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The unresolved riddle of glucocorticoid withdrawal

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Abstract

Glucocorticoid (GC) therapy is the most common cause of adrenal insufficiency (AI). The real prevalence of AI after GC is unknown but it could involve more than 30% of patients. Some gene variation has been associated with the variability of hypothalamic-pituitary-adrenal (HPA) axis and this issue could contribute to the individual variation of adrenal function after GC treatment. Symptoms and signs of AI are nonspecific and frequently the diagnosis is delayed. Dosage, duration of treatment, administration route and serum cortisol value are not completely useful to predict AI. Clinical estimation of HPA suppression is difficult and biochemical testing is needed to confirm the diagnosis of AI. The different tapering regimens are based on a very low quality of evidence and considering the sizable individual variation, it is improbable that future research will find a secure GC tapering schedule for all patients. The aim of this review is to address the most important aspects in management of GC withdrawal in light of current knowledge.

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References

  1. Van Staa TP, Leufkens HG, Abenhaim L, Begaud B, Zhang B, Cooper C (2000) Use of oral corticosteroids in the United Kingdom. QJM 93(2):105–111

    Article  PubMed  Google Scholar 

  2. Bornstein SR (2009) Predisposing factors for adrenal insufficiency. N Engl J Med 360(22):2328–2339

    Article  CAS  PubMed  Google Scholar 

  3. Dinsen S, Baslund B, Klose M, Rasmussen AK, Friis-Hansen L, Hilsted L, Feldt-Rasmussen U (2013) Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself. Eur J Intern Med 24(8):714–720

    Article  CAS  PubMed  Google Scholar 

  4. Hochberg Z, Pacak K, Chrousos GP (2003) Endocrine withdrawal syndromes. Endocr Rev 24(4):523–538

    Article  CAS  PubMed  Google Scholar 

  5. Dixon RB, Christy NP (1980) On the various forms of corticosteroid withdrawal syndrome. Am J Med 68(2):224–230

    Article  CAS  PubMed  Google Scholar 

  6. Amatruda TT, Hollingsworth DR, D’Esopo ND, Upton GV, Bondy PK (1960) A study of the mechanism of the steroid withdrawal syndrome. Evidence for integrity of the hypothalamic-pituitary-adrenal system. J Clin Endocrinol Metab 20:339–354

    Article  CAS  PubMed  Google Scholar 

  7. Axelrod L (1976) Glucocorticoid therapy. Medicine 55:39–65

    Article  CAS  PubMed  Google Scholar 

  8. Varis T, Kivisto KT, Backman JT, Neuvonen PJ (2000) The cytochrome P450 3A4 inhibitor itraconazol markedly increases the plasma concentrations of dexamethasone and enhances its adrenal-suppressant effect. Clin Pharmacol Ther 68(5):487–494

    Article  CAS  PubMed  Google Scholar 

  9. Livanou T, Ferriman D, James VH (1967) Recovery of hypothalamo-pituitary-adrenal function after corticosteroid therapy. Lancet 2(7521):856–859

    Article  CAS  PubMed  Google Scholar 

  10. Baek JH, Kim SK, Jung JH, Hahm JR, Jung J (2016) Recovery of adrenal function in patients with glucocorticoids induced secondary adrenal insufficiency. Endocrinol Metab (Seoul) 31(1):153–160

    Article  Google Scholar 

  11. Cooper MS, Stewart PM (2003) Corticosteroid insufficiency in acutely ill patients. N Engl J Med 348:727–734

    Article  CAS  PubMed  Google Scholar 

  12. Levin C, Maibach HI (2002) Topical corticosteroid-induce adrenocortical insufficiency: clinical implications. Am J Clin Dermatol 3(3):141–147

    Article  PubMed  Google Scholar 

  13. Abraham G, Gottschalk J, Ungemach FR (2005) Evidence for ototopical glucocorticoid-induce decrease in hypothalamic-pituitary-adrenal axis response and liver function. Endocrinology 146(7):3163–3171

    Article  CAS  PubMed  Google Scholar 

  14. Kröger L, Kotaniemi K, Jääskeläinen J (2009) Topical treatment of uveitis resulting in adrenal insufficiency. Acta Paediatr 98(3):584–585

    Article  PubMed  Google Scholar 

  15. Sorkness CA, LaForce C, Storms W, Lincourt WR, Edwards L, Rogenes PR (1999) Effects of the inhaled corticosteroid fluticasone propionate, triamcinolone acetonide, and flunisolide and oral prednisone on the hypothalamic-pituitary-adrenal axis in adults patients with asthma. Clin Ther 21(2):353–367

    Article  CAS  PubMed  Google Scholar 

  16. Mader R, Lavi I, Luboshitzky R (2005) Evaluation of the pituitary-adrenal axis function following single intraarticular injection of methylprednisolone. Arthritis Rheum 52(3):924–928

    Article  CAS  PubMed  Google Scholar 

  17. Broersen LH, Pereira AM, Jørgensen JO, Dekkers OM (2015) Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis. J Clin Endocrinol Metab 100(6):2171–2180

    Article  CAS  PubMed  Google Scholar 

  18. Schlaghecke R, Kornely E, Santen RT, Ridderskamp P (1992) The effect of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropin-releasing hormone. N Engl J Med 326(4):226–230

    Article  CAS  PubMed  Google Scholar 

  19. Neidert S, Schuetz P, Mueller B, Christ-Crain M (2010) Dexamethasone suppression test predicts later development of an impaired adrenal function after a 14-day course of prednisone in healthy volunteers. Eur J Endocrinol 162(5):943–949

    Article  CAS  PubMed  Google Scholar 

  20. Derijk RH (2009) Single nucleotide polymorphisms related to HPA axis reactivity. NeuroImmunoModulation 16(5):340–352

    Article  CAS  PubMed  Google Scholar 

  21. Oelkers W (1996) Adrenal insufficiency. N Engl J Med 335:1206–1212

    Article  CAS  PubMed  Google Scholar 

  22. Bleicken B, Hahner S, Ventz M, Quinkler M (2010) Delayed diagnosis of adrenal insufficiency is common: a cross-sectional study in 216 patients. Am J Med Sci 339(6):525–531

    Article  PubMed  Google Scholar 

  23. Furst DE, Saag KG (2016) Glucocorticoid withdrawal. UpToDate

  24. Crowley RK, Argese N, Tomlinson JW, Stewart PM (2014) Central hypoadrenalism. J Endocrinol. Metabolism 99(11):4027–4036

    CAS  Google Scholar 

  25. Krasner AS (1999) Glucocorticoid-induced adrenal insufficiency. JAMA 282(7):671–676

    Article  CAS  PubMed  Google Scholar 

  26. Lindholm J, Kehlet H (1987) Re-evaluation of the clinical value of the 30 min ACTH test in assessing the hypothalamic-pituitary-adrenocortical function. Clin Endocrinol (Oxf) 26(1):53–59

    Article  CAS  Google Scholar 

  27. Smans LC, Zelissen PM (2016) Is diagnosis and subclassification of adrenal insufficiency as easy as it looks? Front Horm Res 46:146–158

    Article  PubMed  Google Scholar 

  28. Inder WJ, Dimeski G, Russell A (2012) Measurement of salivary cortisol in 2012—laboratory techniques and clinical indications. Clin Endocrinol (Oxf) 77(5):645–651

    Article  CAS  Google Scholar 

  29. Sayyed Kassem L, El Sibai K, Chaiban J, Abdelmannan D, Arafah BM (2012) Measurements of serum DHEA and DHEA sulphate levels improve the accuracy of the low-dose cosyntropin test in the diagnosis of central adrenal insufficiency. J Clin Endocrinol Metab 97(10):3655–3662

    Article  PubMed  PubMed Central  Google Scholar 

  30. Nasrallah MP, Arafah BM (2003) The value of dehydroepiandrosterone sulfate measurements in the assessment of adrenal function. J Clin Endocrinol Metab 88(11):5293–5298

    Article  CAS  PubMed  Google Scholar 

  31. Guaraldi F, Karamouzis I, Berardelli R, D’Angelo V, Rampino A, Zichi C, Ghigo E, Giordano R (2016) Secondary adrenal insufficiency: where is it hidden and what does it look like? Front Horm Res 46:159–170

    Article  PubMed  Google Scholar 

  32. Stewart PM, Newell-Price J (2016) The adrenal cortex. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM. Williams Textbook of Endocrinology. 13th edition by Elsevier Inc p 490-588

  33. Dickstein G, Saiegh L (2008) Low-dose and high dose adrenocorticotropin testing: indications and shortcomings. Curr Opin Endocrinol Diabetes Obes 15(3):244–249

    Article  CAS  PubMed  Google Scholar 

  34. Reynolds RM, Stewart PM, Seckl JR, Padfield PL (2006) Assessing the HPA axis in patients with pituitary disease: a UK survey. Clin Endocrinol (Oxf) 64(1):82–85

    Article  Google Scholar 

  35. Gleeson HK, Walker BR, Seckl JR, Padfield PL (2003) Ten years on: safety of short synacthen test in assessing adrenocorticotropin deficiency in clinical practice. J Clin Endocrinol Metab 88(5):2106–2111

    Article  CAS  PubMed  Google Scholar 

  36. Oelkers W (1996) Dose-response aspects in the clinical assessment of the hypothalamo pituitary-adrenal axis, and the low-dose adrenocorticotropin test. Eur J Endocrinol 135(1):27–33

    Article  CAS  PubMed  Google Scholar 

  37. Kazlauskaite R, Evans AT, Villabona CV, Abdu TA, Ambrosi B, Atkinson AB, Choi CH, Clayton RN, Courtney CH, Gonc EN, Maghnie M, Rose SR, Soule SG, Tordjman K (2008) Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab 93(11):4245–4253

    Article  CAS  PubMed  Google Scholar 

  38. Stewart PM, Clark PM (2009) The low-dose corticotropin-stimulation test revisited: the less, the better? Nat Clin Pract Endocrinol Metab 5(2):68–69

    Article  CAS  PubMed  Google Scholar 

  39. Ospina NS, Al Nofal A, Bancos I, Javed A, Benkhadra K, Kapoor E, Lteif AN, Natt N, Murad MH (2016) ACTH Stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab 101(2):427–434

    Article  CAS  PubMed  Google Scholar 

  40. Gonzálbez J, Villabona C, Ramón J, Navarro MA, Giménez O, Ricart W, Soler J (2000) Establishment of reference values for standard dose short synacthen test (250 microgram), low dose short synacthen test (1 microgram) and insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in normal subjects. Clin Endocrinol (Oxf) 53(2):199–2004

    Article  Google Scholar 

  41. Dickstein G, Shechner C, Nicholson WE, Rosner I, Shen-Orr Z, Adawi F, Lahav M (1991) Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day and suggested new sensitive low dose test. J Clin Endocrinol Metab 72(4):773–778

    Article  CAS  PubMed  Google Scholar 

  42. Oelkers W (1998) The role of high and low dose corticotropin test in diagnosis of secondary adrenal insufficiency. Eur J Endocrinol 139(6):567–570

    Article  CAS  PubMed  Google Scholar 

  43. Dickstein G (2001) Hypothalamo-pituitary-adrenal axis testing: nothing is sacred and caution in interpretation is needed. Clin Endocrinol (Oxf) 54(1):15–16

    Article  CAS  Google Scholar 

  44. Swiglo BA, Murad MH, Schünemann HJ, Kunz R, Vigersky RA, Guyatt GH, Montori VM (2008) A case for clarity, consistency, and helpfulness: state-of-art clinical practice guidelines in endocrinology using the grading of recommendations assessment, development, and evaluation system. J Clin Endocrinol Metab 93(3):666–673

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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Acknowledgements

Georgina Konstandakopoulos for the language review of the paper.

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Guerrero Pérez, F., Marengo, A.P. & Villabona Artero, C. The unresolved riddle of glucocorticoid withdrawal. J Endocrinol Invest 40, 1175–1181 (2017). https://doi.org/10.1007/s40618-017-0691-1

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