/10.1210/jc.2014-2433 Endocrine 46. U. Neumann, D. Burau, S. Spielmann, M.J. Whitaker, R.J. Ross, Eur. J. Endocrinol. 169(2), 147–154 (2013). https://doi.org/10. C. Kloft, O. Blankenstein, Quality of compounded hydrocortisone 1530/EJE-12-1057 capsules used in the treatment of children. Eur. J. Endocrinol. 177 59. S. Hahner, C. Spinnler, M. Fassnacht, S. Burger-Stritt, K. Lang, (2), 239–242 (2017). https://doi.org/10.1530/EJE-17-0248 D. Milovanovic, F. Beuschlein, H.S. Willenberg, M. Quinkler, B. 47. U. Neumann, K. Braune, M.J. Whitaker, S. Wiegand, H. Krude, J. Allolio, High incidence of adrenal crisis in educated patients with Porter, D. Digweed., B. Voet, R.J.M. Ross, O. Blankenstein, A chronic adrenal insufficiency: a prospective study. J. Clin. Endo- prospective study of children 0-7 years with cah and adrenal crinol. Metab. 100(2), 407–416 (2015). https://doi.org/10.1210/jc. insufficiency treated with hydrocortisone granules. J. Clin. Endo- 2014-3191 crinol. Metab. (2020). https://doi.org/10.1210/clinem/dgaa626 60. W. Arlt; Society for Endocrinology Clinical, C., Society for 48. B. Allolio, Extensive expertise in endocrinology. Adrenal Crisis endocrinology endocrine emergency guidance: emergency man- Eur. J. Endocrinol. 172(3), R115–124 (2015). https://doi.org/10. agement of acute adrenal insufficiency (adrenal crisis) in adult 1530/EJE-14-0824 patients. Endocr. Connect 5(5), G1–G3 (2016). https://doi.org/10. 49. R.L. Rushworth, D.J. Torpy, H. Falhammar, Adrenal crisis. N. 1530/EC-16-0054 Engl. J. Med. 381(9), 852–861 (2019). https://doi.org/10.1056/ 61. P.S. Esperon, [Hyponatremic coma as a manifestation of Addisons NEJMra1807486 disease]. J. Pediatr. (Rio J.) 77(4), 337–342 (2001). https://doi.org/ 50. R.L. Rushworth, D.J. Torpy, H. Falhammar, Adrenal crises in 10.2223/jped.244 older patients. Lancet Diabetes Endocrinol. 8(7), 628–639 (2020). 62. M. Sherlock, N.J. Gittoes, W. Arlt, Adrenal crisis causing critical https://doi.org/10.1016/S2213-8587(20)30122-4 illness related reversible myocardial dysfunction. Clin. Endocri- 51. S.R. Ali, J. Bryce, H. Haghpanahan, J.D. Lewsey, L.E. Tan, N. nol. (Oxf.) 68(4), 667–669 (2008). https://doi.org/10.1111/j.1365- Atapattu, N.H. Birkebaek, O. Blankenstein, U. Neumann, A. 2265.2007.03061.x Balsamo, R. Ortolano, W. Bonfig, H.L. Claahsen-van der Grinten, 63. A. Afzal, F. Khaja, Reversible cardiomyopathy associated with M. Cools, E.C. Costa, F. Darendeliler, S. Poyrazoglu, H. Elsedfy, Addison’s disease. Can. J. Cardiol. 16(3), 377–379 (2000) M.J.J. Finken, C.E. Fluck, E. Gevers, M. Korbonits, G. Guaragna- 64. B. Allolio, K. Lang, S. Hahner, Addisonian crisis in a young man Filho, T. Guran, A. Guven, S.E. Hannema, C. Higham, I.A. with atypical anorexia nervosa. Nat. Rev. Endocrinol. 7(2), Hughes, R. Tadokoro-Cuccaro, A. Thankamony, V. Iotova, N.P. 115–121 (2011). https://doi.org/10.1038/nrendo.2010.211 Krone, R. Krone, C. Lichiardopol, A. Luczay, B.B. Mendonca, T. 65. N. Reisch, M. Willige, D. Kohn, H.P. Schwarz, B. Allolio, M. Bachega, M.C. Miranda, T. Milenkovic, K. Mohnike, A. Nor- Reincke, M. Quinkler, S. Hahner, F. Beuschlein, Frequency and denstrom, S. Einaudi, H. van der Kamp, A. Vieites, L. de Vries, R. causes of adrenal crises over lifetime in patients with 21- J.M. Ross, S.F. Ahmed, Real world estimates of adrenal insuffi- hydroxylase deficiency. Eur. J. Endocrinol. 167(1), 35–42 ciency related adverse events in children with congenital adrenal (2012). https://doi.org/10.1530/EJE-12-0161 hyperplasia. J. Clin. Endocrinol. Metab. (2020). https://doi.org/10. 66. H.M. Elasha, F. Anjum, M.H. Almalki, A young man with a dizzy 1210/clinem/dgaa694 spell and acute abdominal pain. Clin. Med (Lond.) 13(5), 520–521 52. W. Arlt, S.E. Baldeweg, S.H.S. Pearce, H.L. Simpson, Endocri- (2013). https://doi.org/10.7861/clinmedicine.13-5-520 nology in the time of covid-19: management of adrenal insuffi- 67. S. Hahner, M. Loeffler, B. Bleicken, C. Drechsler, D. Milova- ciency. Eur. J. Endocrinol. 183(1), G25–G32 (2020). https://doi. novic, M. Fassnacht, M. Ventz, M. Quinkler, B. Allolio, Epide- org/10.1530/EJE-20-0361 miology of adrenal crisis in chronic adrenal insufficiency: the need 53. A.M. Isidori, G. Arnaldi, M. Boscaro, A. Falorni, C. Giordano, R. for new prevention strategies. Eur. J. Endocrinol. 162(3), 597–602 Giordano, R. Pivonello, R. Pofi, V. Hasenmajer, M.A. Venneri, E. (2010). https://doi.org/10.1530/EJE-09-0884 Sbardella, C. Simeoli, C. Scaroni, A. Lenzi, COVID-19 infection 68. T. Woodcock, P. Barker, S. Daniel, S. Fletcher, J.A.H. Wass, J.W. and glucocorticoids: update from the Italian Society of Endocri- Tomlinson, U. Misra, M. Dattani, W. Arlt, A. Vercueil, Guide- nology Expert Opinion on steroid replacement in adrenal insuf- lines for the management of glucocorticoids during the peri- ficiency. J Endocrinol Invest (2020). https://doi.org/10.1007/ operative period for patients with adrenal insufficiency: Guide- s40618-020-01266-w lines from the Association of Anaesthetists, the Royal College of 54. A.M. Isidori, R. Pofi, V. Hasenmajer, A. Lenzi, R. Pivonello, Use Physicians and the Society for Endocrinology UK. Anaesthesia of glucocorticoids in patients with adrenal insufficiency and (2020). https://doi.org/10.1111/anae.14963 COVID-19 infection. Lancet Diabetes Endocrinol. 8(6), 472–473 69. C. Cortet, P. Barat, D. Zenaty, L. Guignat, P. Chanson, Group 5: (2020). https://doi.org/10.1016/S2213-8587(20)30149-2 Acute adrenal insufficiency in adults and pediatric patients. Ann. 55. S. Burger-Stritt, A. Eff, M. Quinkler, T. Kienitz, B. Stamm, H.S. Endocrinol. (Paris) 78(6), 535–543 (2017). https://doi.org/10. Willenberg, G. Meyer, J. Klein, N. Reisch, M. Droste, S. Hahner, 1016/j.ando.2017.10.008 Standardised patient education in adrenal insufficiency: a pro- 70. B.S. Miller, S.P. Spencer, M.E. Geffner, E. Gourgari, A. Lahoti, spective multi-centre evaluation. Eur. J. Endocrinol. 183(2), M.K. Kamboj, T.L. Stanley, N.K. Uli, B.A. Wicklow, K. Sar- 119–127 (2020). https://doi.org/10.1530/EJE-20-0181 afoglou, Emergency management of adrenal insufficiency in 56. S. Burger-Stritt, P. Kardonski, A. Pulzer, G. Meyer, M. Quinkler, S. children: advocating for treatment options in outpatient and field Hahner, Management of adrenal emergencies in educated patients settings. J. Investig. Med. 68(1), 16–25 (2020). https://doi.org/10. with adrenal insufficiency-A prospective study. Clin. Endocrinol. 1136/jim-2019-000999 (Oxf.) 89(1), 22–29 (2018). https://doi.org/10.1111/cen.13608 71. D.A. Nickels, D.C. Moore, Serum cortisol responses in febrile 57. M. Quinkler, P. Dahlqvist, E.S. Husebye, O. Kampe, A European children. Pediatr. Infect. Dis. J. 8(1), 16–20 (1989). https://doi.org/ Emergency Card for adrenal insufficiency can save lives. Eur. J. 10.1097/00006454-198901000-00005 Intern Med 26(1), 75–76 (2015). https://doi.org/10.1016/j.ejim. 72. E.A. Webb, N. Krone, Current and novel approaches to children 2014.11.006 and young people with congenital adrenal hyperplasia and adrenal 58. S. Hahner, S. Burger-Stritt, B. Allolio, Subcutaneous hydro- insufficiency. Best. Pr. Res Clin. Endocrinol. Metab. 29(3), cortisone administration for emergency use in adrenal insufficiency. 449–468 (2015). https://doi.org/10.1016/j.beem.2015.04.002