Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Iatrogenic adrenal insufficiency in adults

Nature Reviews Endocrinology volume 20, pages 209–227 (2024)Cite this article

Subjects

Abstract

Iatrogenic adrenal insufficiency (IAI) is the most common form of adrenal insufficiency in adult patients, although its overall exact prevalence remains unclear. IAI is associated with adverse clinical outcomes, including adrenal crisis, impaired quality of life and increased mortality; therefore, it is imperative that clinicians maintain a high index of suspicion in patients at risk of IAI to facilitate timely diagnosis and appropriate management. Herein, we review the major causes, clinical consequences, diagnosis and care of patients with IAI. The management of IAI, particularly glucocorticoid-induced (or tertiary) adrenal insufficiency, can be particularly challenging, and the provision of adequate glucocorticoid replacement must be balanced against minimizing the cardiometabolic effects of excess glucocorticoid exposure and optimizing recovery of the hypothalamic–pituitary–adrenal axis. We review current treatment strategies and their limitations and discuss developments in optimizing treatment of IAI. This comprehensive Review aims to aid clinicians in identifying who is at risk of IAI, how to approach screening of at-risk populations and how to treat patients with IAI, with a focus on emergency management and prevention of an adrenal crisis.

Key points

  • Iatrogenic adrenal insufficiency (IAI) is the most common cause of adrenal insufficiency. Exogenous glucocorticoid use is a major contributor to IAI, which can occur even with the use of relatively low doses of glucocorticoids.

  • Patients with glucocorticoid-induced adrenal insufficiency are at risk of concomitant Cushing syndrome and vice versa.

  • Patients with cancer are particularly at risk of adrenal insufficiency in the setting of radiation exposure, immune-checkpoint inhibitor therapy, opioid analgesia and glucocorticoid use. Clinical suspicion and input from clinical endocrinologists are vital for this vulnerable group of patients.

  • If adrenal insufficiency is suspected in an acutely unwell patient, emergency glucocorticoid treatment should be initiated without delay. A diagnosis can be confirmed once the patient is stabilized.

  • Prevention of adrenal crisis and patient education is a vital part of the management of adrenal insufficiency. All patients with confirmed adrenal insufficiency or at high risk of adrenal insufficiency should be educated on the steroid ‘sick day rules’ and should carry a steroid emergency card.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Hypothalamic–pituitary–adrenal axis.
Fig. 2: Suggested diagnostic algorithm for iatrogenic adrenal insufficiency.

Similar content being viewed by others

References

  1. Arlt, W. & Allolio, B. Adrenal insufficiency. Lancet 361, 1881–1893 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Bornstein, S. R. Predisposing factors for adrenal insufficiency. N. Engl. J. Med. 360, 2328–2339 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Björnsdottir, S. et al. Drug prescription patterns in patients with Addison’s disease: a Swedish population-based cohort study. J. Clin. Endocrinol. Metab. 98, 2009–2018 (2013).

    Article  PubMed  Google Scholar 

  4. Erichsen, M. M. et al. Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. J. Clin. Endocrinol. Metab. 94, 4882–4890 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Olafsson, A. S. & Sigurjonsdottir, H. A. Increasing prevalence of Addison disease: results from a nationwide study. Endocr. Pract. 22, 30–35 (2016).

    Article  PubMed  Google Scholar 

  6. Regal, M., Páramo, C., Sierra, J. M. & García-Mayor, R. V. Prevalence and incidence of hypopituitarism in an adult Caucasian population in northwestern Spain. Clin. Endocrinol. 55, 735–740 (2001).

    Article  CAS  Google Scholar 

  7. Bancos, I., Hahner, S., Tomlinson, J. & Arlt, W. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol. 3, 216–226 (2015).

    Article  PubMed  Google Scholar 

  8. Hannon, A. M. et al. Clinical features and autoimmune associations in patients presenting with idiopathic isolated ACTH deficiency. Clin. Endocrinol. 88, 491–497 (2018).

    Article  CAS  Google Scholar 

  9. Martin-Grace, J., Dineen, R., Sherlock, M. & Thompson, C. J. Adrenal insufficiency: physiology, clinical presentation and diagnostic challenges. Clin. Chim. Acta 505, 78–91 (2020).

    Article  CAS  PubMed  Google Scholar 

  10. Raff, H., Sharma, S. T. & Nieman, L. K. Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Compr. Physiol. 4, 739–769 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Crowley, R. K., Argese, N., Tomlinson, J. W. & Stewart, P. M. Central hypoadrenalism. J. Clin. Endocrinol. Metab. 99, 4027–4036 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Arlt, W., Society for Endocrinology Clinical Committee. SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients. Endocr. Connect. 5, G1–G3 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hahner, S. et al. Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. Eur. J. Endocrinol. 162, 597–602 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Ho, W. & Druce, M. Quality of life in patients with adrenal disease: a systematic review. Clin. Endocrinol. 89, 119–128 (2018).

    Article  Google Scholar 

  15. Aulinas, A. & Webb, S. M. Health-related quality of life in primary and secondary adrenal insufficiency. Expert Rev. Pharmacoecon. Outcomes Res. 14, 873–888 (2014).

    Article  PubMed  Google Scholar 

  16. Løvås, K., Loge, J. H. & Husebye, E. S. Subjective health status in Norwegian patients with Addison’s disease. Clin. Endocrinol. 56, 581–588 (2002).

    Article  Google Scholar 

  17. Hahner, S. et al. Impaired subjective health status in 256 patients with adrenal insufficiency on standard therapy based on cross-sectional analysis. J. Clin. Endocrinol. Metab. 92, 3912–3922 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Li, D. et al. Determinants of self-reported health outcomes in adrenal insufficiency: a multisite survey study. J. Clin. Endocrinol. Metab. 106, e1408–e1419 (2021).

    Article  PubMed  Google Scholar 

  19. Sherlock, M. et al. ACTH deficiency, higher doses of hydrocortisone replacement, and radiotherapy are independent predictors of mortality in patients with acromegaly. J. Clin. Endocrinol. Metab. 94, 4216–4223 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. O’Reilly, M. W. et al. ACTH and gonadotropin deficiencies predict mortality in patients treated for nonfunctioning pituitary adenoma: long-term follow-up of 519 patients in two large European centres. Clin. Endocrinol. 85, 748–756 (2016).

    Article  Google Scholar 

  21. Burman, P. et al. Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality. J. Clin. Endocrinol. Metab. 98, 1466–1475 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Mebrahtu, T. F. et al. Dose dependency of iatrogenic glucocorticoid excess and adrenal insufficiency and mortality: a cohort study in England. J. Clin. Endocrinol. Metab. 104, 3757–3767 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Bergthorsdottir, R., Leonsson-Zachrisson, M., Oden, A. & Johannsson, G. Premature mortality in patients with Addison’s disease: a population-based study. J. Clin. Endocrinol. Metab. 91, 4849–4853 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Rushworth, R. L. & Torpy, D. J. The changing epidemiology of adrenal insufficiency: iatrogenic factors predominate. J. Endocr. Soc. 7, bvad017 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Aguilera, G., Kiss, A., Liu, Y. & Kamitakahara, A. Negative regulation of corticotropin releasing factor expression and limitation of stress response. Stress 10, 153–161 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Husebye, E. S., Pearce, S. H., Krone, N. P. & Kämpe, O. Adrenal insufficiency. Lancet 397, 613–629 (2021).

    Article  CAS  PubMed  Google Scholar 

  27. Rhodes, M. E. In: Stress: Neuroendocrinology and Neurobiology (ed. Fink, G.) 109-116 (Academic Press, 2017).

  28. Saito, T. et al. Vasopressin-dependent upregulation of aquaporin-2 gene expression in glucocorticoid-deficient rats. Am. J. Physiol. Ren. Physiol. 279, F502–508 (2000).

    Article  CAS  ADS  Google Scholar 

  29. Sævik, Å. B. et al. Clues for early detection of autoimmune Addison’s disease – myths and realities. J. Intern. Med. 283, 190–199 (2018).

    Article  PubMed  Google Scholar 

  30. Taïeb, D. et al. European Association of Nuclear Medicine practice guideline/Society of Nuclear Medicine and Molecular Imaging procedure standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur. J. Nucl. Med. Mol. Imaging 46, 2112–2137 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Verbalis, J. G. et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am. J. Med. 126, S1–42 (2013).

    Article  PubMed  Google Scholar 

  32. Spasovski, G. et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur. J. Endocrinol. 170, G1–47 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Li, D. et al. Quality of life and its determinants in patients with adrenal insufficiency: a survey study at three centers in the USA. J. Clin. Endocrinol. Metab. 107, e2851–e2861 (2022).

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  34. Stewart, P. M. et al. Exploring inpatient hospitalizations and morbidity in patients with adrenal insufficiency. J. Clin. Endocrinol. Metab. 101, 4843–4850 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Han, H.-S. et al. A pilot study of adrenal suppression after dexamethasone therapy as an antiemetic in cancer patients. Support. Care Cancer 20, 1565–1572 (2012).

    Article  PubMed  Google Scholar 

  36. Li, T., Donegan, D., Hooten, W. M. & Bancos, I. Clinical presentation and outcomes of opioid-induced adrenal insufficiency. Endocr. Pract. 26, 1291–1297 (2020).

    Article  PubMed  Google Scholar 

  37. Dineen, R., Thompson, C. J. & Sherlock, M. Adrenal crisis: prevention and management in adult patients. Ther. Adv. Endocrinol. Metab. 10, 2042018819848218 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hahner, S. et al. High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. J. Clin. Endocrinol. Metab. 100, 407–416 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Allolio, B. Extensive expertise in endocrinology. Adrenal crisis. Eur. J. Endocrinol. 172, R115–124 (2015).

    Article  CAS  PubMed  Google Scholar 

  40. Smans, L. C. C. J., Van der Valk, E. S., Hermus, A. R. M. M. & Zelissen, P. M. J. Incidence of adrenal crisis in patients with adrenal insufficiency. Clin. Endocrinol. 84, 17–22 (2016).

    Article  CAS  Google Scholar 

  41. Erichsen, M. M. et al. Normal overall mortality rate in Addison’s disease, but young patients are at risk of premature death. Eur. J. Endocrinol. 160, 233–237 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Quinkler, M., Ekman, B., Zhang, P., Isidori, A. M. & Murray, R. D. Mortality data from the European Adrenal Insufficiency Registry — patient characterization and associations. Clin. Endocrinol. 89, 30–35 (2018).

    Article  CAS  Google Scholar 

  43. Todd, G. R. G. Adrenal crisis due to inhaled steroids is underestimated. Arch. Dis. Child. 88, 554–555 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Todd, G. R. G. et al. Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch. Dis. Child. 87, 457–461 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fraser, C. G., Preuss, F. S. & Bigford, W. D. Adrenal atrophy and irreversible shock associated with cortisone therapy. J. Am. Med. Assoc. 149, 1542–1543 (1952).

    Article  CAS  PubMed  Google Scholar 

  46. Oltmanns, K. M., Fehm, H. L. & Peters, A. Chronic fentanyl application induces adrenocortical insufficiency. J. Intern. Med. 257, 478–480 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Wright, J. J. & Johnson, D. B. Approach to the patient with immune checkpoint inhibitor-associated endocrine dysfunction. J. Clin. Endocrinol. Metab. 108, 1514–1525 (2022).

    Article  PubMed Central  Google Scholar 

  48. Mizukoshi, T., Fukuoka, H. & Takahashi, Y. Immune checkpoint inhibitor-related hypophysitis. Best Pract. Res. Clin. Endocrinol. Metab. 36, 101668 (2022).

    Article  CAS  PubMed  Google Scholar 

  49. Oßwald, A. et al. Favorable long-term outcomes of bilateral adrenalectomy in Cushing’s disease. Eur. J. Endocrinol. 171, 209–215 (2014).

    Article  PubMed  Google Scholar 

  50. Ritzel, K. et al. Outcome of bilateral adrenalectomy in Cushing’s syndrome: a systematic review. J. Clin. Endocrinol. Metab. 98, 3939–3948 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Quinkler, M. et al. Characterization of patients with adrenal insufficiency and frequent adrenal crises. Eur. J. Endocrinol. 184, 761–771 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Driessens, N. et al. PAI-BEL: a Belgian multicentre survey of primary adrenal insufficiency. Endocr. Connect. 12, e230044 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Cuesta, M. et al. The contribution of undiagnosed adrenal insufficiency to euvolaemic hyponatraemia: results of a large prospective single-centre study. Clin. Endocrinol. 85, 836–844 (2016).

    Article  CAS  Google Scholar 

  54. Laugesen, K., Petersen, I., Sørensen, H. T. & Jørgensen, J. O. L. Clinical indicators of adrenal insufficiency following discontinuation of oral glucocorticoid therapy: a Danish population-based self-controlled case series analysis. PLoS One 14, e0212259 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bleecker, E. R. et al. Systematic literature review of systemic corticosteroid use for asthma management. Am. J. Respir. Crit. Care Med. 201, 276–293 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Bloechliger, M. et al. Adverse events profile of oral corticosteroids among asthma patients in the UK: cohort study with a nested case-control analysis. Respir. Res. 19, 75 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Sarnes, E. et al. Incidence and US costs of corticosteroid-associated adverse events: a systematic literature review. Clin. Ther. 33, 1413–1432 (2011).

    Article  PubMed  Google Scholar 

  58. Savas, M. et al. Associations between systemic and local corticosteroid use with metabolic syndrome and body mass index. J. Clin. Endocrinol. Metab. 102, 3765–3774 (2017).

    Article  PubMed  Google Scholar 

  59. Souverein, P. C. et al. Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case–control study. Heart 90, 859–865 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wei, L., MacDonald, T. M. & Walker, B. R. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann. Intern. Med. 141, 764–770 (2004).

    Article  PubMed  Google Scholar 

  61. Prete, A. & Bancos, I. Glucocorticoid induced adrenal insufficiency. BMJ 374, n1380 (2021).

    Article  PubMed  Google Scholar 

  62. Filipsson, H., Monson, J. P., Koltowska-Häggström, M., Mattsson, A. & Johannsson, G. The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. J. Clin. Endocrinol. Metab. 91, 3954–3961 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Sherlock, M. et al. Adrenal incidentaloma. Endocr. Rev. 41, 775–820 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Di Dalmazi, G., Berr, C. M., Fassnacht, M., Beuschlein, F. & Reincke, M. Adrenal function after adrenalectomy for subclinical hypercortisolism and Cushing’s syndrome: a systematic review of the literature. J. Clin. Endocrinol. Metab. 99, 2637–2645 (2014).

    Article  PubMed  Google Scholar 

  65. Fassnacht, M. et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur. J. Endocrinol. 175, G1–G34 (2016).

    Article  CAS  PubMed  Google Scholar 

  66. Arlt, W. et al. Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism. JCI Insight 2, e93196 (2017).

    Article  Google Scholar 

  67. Heinrich, D. A. et al. Adrenal insufficiency after unilateral adrenalectomy in primary aldosteronism: long-term outcome and clinical impact. J. Clin. Endocrinol. Metab. 104, 5658–5664 (2019).

    Article  PubMed  Google Scholar 

  68. Fleseriu, M. et al. Hormonal replacement in hypopituitarism in adults: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 101, 3888–3921 (2016).

    Article  CAS  PubMed  Google Scholar 

  69. Arafah, B. M. Reversible hypopituitarism in patients with large nonfunctioning pituitary adenomas. J. Clin. Endocrinol. Metab. 62, 1173–1179 (1986).

    Article  CAS  PubMed  Google Scholar 

  70. Al-Shamkhi, N. et al. Pituitary function before and after surgery for nonfunctioning pituitary adenomas — data from the Swedish Pituitary Register. Eur. J. Endocrinol. 189, 217–224 (2023).

    Article  PubMed  Google Scholar 

  71. Araujo-Castro, M., Mariño-Sánchez, F., García Fernández, A., Acitores Cancela, A. & Rodríguez Berrocal, V. Endoscopic endonasal approach to pituitary adenomas: impact on adenohypophyseal function. Study of 231 cases. Neurocirugia 33, 300–309 (2022).

    Article  Google Scholar 

  72. Staby, I. et al. Pituitary function after transsphenoidal surgery including measurement of basal morning cortisol as predictor of adrenal insufficiency. Endocr. Connect. 10, 750–757 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Nys, C. et al. Transnasal transsphenoidal pituitary surgery in a large tertiary hospital, a retrospective study. Acta Chir. Belg. 123, 272–280 (2021).

    Article  PubMed  Google Scholar 

  74. Prete, A., Corsello, S. M. & Salvatori, R. Current best practice in the management of patients after pituitary surgery. Ther. Adv. Endocrinol. Metab. 8, 33–48 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Ciric, I., Ragin, A., Baumgartner, C. & Pierce, D. Complications of transsphenoidal surgery: results of a national survey, review of the literature, and personal experience. Neurosurgery 40, 225–236 (1997).

    Article  CAS  PubMed  Google Scholar 

  76. Zamanipoor Najafabadi, A. H. et al. Starting point for benchmarking outcomes and reporting of pituitary adenoma surgery within the European Reference Network on Rare Endocrine Conditions (Endo-ERN): results from a meta-analysis and survey study. Endocr. Connect. 12, e220349 (2023).

    Article  PubMed  Google Scholar 

  77. Castle-Kirszbaum, M., Wang, Y. Y., King, J., Kam, J. & Goldschlager, T. Quality of life and surgical outcomes in incidental pituitary adenomas undergoing endoscopic endonasal resection. J. Neurosurg. 138, 567–573 (2023).

    Article  PubMed  Google Scholar 

  78. Tohti, M. et al. Is peri-operative steroid replacement therapy necessary for the pituitary adenomas treated with surgery? A systematic review and meta analysis. PLoS One 10, e0119621 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  79. O’Sullivan, E. P. et al. The natural history of surgically treated but radiotherapy-naive nonfunctioning pituitary adenomas. Clin. Endocrinol. 71, 709–714 (2009).

    Article  Google Scholar 

  80. Karavitaki, N. et al. Craniopharyngiomas in children and adults: systematic analysis of 121 cases with long-term follow-up. Clin. Endocrinol. 62, 397–409 (2005).

    Article  CAS  Google Scholar 

  81. Crowley, R. K. et al. Morbidity and mortality in patients with craniopharyngioma after surgery. Clin. Endocrinol. 73, 516–521 (2010).

    Article  CAS  Google Scholar 

  82. Yu, S. et al. Evolution of surgical outcomes in endoscopic endonasal resection of craniopharyngiomas. J. Neurol. Surg. Part. B Skull Base 84, 375–383 (2023).

    Article  Google Scholar 

  83. Jung, T. Y. et al. Adult craniopharyngiomas: surgical results with a special focus on endocrinological outcomes and recurrence according to pituitary stalk preservation. J. Neurosurg. 111, 572–577 (2009).

    Article  PubMed  Google Scholar 

  84. Ordóñez-Rubiano, E. G. et al. Preserve or sacrifice the stalk? Endocrinological outcomes, extent of resection, and recurrence rates following endoscopic endonasal resection of craniopharyngiomas. J. Neurosurg. 131, 1163–1171 (2019).

    Article  Google Scholar 

  85. Marko, N. F. et al. Use of morning serum cortisol level after transsphenoidal resection of pituitary adenoma to predict the need for long-term glucocorticoid supplementation. J. Neurosurg. 111, 540–544 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Filipsson, H. & Johannsson, G. GH replacement in adults: interactions with other pituitary hormone deficiencies and replacement therapies. Eur. J. Endocrinol. 161, S85–S95 (2009).

    Article  CAS  PubMed  Google Scholar 

  87. Toogood, A. A., Taylor, N. F., Shalet, S. M. & Monson, J. P. Modulation of cortisol metabolism by low-dose growth hormone replacement in elderly hypopituitary patients. J. Clin. Endocrinol. Metab. 85, 1727–1730 (2000).

    CAS  PubMed  Google Scholar 

  88. Walker, B. R., Andrew, R., MacLeod, K. M. & Padfield, P. L. Growth hormone replacement inhibits renal and hepatic 11β-hydroxysteroid dehydrogenases in ACTH-deficient patients. Clin. Endocrinol. 49, 257–263 (1998).

    Article  CAS  Google Scholar 

  89. Stewart, P. M., Toogood, A. A. & Tomlinson, J. W. Growth hormone, insulin-like growth factor-I and the cortisol-cortisone shuttle. Horm. Res. 56, 1–6 (2001).

    CAS  PubMed  Google Scholar 

  90. Fonseca, V., Brown, R., Hochhauser, D., Ginsburg, J. & Havard, C. W. Acute adrenal crisis precipitated by thyroxine. Br. Med. J. 292, 1185–1186 (1986).

    Article  CAS  Google Scholar 

  91. Follin, C., Wiebe, T., Moëll, C. & Erfurth, E. M. Moderate dose cranial radiotherapy causes central adrenal insufficiency in long-term survivors of childhood leukaemia. Pituitary 17, 7–12 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. Appelman-Dijkstra, N. M. et al. Pituitary dysfunction in adult patients after cranial radiotherapy: systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 96, 2330–2340 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Appelman-Dijkstra, N. M. et al. Pituitary dysfunction in adult patients after cranial irradiation for head and nasopharyngeal tumours. Radiother. Oncol. 113, 102–107 (2014).

    Article  PubMed  Google Scholar 

  94. Castinetti, F. et al. Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. J. Clin. Endocrinol. Metab. 94, 3400–3407 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Agha, A. et al. Hypothalamic-pituitary dysfunction after irradiation of nonpituitary brain tumors in adults. J. Clin. Endocrinol. Metab. 90, 6355–6360 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Kyriakakis, N. et al. Pituitary dysfunction following cranial radiotherapy for adult-onset nonpituitary brain tumours. Clin. Endocrinol. 84, 372–379 (2016).

    Article  CAS  Google Scholar 

  97. Patterson, B. C., Truxillo, L., Wasilewski-Masker, K., Mertens, A. C. & Meacham, L. R. Adrenal function testing in pediatric cancer survivors. Pediatr. Blood Cancer 53, 1302–1307 (2009).

    Article  PubMed  Google Scholar 

  98. Crowne, E., Gleeson, H., Benghiat, H., Sanghera, P. & Toogood, A. Effect of cancer treatment on hypothalamic-pituitary function. Lancet Diabetes Endocrinol. 3, 568–576 (2015).

    Article  CAS  PubMed  Google Scholar 

  99. Graffeo, C. S. et al. Biological effective dose as a predictor of hypopituitarism after single-fraction pituitary adenoma radiosurgery: dosimetric analysis and cohort study of patients treated using contemporary techniques. Neurosurgery 88, E330–E335 (2021).

    Article  PubMed  Google Scholar 

  100. Schmiegelow, M. et al. Assessment of the hypothalamo-pituitary-adrenal axis in patients treated with radiotherapy and chemotherapy for childhood brain tumor. J. Clin. Endocrinol. Metab. 88, 3149–3154 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Sherlock, M. & Toogood, A. A. Sensitivity of anterior pituitary hormones to irradiation. Expert Rev. Endocrinol. Metab. 1, 633–649 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Kyriakakis, N. et al. Hypothalamic-pituitary axis irradiation dose thresholds for the development of hypopituitarism in adult-onset gliomas. Clin. Endocrinol. 91, 131–140 (2019).

    Article  CAS  Google Scholar 

  103. Darzy, K. H. & Shalet, S. M. Hypopituitarism as a consequence of brain tumours and radiotherapy. Pituitary 8, 203–211 (2005).

    Article  PubMed  Google Scholar 

  104. Ratnasingam, J. et al. Hypothalamic pituitary dysfunction amongst nasopharyngeal cancer survivors. Pituitary 18, 448–455 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Lam, K. S. L., Tse, V. K. C., Wang, C., Yeung, R. T. T. & Ho, J. H. C. Effects of cranial irradiation on hypothalamic-pituitary function — a 5-year longitudinal-study in patients with nasopharyngeal carcinoma. Q. J. Med. 78, 165–176 (1991).

    CAS  PubMed  Google Scholar 

  106. Pomeraniec, I. J. et al. Dose to neuroanatomical structures surrounding pituitary adenomas and the effect of stereotactic radiosurgery on neuroendocrine function: an international multicenter study. J. Neurosurg. 136, 813–821 (2022).

    Article  PubMed  Google Scholar 

  107. Palmisciano, P. et al. Endocrine disorders after primary gamma knife radiosurgery for pituitary adenomas: a systematic review and meta-analysis. Pituitary 25, 404–419 (2022).

    Article  CAS  PubMed  Google Scholar 

  108. Ironside, N. et al. Effect of distance from target on hypopituitarism after stereotactic radiosurgery for pituitary adenomas. J. Neurooncol. 158, 41–50 (2022).

    Article  CAS  PubMed  Google Scholar 

  109. Mathieu, D. et al. Stereotactic radiosurgery for secretory pituitary adenomas: systematic review and International Stereotactic Radiosurgery Society practice recommendations. J. Neurosurg. 136, 801–812 (2022).

    Article  CAS  PubMed  Google Scholar 

  110. Sims-Williams, H. P. et al. Long-term safety of gamma knife radiosurgery (SRS) for acromegaly. Pituitary 24, 724–736 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Abu Dabrh, A. M. et al. Radiotherapy versus radiosurgery in treating patients with acromegaly: a systematic review and meta-analysis. Endocr. Pract. 21, 943–956 (2015).

    Article  PubMed  Google Scholar 

  112. Keller-Wood, M. E. & Dallman, M. F. Corticosteroid inhibition of ACTH secretion. Endocr. Rev. 5, 1–24 (1984).

    Article  CAS  PubMed  Google Scholar 

  113. Ingle, D. J. & Kendall, E. C. Atrophy of the adrenal cortex of the rat produced by the administration of large amounts of cortin. Science 86, 245–245 (1937).

    Article  CAS  PubMed  ADS  Google Scholar 

  114. Broersen, L. H., Pereira, A. M., Jorgensen, J. O. & Dekkers, O. M. Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 100, 2171–2180 (2015).

    Article  CAS  PubMed  Google Scholar 

  115. Güven, A. Different potent glucocorticoids, different routes of exposure but the same result: iatrogenic Cushing’s syndrome and adrenal insufficiency. J. Clin. Res. Pediatr. Endocrinol. 12, 383–392 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Borresen, S. W. et al. Approach to the patient with glucocorticoid-induced adrenal insufficiency. J. Clin. Endocrinol. Metab. 24, 2065–2076 (2022).

    Article  Google Scholar 

  117. Hochberg, Z. E., Pacak, K. & Chrousos, G. P. Endocrine withdrawal syndromes. Endocr. Rev. 24, 523–538 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Zhang, C. D. et al. Glucocorticoid withdrawal syndrome following surgical remission of endogenous hypercortisolism: a longitudinal observational study. Eur. J. Endocrinol. 188, 592–602 (2023).

    PubMed  Google Scholar 

  119. Hurtado, M. D., Cortes, T., Natt, N., Young, W. F. Jr & Bancos, I. Extensive clinical experience: hypothalamic-pituitary-adrenal axis recovery after adrenalectomy for corticotropin-independent cortisol excess. Clin. Endocrinol. 89, 721–733 (2018).

    Article  CAS  Google Scholar 

  120. Laugesen, K. et al. Management of endocrine disease: glucocorticoid-induced adrenal insufficiency: replace while we wait for evidence? Eur. J. Endocrinol. 184, R111–R122 (2021).

    Article  CAS  PubMed  Google Scholar 

  121. Theiler-Schwetz, V. & Prete, A. Glucocorticoid withdrawal syndrome: what to expect and how to manage. Curr. Opin. Endocrinol. Diabetes Obes. 30, 167–174 (2023).

    Article  PubMed  Google Scholar 

  122. He, X., Findling, J. W. & Auchus, R. J. Glucocorticoid withdrawal syndrome following treatment of endogenous Cushing syndrome. Pituitary 25, 393–403 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Fardet, L., Petersen, I. & Nazareth, I. Prevalence of long-term oral glucocorticoid prescriptions in the UK over the past 20 years. Rheumatology 50, 1982–1990 (2011).

    Article  PubMed  Google Scholar 

  124. Overman, R. A., Yeh, J. Y. & Deal, C. L. Prevalence of oral glucocorticoid usage in the United States: a general population perspective. Arthritis Care Res. 65, 294–298 (2013).

    Article  Google Scholar 

  125. Gudbjornsson, B., Juliusson, U. I. & Gudjonsson, F. V. Prevalence of long term steroid treatment and the frequency of decision making to prevent steroid induced osteoporosis in daily clinical practice. Ann. Rheum. Dis. 61, 32–36 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. van Staa, T. P. et al. Use of oral corticosteroids in the United Kingdom. QJM 93, 105–111 (2000).

    Article  PubMed  Google Scholar 

  127. Bénard-Laribière, A. et al. Prevalence and prescription patterns of oral glucocorticoids in adults: a retrospective cross-sectional and cohort analysis in France. BMJ Open. 7, e015905 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Einarsdottir, M. J. et al. High prescription rate of oral glucocorticoids in children and adults: a retrospective cohort study from Western Sweden. Clin. Endocrinol. 92, 21–28 (2020).

    Article  Google Scholar 

  129. Derendorf, H., Nave, R., Drollmann, A., Cerasoli, F. & Wurst, W. Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma. Eur. Respir. J. 28, 1042–1050 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Joseph, R. M., Hunter, A. L., Ray, D. W. & Dixon, W. G. Systemic glucocorticoid therapy and adrenal insufficiency in adults: a systematic review. Semin. Arthritis Rheum. 46, 133–141 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Hawcutt, D. B. et al. Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study. Lancet Respir. Med. 6, 442–450 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Brennan, V. et al. The contribution of oral and inhaled glucocorticoids to adrenal insufficiency in asthma. J. Allergy Clin. Immunol. Pract. 46, 2614–2623 (2022).

    Article  Google Scholar 

  133. Kachroo, P. et al. Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma. Nat. Med. 28, 1723 (2022).

    Article  CAS  PubMed  Google Scholar 

  134. Simpson, H. L. & Erskine, D. Exogenous steroids treatment in adults. Adrenal insufficiency and adrenal crisis — who is at risk and how should they be managed safely. Society for Endocrinology https://www.endocrinology.org/media/4091/spssfe_supporting_sec_-final_10032021-1.pdf (2021).

  135. Simpson, H., Tomlinson, J., Wass, J., Dean, J. & Arlt, W. Guidance for the prevention and emergency management of adult patients with adrenal insufficiency. Clin. Med. 20, 371–378 (2020).

    Article  Google Scholar 

  136. Tomkins, M. et al. Adrenal insufficiency is common amongst kidney transplant recipients receiving maintenance prednisolone and can be predicted using morning cortisol. Nephrol. Dial. Transpl. 38, 236–245 (2022).

    Article  Google Scholar 

  137. Schlaghecke, R., Kornely, E., Santen, R. T. & Ridderskamp, P. The effect of long-term glucocorticoid therapy on pituitary–adrenal responses to exogenous corticotropin-releasing hormone. N. Engl. J. Med. 326, 226–230 (1992).

    Article  CAS  PubMed  Google Scholar 

  138. Dinsen, S. et al. Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself. Eur. J. Intern. Med. 24, 714–720 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. Skov, I. R. et al. Low-dose oral corticosteroids in asthma associates with increased morbidity and mortality. Eur. Respir. J. 60, 2103054 (2022).

    Article  PubMed  Google Scholar 

  140. Woods, C. P. et al. Adrenal suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be guided by morning cortisol. Eur. J. Endocrinol. 173, 633–642 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Daley-Yates, P. et al. Therapeutic index of inhaled corticosteroids in asthma: a dose-response comparison on airway hyperresponsiveness and adrenal axis suppression. Br. J. Clin. Pharmacol. 87, 483–493 (2020).

    Article  PubMed  Google Scholar 

  142. Lapi, F., Kezouh, A., Suissa, S. & Ernst, P. The use of inhaled corticosteroids and the risk of adrenal insufficiency. Eur. Respir. J. 42, 79–86 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Woodcock, T. et al. Guidelines for the management of glucocorticoids during the peri-operative period for patients with adrenal insufficiency: guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK. Anaesthesia 75, 654–663 (2020).

    Article  CAS  PubMed  Google Scholar 

  144. Wass, J., Simpson, H., Pearce, S. Arlt, W. Surgical Guidelines for Addison’s Disease and Other Forms of Adrenal Insufficiency https://www.addisonsdisease.org.uk/Handlers/Download.ashx?IDMF=26887766-029d-4728-9163-e4ce24eb34a7 (2021).

  145. Martin-Grace, J., Costello, R. W. & Sherlock, M. Corticosteroid suppression in patients receiving inhaled glucocorticoids: time to reassess risk? J. Clin. Endocrinol. Metab. 107, e4256–e4258 (2022).

    Article  PubMed  Google Scholar 

  146. Guaraldi, F. et al. Comparative assessment of hypothalamic-pituitary-adrenal axis suppression secondary to intrabursal injection of different glucocorticoids: a pilot study. J. Endocrinol. Invest. 42, 1117–1124 (2019).

    Article  CAS  PubMed  Google Scholar 

  147. Daley-Yates, P. T. & Baker, R. C. Systemic bioavailability of fluticasone propionate administered as nasal drops and aqueous nasal spray formulations. Br. J. Clin. Pharmacol. 51, 103–105 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Sastre, J. & Mosges, R. Local and systemic safety of intranasal corticosteroids. J. Investig. Allergol. Clin. Immunol. 22, 1–12 (2012).

    CAS  PubMed  Google Scholar 

  149. Schuetz, P. et al. Prospective analysis of adrenal function in patients with acute exacerbations of COPD: the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial. Eur. J. Endocrinol. 173, 19–27 (2015).

    Article  CAS  PubMed  Google Scholar 

  150. Henzen, C. et al. Suppression and recovery of adrenal response after short-term, high-dose glucocorticoid treatment. Lancet 355, 542–545 (2000).

    Article  CAS  PubMed  Google Scholar 

  151. Debono, M., Chan, S., Rolfe, C. & Jones, T. H. Tramadol-induced adrenal insufficiency. Eur. J. Clin. Pharmacol. 67, 865–867 (2011).

    Article  PubMed  Google Scholar 

  152. Abs, R. et al. Endocrine consequences of long-term intrathecal administration of opioids. J. Clin. Endocrinol. Metab. 85, 2215–2222 (2000).

    Article  CAS  PubMed  Google Scholar 

  153. Vescovi, P. P. et al. Metyrapone effects on β-endorphin, ACTH and cortisol levels after chronic opiate receptor stimulation in man. Neuropeptides 15, 129–132 (1990).

    Article  CAS  PubMed  Google Scholar 

  154. Facchinetti, F. et al. Hypothalamus-pituitary-adrenal axis of heroin addicts. Drug Acohol Depend. 15, 361–366 (1985).

    Article  CAS  Google Scholar 

  155. Valverde-Filho, J., da Cunha Neto, M. B., Fonoff, E. T., Meirelles Ede, S. & Teixeira, M. J. Chronic spinal and oral morphine-induced neuroendocrine and metabolic changes in noncancer pain patients. Pain Med. 16, 715–725 (2015).

    Article  PubMed  Google Scholar 

  156. Taylor, T., Dluhy, R. G. & Williams, G. H. β-Endorphin suppresses adrenocorticotropin and cortisol levels in normal human subjects. J. Clin. Endocrinol. Metab. 57, 592–596 (1983).

    Article  CAS  PubMed  Google Scholar 

  157. Palm, S., Moenig, H. & Maier, C. Effects of oral treatment with sustained release morphine tablets on hypothalamic-pituitary-adrenal axis. Methods Find. Exp. Clin. Pharmacol. 19, 269–273 (1997).

    CAS  PubMed  Google Scholar 

  158. Fountas, A., Van Uum, S. & Karavitaki, N. Opioid-induced endocrinopathies. Lancet Diabetes Endocrinol. 8, 68–80 (2020).

    Article  CAS  PubMed  Google Scholar 

  159. Glahn, A. et al. Atrial natriuretic peptide, arginine vasopressin peptide and cortisol serum levels in opiate-dependent patients. Neuropsychobiology 67, 111–115 (2013).

    Article  CAS  PubMed  Google Scholar 

  160. Daniell, H. W. DHEAS deficiency during consumption of sustained-action prescribed opioids: evidence for opioid-induced inhibition of adrenal androgen production. J. Pain 7, 901–907 (2006).

    Article  CAS  PubMed  Google Scholar 

  161. Facchinetti, F. et al. Impaired circadian rhythmicity of beta-lipotrophin, beta-endorphin and ACTH in heroin addicts. Acta Endocrinol. 105, 149–155 (1984).

    CAS  Google Scholar 

  162. Gadelha, M. R. et al. Opioids and pituitary function: expert opinion. Pituitary 25, 52–63 (2022).

    Article  PubMed  Google Scholar 

  163. Lamprecht, A., Sorbello, J., Jang, C., Torpy, D. J. & Inder, W. J. Secondary adrenal insufficiency and pituitary dysfunction in oral/transdermal opioid users with non-cancer pain. Eur. J. Endocrinol. 179, 353–362 (2018).

    Article  CAS  PubMed  Google Scholar 

  164. Donegan, D. Opioid induced adrenal insufficiency: what is new? Curr. Opin. Endocrinol. Diabetes Obes. 26, 133–138 (2019).

    Article  CAS  PubMed  Google Scholar 

  165. Li, T. et al. Prevalence of opioid-induced adrenal insufficiency in patients taking chronic opioids. J. Clin. Endocrinol. Metab. 105, e3766–3775 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Saeed, Z. I., Bancos, I. & Donegan, D. Current knowledge and practices of heath care professionals on opioid-induced adrenal insufficiency. Endocr. Pract. 25, 1012–1021 (2019).

    Article  PubMed  Google Scholar 

  167. de Vries, F. et al. Opioids and their endocrine effects: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 105, 1020–1029 (2020).

    Article  PubMed  Google Scholar 

  168. Nenke, M. A. et al. Low-dose hydrocortisone replacement improves wellbeing and pain tolerance in chronic pain patients with opioid-induced hypocortisolemic responses. A pilot randomized, placebo-controlled trial. Psychoneuroendocrinology 56, 157–167 (2015).

    Article  CAS  PubMed  Google Scholar 

  169. Gibb, F. W., Stewart, A., Walker, B. R. & Strachan, M. W. Adrenal insufficiency in patients on long-term opioid analgesia. Clin. Endocrinol. 85, 831–835 (2016).

    Article  CAS  Google Scholar 

  170. Shalaby, A. M., Aboregela, A. M., Alabiad, M. A. & El Shaer, D. F. Tramadol promotes oxidative stress, fibrosis, apoptosis, ultrastructural and biochemical alterations in the adrenal cortex of adult male rat with possible reversibility after withdrawal. Microsc. Microanal. 26, 509–523 (2020).

    Article  CAS  PubMed  ADS  Google Scholar 

  171. Müssig, K., Knaus-Dittmann, D., Schmidt, H., Mörike, K. & Häring, H.-U. Secondary adrenal failure and secondary amenorrhoea following hydromorphone treatment. Clin. Endocrinol. 66, 604–605 (2007).

    Article  Google Scholar 

  172. Fountas, A., Chai, S. T., Kourkouti, C. & Karavitaki, N. MECHANISMS OF ENDOCRINOLOGY: endocrinology of opioids. Eur. J. Endocrinol. 179, R183–r196 (2018).

    Article  PubMed  Google Scholar 

  173. Pofi, R. et al. The short synacthen (corticotropin) test can be used to predict recovery of hypothalamo-pituitary-adrenal axis function. J. Clin. Endocrinol. Metab. 103, 3050–3059 (2018).

    Article  PubMed  Google Scholar 

  174. Byun, D. J., Wolchok, J. D., Rosenberg, L. M. & Girotra, M. Cancer immunotherapy — immune checkpoint blockade and associated endocrinopathies. Nat. Rev. Endocrinol. 13, 195–207 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Husebye, E. S. et al. Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline. Eur. J. Endocrinol. 187, G1–G21 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Tan, M. H. et al. Spectrum of immune checkpoint inhibitors-induced endocrinopathies in cancer patients: a scoping review of case reports. Clin. Diabetes Endocrinol. 5, 1 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Di Dalmazi, G., Ippolito, S., Lupi, I. & Caturegli, P. Hypophysitis induced by immune checkpoint inhibitors: a 10-year assessment. Expert Rev. Endocrinol. Metab. 14, 381–398 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Johnson, J. et al. Hypophysitis and secondary adrenal insufficiency from immune checkpoint inhibitors: diagnostic challenges and link with survival. J. Natl Compr. Canc. Netw. 21, 281–287 (2023).

    Article  CAS  PubMed  Google Scholar 

  179. Kotwal, A. et al. Immune checkpoint inhibitor-induced hypophysitis: lessons learnt from a large cancer cohort. J. Investig. Med. 70, 939–946 (2022).

    Article  PubMed  Google Scholar 

  180. Jessel, S. et al. Immune checkpoint inhibitor-induced hypophysitis and patterns of loss of pituitary function. Front. Oncol. 12, 836859 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Nguyen, H. et al. Immune checkpoint inhibitor related hypophysitis: diagnostic criteria and recovery patterns. Endocr. Relat. Cancer 28, 419–431 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Albarel, F. et al. Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma. Eur. J. Endocrinol. 172, 195–204 (2015).

    Article  CAS  PubMed  Google Scholar 

  183. Faje, A. Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights. Pituitary 19, 82–92 (2016).

    Article  CAS  PubMed  Google Scholar 

  184. Cooksley, T. et al. Immune checkpoint inhibitor-mediated hypophysitis: no place like home. Clin. Med. 23, 81–84 (2023).

    Article  Google Scholar 

  185. Simeni Njonnou, S. R. et al. Isolated adrenocorticotropic hormone deficiency and sialadenitis associated with nivolumab: a case report. J. Med. Case Rep. 16, 456 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Lin, S. H. et al. Isolated adrenocorticotropic hormone deficiency associated with sintilimab therapy in a patient with advanced lung adenocarcinoma: a case report and literature review. BMC Endocr. Disord. 22, 239 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Yamauchi, I. et al. Clinical features and thyroid dysfunction in adverse events involving the pituitary gland during PD-1 blockade therapy. Clin. Endocrinol. 94, 258–268 (2021).

    Article  CAS  Google Scholar 

  188. Iglesias, P., Sánchez, J. C. & Díez, J. J. Isolated ACTH deficiency induced by cancer immunotherapy: a systematic review. Pituitary 24, 630–643 (2021).

    Article  CAS  PubMed  Google Scholar 

  189. Heck, A. & Winge-Main, A. K. Silent, isolated ACTH deficiency in malignant melanoma patients treated with immune checkpoint inhibitors. BMJ Case Rep. 14, e241981 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Suzuki, K. et al. Nivolumab-induced adrenal insufficiency in patients with renal cell carcinoma. J. Immunother. 43, 38–42 (2020).

    Article  CAS  PubMed  Google Scholar 

  191. Faje, A. et al. Hypophysitis secondary to nivolumab and pembrolizumab is a clinical entity distinct from ipilimumab-associated hypophysitis. Eur. J. Endocrinol. 181, 211–219 (2019).

    Article  CAS  PubMed  Google Scholar 

  192. Barroso-Sousa, R. et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol. 4, 173–182 (2018).

    Article  PubMed  Google Scholar 

  193. Grouthier, V. et al. Immune checkpoint inhibitor-associated primary adrenal insufficiency: who vigibase report analysis. Oncologist 25, 696–701 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  194. Bischoff, J. et al. It’s not always SIAD: immunotherapy-triggered endocrinopathies enter the field of cancer-related hyponatremia. J. Endocr. Soc. 6, bvac036 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Hanna, R. M. et al. Acute kidney injury after pembrolizumab-induced adrenalitis and adrenal insufficiency. Case Rep. Nephrol. Dial. 8, 171–177 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Paepegaey, A. C. et al. Polyendocrinopathy resulting from pembrolizumab in a patient with a malignant melanoma. J. Endocr. Soc. 1, 646–649 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Ruggeri, R. M. et al. Endocrine and metabolic adverse effects of immune checkpoint inhibitors: an overview (what endocrinologists should know). J. Endocrinol. Invest. 42, 745–756 (2019).

    Article  CAS  PubMed  Google Scholar 

  198. Atkinson, M. & Lansdown, A. J. Endocrine immune-related adverse events: adrenal, parathyroid, diabetes insipidus, and lipoatrophy. Best Pract. Res. Clin. Endocrinol. Metab. 36, 101635 (2022).

    Article  CAS  PubMed  Google Scholar 

  199. Bacanovic, S., Burger, I. A., Stolzmann, P., Hafner, J. & Huellner, M. W. Ipilimumab-induced adrenalitis: a possible pitfall in 18F-FDG-PET/CT. Clin. Nucl. Med. 40, e518–519 (2015).

    Article  PubMed  Google Scholar 

  200. Shi, Y. et al. ICPis-induced autoimmune polyendocrine syndrome type 2: a review of the literature and a protocol for optimal management. J. Clin. Endocrinol. Metab. 105, dgaa553 (2020).

    Article  PubMed  Google Scholar 

  201. Higham, C. E. et al. SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: acute management of the endocrine complications of checkpoint inhibitor therapy. Endocr. Connect. 7, G1–G7 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Nieman, L. K. et al. Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 100, 2807–2831 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Daniel, E. et al. Effectiveness of metyrapone in treating Cushing’s syndrome: a retrospective multicenter study in 195 patients. J. Clin. Endocrinol. Metab. 100, 4146–4154 (2015).

    Article  CAS  PubMed  Google Scholar 

  204. Nieman, L. K. et al. Metyrapone treatment in endogenous Cushing’s syndrome: results at week 12 from PROMPT, a prospective international multicenter, open-label, phase III/IV study. J. Endocr. Soc. 5, A515 (2021).

    Article  PubMed Central  Google Scholar 

  205. Pivonello, R. et al. Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS). Pituitary 25, 911–926 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Fleseriu, M. et al. Levoketoconazole treatment in endogenous Cushing’s syndrome: extended evaluation of clinical, biochemical, and radiologic outcomes. Eur. J. Endocrinol. 187, 859–871 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Pivonello, R., Simeoli, C., Di Paola, N. & Colao, A. Cushing’s disease: adrenal steroidogenesis inhibitors. Pituitary 25, 726–732 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Bonnet-Serrano, F. et al. Differences in the spectrum of steroidogenic enzyme inhibition between osilodrostat and metyrapone in ACTH-dependent Cushing syndrome patients. Eur. J. Endocrinol. 187, 315–322 (2022).

    Article  CAS  PubMed  Google Scholar 

  209. Hahner, S. et al. Etomidate unmasks intraadrenal regulation of steroidogenesis and proliferation in adrenal cortical cell lines. Horm. Metab. Res. 42, 528–534 (2010).

    Article  CAS  PubMed  ADS  Google Scholar 

  210. Preda, V. A., Sen, J., Karavitaki, N. & Grossman, A. B. THERAPY IN ENDOCRINE DISEASE: etomidate in the management of hypercortisolaemia in Cushing’s syndrome: a review. Eur. J. Endocrinol. 167, 137–143 (2012).

    Article  CAS  PubMed  Google Scholar 

  211. Fleseriu, M. et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 9, 847–875 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Castinetti, F., Nieman, L. K., Reincke, M. & Newell-Price, J. Approach to the patient treated with steroidogenesis inhibitors. J. Clin. Endocrinol. Metab. 106, 2114–2123 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Fleseriu, M. & Biller, B. M. K. Treatment of Cushing’s syndrome with osilodrostat: practical applications of recent studies with case examples. Pituitary 25, 795–809 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Tritos, N. A. Adrenally directed medical therapies for Cushing syndrome. J. Clin. Endocrinol. Metab. 106, 16–25 (2020).

    Article  Google Scholar 

  215. Poli, G. et al. Morphofunctional effects of mitotane on mitochondria in human adrenocortical cancer cells. Endocr. Relat. Cancer 20, 537–550 (2013).

    Article  CAS  PubMed  Google Scholar 

  216. Chortis, V. et al. Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5alpha-reductase, explaining the need for personalized glucocorticoid and androgen replacement. J. Clin. Endocrinol. Metab. 98, 161–171 (2013).

    Article  CAS  PubMed  Google Scholar 

  217. Fassnacht, M. et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur. J. Endocrinol. 179, G1–G46 (2018).

    Article  CAS  PubMed  Google Scholar 

  218. Fleseriu, M. et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J. Clin. Endocrinol. Metab. 97, 2039–2049 (2012).

    Article  CAS  PubMed  Google Scholar 

  219. Molitch, M. E. Glucocorticoid receptor blockers. Pituitary 25, 733–736 (2022).

    Article  CAS  PubMed  Google Scholar 

  220. Hopkins, S. & Fleseriu, M. In: Edward R. Laws (ed.) Cushing’s Disease 103-123 (Academic Press, 2017).

  221. Sai, K., Lal, A., Lakshmi Maradana, J., Velamala, P. R. & Nitin, T. Hypokalemia associated with mifepristone use in the treatment of Cushing’s syndrome. Endocrinol. Diabetes Metab. Case Rep. 2019, https://doi.org/10.1530/EDM-19-0064 (2019).

  222. Arosemena, M. A., Rodriguez, A. & Ediriweera, H. Bilateral adrenal haemorrhage secondary to rivaroxaban in a patient with antiphospholipid syndrome. BMJ Case Rep. 13, e234947 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Saleem, N., Khan, M., Parveen, S. & Balavenkatraman, A. Bilateral adrenal haemorrhage: a cause of haemodynamic collapse in heparin-induced thrombocytopaenia. BMJ Case Rep. 2016, bcr2016214679 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Patousis, A., Patousis, P., Barbakis, G. & Sachinis, N. P. Bilateral adrenal hemorrhage following femoral hip hemiarthroplasty: a case report. Cureus 14, e27748 (2022).

    PubMed  PubMed Central  Google Scholar 

  225. VanderVeer, E. A., Torbiak, R. P., Prebtani, A. P. & Warkentin, T. E. Spontaneous heparin-induced thrombocytopenia syndrome presenting as bilateral adrenal infarction after knee arthroplasty. BMJ Case Rep. 12, e232769 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Elhassan, Y. S., Ronchi, C. L., Wijewickrama, P. & Baldeweg, S. E. Approach to the patient with adrenal hemorrhage. J. Clin. Endocrinol. Metab. 108, 995–1006 (2022).

    Article  PubMed Central  Google Scholar 

  227. Ali, A., Singh, G. & Balasubramanian, S. P. Acute non-traumatic adrenal haemorrhage-management, pathology and clinical outcomes. Gland. Surg. 7, 428–432 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  228. Dunlop, D. Eighty-six cases of Addison’s disease. Br. Med. J. 2, 887–891 (1963).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Dineen, R. et al. Outcomes of the short synacthen test: what is the role of the 60 min sample in clinical practice? Postgrad. Med. J. 96, 67–72 (2020).

    Article  PubMed  Google Scholar 

  230. Sbardella, E. et al. Baseline morning cortisol level as a predictor of pituitary-adrenal reserve: a comparison across three assays. Clin. Endocrinol. 86, 177–184 (2017).

    Article  CAS  Google Scholar 

  231. Sagar, R., Mackie, S., Morgan, A. W., Stewart, P. & Abbas, A. Evaluating tertiary adrenal insufficiency in rheumatology patients on long-term systemic glucocorticoid treatment. Clin. Endocrinol. 94, 361–370 (2021).

    Article  CAS  Google Scholar 

  232. Bornstein, S. R. et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 101, 364–389 (2016).

    Article  CAS  PubMed  Google Scholar 

  233. El-Farhan, N. et al. Method-specific serum cortisol responses to the adrenocorticotrophin test: comparison of gas chromatography-mass spectrometry and five automated immunoassays. Clin. Endocrinol. 78, 673–680 (2013).

    Article  CAS  Google Scholar 

  234. Prete, A. et al. Prevention of adrenal crisis: cortisol responses to major stress compared to stress dose hydrocortisone delivery. J. Clin. Endocrinol. Metab. 105, 2262–2274 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Elecsys® Cortisol II https://labogids.sintmaria.be/sites/default/files/files/cortisol_ii_2020-03_v6.pdf (Roche Diagnostics, 2020).

  236. Stokes, F. J., Bailey, L. M., Ganguli, A. & Davison, A. S. Assessment of endogenous, oral and inhaled steroid cross-reactivity in the Roche cortisol immunoassay. Ann. Clin. Biochem. 51, 503–506 (2014).

    Article  CAS  PubMed  Google Scholar 

  237. Taylor, A. E., Keevil, B. & Huhtaniemi, I. T. Mass spectrometry and immunoassay: how to measure steroid hormones today and tomorrow. Eur. J. Endocrinol. 173, D1–12 (2015).

    Article  CAS  PubMed  Google Scholar 

  238. Monaghan, P. J. et al. Comparison of serum cortisol measurement by immunoassay and liquid chromatography-tandem mass spectrometry in patients receiving the 11β-hydroxylase inhibitor metyrapone. Ann. Clin. Biochem. 48, 441–446 (2011).

    Article  CAS  PubMed  Google Scholar 

  239. Klose, M. et al. Factors influencing the adrenocorticotropin test: role of contemporary cortisol assays, body composition, and oral contraceptive agents. J. Clin. Endocrinol. Metab. 92, 1326–1333 (2007).

    Article  CAS  PubMed  Google Scholar 

  240. Edo, N. et al. Diagnostic value of standard deviation score of log-transformed serum dehydroepiandrosterone sulfate in patients with hypothalamic-pituitary-adrenal axis insufficiency. Endocr. J. 68, 1337–1345 (2021).

    Article  CAS  PubMed  Google Scholar 

  241. Blair, J., Adaway, J., Keevil, B. & Ross, R. Salivary cortisol and cortisone in the clinical setting. Curr. Opin. Endocrinol. Diabetes Obes. 24, 161–168 (2017).

    Article  CAS  PubMed  Google Scholar 

  242. Debono, M. et al. Home waking salivary cortisone to screen for adrenal insufficiency. NEJM Evid. 2, EVIDoa2200182 (2023).

    Article  PubMed  Google Scholar 

  243. Debono, M. et al. Waking salivary cortisone as screening test for adrenal insufficiency. Endocr. Abstr. 81, P7 (2022).

    Google Scholar 

  244. El-Farhan, N., Rees, D. A. & Evans, C. Measuring cortisol in serum, urine and saliva — are our assays good enough? Ann. Clin. Biochem. 54, 308–322 (2017).

    Article  CAS  PubMed  Google Scholar 

  245. Agha, A., Tomlinson, J. W., Clark, P. M., Holder, G. & Stewart, P. M. The long-term predictive accuracy of the short synacthen (corticotropin) stimulation test for assessment of the hypothalamic-pituitary-adrenal axis. J. Clin. Endocrinol. Metab. 91, 43–47 (2006).

    Article  CAS  PubMed  Google Scholar 

  246. Stewart, P. M., Corrie, J., Seckl, J. R., Edwards, C. R. & Padfield, P. L. A rational approach for assessing the hypothalamo-pituitary-adrenal axis. Lancet 1, 1208–1210 (1988).

    Article  CAS  PubMed  Google Scholar 

  247. Bangar, V. & Clayton, R. N. How reliable is the short synacthen test for the investigation of the hypothalamic-pituitary-adrenal axis? Eur. J. Endocrinol. 139, 580–583 (1998).

    Article  CAS  PubMed  Google Scholar 

  248. Dekkers, O. M., Timmermans, J. M., Smit, J. W., Romijn, J. A. & Pereira, A. M. Comparison of the cortisol responses to testing with two doses of ACTH in patients with suspected adrenal insufficiency. Eur. J. Endocrinol. 164, 83–87 (2011).

    Article  CAS  PubMed  Google Scholar 

  249. Ospina, N. S. et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 101, 427–434 (2016).

    Article  CAS  PubMed  Google Scholar 

  250. Mukherjee, J. J. et al. A comparison of the insulin tolerance/glucagon test with the short ACTH stimulation test in the assessment of the hypothalamo-pituitary-adrenal axis in the early post-operative period after hypophysectomy. Clin. Endocrinol. 47, 51–60 (1997).

    Article  CAS  Google Scholar 

  251. Sherlock, M. & Stewart, P. M. The short synacthen test and its utility in assessing recovery of adrenal function in patients with central adrenal insufficiency. J. Clin. Endocrinol. Metab. 104, 17–20 (2019).

    Article  PubMed  Google Scholar 

  252. Lawrence, N. R. et al. Multivariable model to predict an ACTH stimulation test to diagnose adrenal insufficiency using previous test results. J. Endocr. Soc. 7, bvad127 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  253. Plumpton, F. S. & Besser, G. M. The adrenocortical response to surgery and insulin-induced hypoglycaemia in corticosteroid-treated and normal subjects. Br. J. Surg. 56, 216–219 (1969).

    Article  CAS  PubMed  Google Scholar 

  254. Agha, A. et al. Anterior pituitary dysfunction in survivors of traumatic brain injury. J. Clin. Endocrinol. Metab. 89, 4929–4936 (2004).

    Article  CAS  PubMed  Google Scholar 

  255. Garrahy, A., Sherlock, M. & Thompson, C. J. MANAGEMENT OF ENDOCRINE DISEASE: neuroendocrine surveillance and management of neurosurgical patients. Eur. J. Endocrinol. 176, R217–R233 (2017).

    Article  CAS  PubMed  Google Scholar 

  256. Fiad, T. M., Kirby, J. M., Cunningham, S. K. & McKenna, T. J. The overnight single-dose metyrapone test is a simple and reliable index of the hypothalamic-pituitary-adrenal axis. Clin. Endocrinol. 40, 603–609 (1994).

    Article  CAS  Google Scholar 

  257. Cegla, J. et al. Comparison of the overnight metyrapone and glucagon stimulation tests in the assessment of secondary hypoadrenalism. Clin. Endocrinol. 78, 738–742 (2013).

    Article  CAS  Google Scholar 

  258. Johannsson, G., Skrtic, S., Lennernäs, H., Quinkler, M. & Stewart, P. M. Improving outcomes in patients with adrenal insufficiency: a review of current and future treatments. Curr. Med. Res. Opin. 30, 1833–1847 (2014).

    Article  CAS  PubMed  Google Scholar 

  259. Walker, J. J. et al. The origin of glucocorticoid hormone oscillations. PLoS Biol. 10, e1001341 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Lightman, S. L. & Conway-Campbell, B. L. The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration. Nat. Rev. Neurosci. 11, 710–718 (2010).

    Article  CAS  PubMed  Google Scholar 

  261. Gjerstad, J. K., Lightman, S. L. & Spiga, F. Role of glucocorticoid negative feedback in the regulation of HPA axis pulsatility. Stress 21, 403–416 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Krieger, D. T., Allen, W., Rizzo, F. & Krieger, H. P. Characterization of the normal temporal pattern of plasma corticosteroid levels. J. Clin. Endocrinol. Metab. 32, 266–284 (1971).

    Article  CAS  PubMed  Google Scholar 

  263. Behan, L.-A. et al. Optimizing glucocorticoid replacement therapy in severely adrenocorticotropin-deficient hypopituitary male patients. Clin. Endocrinol. 75, 505–513 (2011).

    Article  CAS  Google Scholar 

  264. Upton, T. J. et al. High-resolution daily profiles of tissue adrenal steroids by portable automated collection. Sci. Transl. Med. 15, eadg8464 (2023).

    Article  CAS  PubMed  Google Scholar 

  265. Dineen, R., Martin-Grace, J., Thompson, C. J. & Sherlock, M. The management of glucocorticoid deficiency: current and future perspectives. Clin. Chim. Acta 505, 148–159 (2020).

    Article  CAS  PubMed  Google Scholar 

  266. Murray, R. D. et al. Management of glucocorticoid replacement in adrenal insufficiency shows notable heterogeneity — data from the EU-AIR. Clin. Endocrinol. 86, 340–346 (2017).

    Article  CAS  Google Scholar 

  267. Quinkler, M. et al. Prednisolone is associated with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency. Endocr. Connect. 6, 1–8 (2017).

    Article  CAS  PubMed  Google Scholar 

  268. Husebye, E. S. et al. Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J. Intern. Med. 275, 104–115 (2014).

    Article  CAS  PubMed  Google Scholar 

  269. Plat, L. et al. Metabolic effects of short-term elevations of plasma cortisol are more pronounced in the evening than in the morning. J. Clin. Endocrinol. Metab. 84, 3082–3092 (1999).

    CAS  PubMed  Google Scholar 

  270. Esteban, N. V. et al. Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J. Clin. Endocrinol. Metab. 72, 39–45 (1991).

    Article  CAS  PubMed  Google Scholar 

  271. Vulto, A. et al. Residual endogenous corticosteroid production in patients with adrenal insufficiency. Clin. Endocrinol. 91, 383–390 (2019).

    Article  CAS  Google Scholar 

  272. Werumeus Buning, J. et al. Effects of hydrocortisone on the regulation of blood pressure: results from a randomized controlled trial. J. Clin. Endocrinol. Metab. 101, 3691–3699 (2016).

    Article  PubMed  Google Scholar 

  273. Mohammedi, K. et al. Evidence of persistent mild hypercortisolism in patients medically treated for Cushing disease: the Haircush study. J. Clin. Endocrinol. Metab. 108, e963–e970 (2023).

    Article  PubMed  Google Scholar 

  274. Simon, N. et al. Pharmacokinetic evidence for suboptimal treatment of adrenal insufficiency with currently available hydrocortisone tablets. Clin. Pharmacokinet. 49, 455–463 (2010).

    Article  CAS  PubMed  Google Scholar 

  275. Gagliardi, L. et al. Continuous subcutaneous hydrocortisone infusion therapy in Addison’s disease: a randomized, placebo-controlled clinical trial. J. Clin. Endocrinol. Metab. 99, 4149–4157 (2014).

    Article  CAS  PubMed  Google Scholar 

  276. Isidori, A. M. et al. Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomised controlled trial. Lancet Diabetes Endocrinol. 6, 173–185 (2018).

    Article  CAS  PubMed  Google Scholar 

  277. Mallappa, A. et al. A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 100, 1137–1145 (2015).

    Article  CAS  PubMed  Google Scholar 

  278. Øksnes, M. et al. Continuous subcutaneous hydrocortisone infusion versus oral hydrocortisone replacement for treatment of Addison’s disease: a randomized clinical trial. J. Clin. Endocrinol. Metab. 99, 1665–1674 (2014).

    Article  PubMed  Google Scholar 

  279. Dineen, R. et al. Cardiometabolic and psychological effects of dual-release hydrocortisone: a cross-over study. Eur. J. Endocrinol. 184, 253–265 (2021).

    Article  CAS  PubMed  Google Scholar 

  280. Quinkler, M., Miodini Nilsen, R., Zopf, K., Ventz, M. & Øksnes, M. Modified-release hydrocortisone decreases BMI and HbA1c in patients with primary and secondary adrenal insufficiency. Eur. J. Endocrinol. 172, 619–626 (2015).

    Article  CAS  PubMed  Google Scholar 

  281. Oprea, A., Bonnet, N. C. G., Pollé, O. & Lysy, P. A. Novel insights into glucocorticoid replacement therapy for pediatric and adult adrenal insufficiency. Ther. Adv. Endocrinol. Metab. 10, 2042018818821294 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Grossman, A. B. Clinical review#: the diagnosis and management of central hypoadrenalism. J. Clin. Endocrinol. Metab. 95, 4855–4863 (2010).

    Article  CAS  PubMed  Google Scholar 

  283. Hahner, S. et al. Adrenal insufficiency. Nat. Rev. Dis. Prim. 7, 19 (2021).

    Article  PubMed  Google Scholar 

  284. Rushworth, R. L., Torpy, D. J. & Falhammar, H. Adrenal crises: perspectives and research directions. Endocrine 55, 336–345 (2017).

    Article  CAS  PubMed  Google Scholar 

  285. Rushworth, R. L., Torpy, D. J. & Falhammar, H. Adrenal crisis. N. Engl. J. Med. 381, 852–861 (2019).

    Article  CAS  PubMed  Google Scholar 

  286. Puar, T. H. K., Stikkelbroeck, N. M. M. L., Smans, L. C. C. J., Zelissen, P. M. J. & Hermus, A. R. M. M. Adrenal crisis: still a deadly event in the 21st century. Am. J. Med. 129, 339.e1-9 (2016).

    Article  PubMed  Google Scholar 

  287. Allolio, B. EXTENSIVE EXPERTISE IN ENDOCRINOLOGY: adrenal crisis. Eur. J. Endocrinol. 172, R115–R124 (2015).

    Article  CAS  PubMed  Google Scholar 

  288. Arlt, W., Baldeweg, S. E., Pearce, S. H. S. & Simpson, H. L. ENDOCRINOLOGY IN THE TIME OF COVID-19: management of adrenal insufficiency. Eur. J. Endocrinol. 183, G25 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Roberts, A., James, J. & Dhatariya, K. Management of hyperglycaemia and steroid (glucocorticoid) therapy: a guideline from the Joint British Diabetes Societies (JBDS) for Inpatient Care group. Diabet. Med. 35, 1011–1017 (2018).

    Article  CAS  PubMed  Google Scholar 

  290. Othonos, N. et al. 11β-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial. Nat. Commun. 14, 1025 (2023).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  291. Betterle, C., Dal Pra, C., Mantero, F. & Zanchetta, R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr. Rev. 23, 327–364 (2002).

    Article  CAS  PubMed  Google Scholar 

  292. Nerup, J. Addison’s disease — clinical studies. A report fo 108 cases. Acta Endocrinol. 76, 127–141 (1974).

    CAS  Google Scholar 

  293. Martin-Grace, J., Tomkins, M., O’Reilly, M. W., Thompson, C. J. & Sherlock, M. Approach to the patient: hyponatremia and the syndrome of inappropriate antidiuresis (SIAD). J. Clin. Endocrinol. Metab. 35, 2362–2376 (2022).

    Article  Google Scholar 

Download references

Acknowledgements

J.M.-G. has received funding from the Irish Endocrine Society Clinical Science Award. M.T. is an Irish Clinical Academic Training programme fellow funded by the Health Research Board (HRB) and Wellcome Trust (grant 203930/B/16/Z). M.W.O'.R. is funded by a HRB Emerging Clinician Scientist Award (ECSA2020-001).

Author information

Authors and Affiliations

  1. Department of Endocrinology, Royal College of Surgeons in Ireland, Dublin, Ireland

    Julie Martin-Grace, Maria Tomkins, Michael W. O’Reilly & Mark Sherlock

  2. Department of Endocrinology, Beaumont Hospital, Dublin, Ireland

    Julie Martin-Grace, Maria Tomkins, Michael W. O’Reilly & Mark Sherlock

Authors
  1. Julie Martin-Grace
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Tomkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael W. O’Reilly
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mark Sherlock
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.S. and M.W.O’R. made a substantial contribution to the discussion of content and wrote, reviewed and edited the manuscript before submission. J.M.-G. and M.T. researched data for the article, made a substantial contribution to the discussion of content, and wrote, reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Mark Sherlock.

Ethics declarations

Competing interests

M.S. receives research grant funding from Shire Ltd. The remaining authors declare no competing interests.

Peer review

Peer-review information

Nature Reviews Endocrinology thanks Olle Kämpe, Charlotte Elder, Frederic Castinetti and Eystein Husebye for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martin-Grace, J., Tomkins, M., O’Reilly, M.W. et al. Iatrogenic adrenal insufficiency in adults. Nat Rev Endocrinol 20, 209–227 (2024). https://doi.org/10.1038/s41574-023-00929-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-023-00929-x

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing