Advertisement

Towards the tailoring of glucocorticoid replacement in adrenal insufficiency: the Italian Society of Endocrinology Expert Opinion

  • A. M. IsidoriEmail author
  • G. Arnaldi
  • M. Boscaro
  • A. Falorni
  • C. Giordano
  • R. Giordano
  • R. Pivonello
  • C. Pozza
  • E. Sbardella
  • C. Simeoli
  • C. Scaroni
  • A. Lenzi
  • On behalf of the Italian Society of Endocrinology
Consensus Statement
  • 29 Downloads

Abstract

Context

Glucocorticoid (GC) replacement therapy in patients with adrenal insufficiency (AI) is life saving. After over 50 years of conventional GC treatment, novel formulations are now entering routine clinical practice.

Methods

Given the spectrum of medications currently available and new insights into the understanding of AI, the authors reviewed relevant medical literature with emphasis on original studies, prospective observational data and randomized controlled trials performed in the past 35 years. The Expert Opinion of a panel of selected endocrinologists was sought to answer specific clinical questions. The objective was to provide an evidence-supported guide, for the use of GC in various settings from university hospitals to outpatient clinics, that offers specific advice tailored to the individual patient.

Results

The Panel reviewed available GC replacement therapies, comprising short-acting, intermediate and long-acting oral formulations, subcutaneous formulations and the novel modified-release hydrocortisone. Advantages and disadvantages of these formulations were reviewed.

Conclusions

In the Panel’s opinion, achieving the optimal GC timing and dosing is needed to improve the outcome of AI. No-single formulation offers the best option for every patients. Recent data suggest that more emphasis should be given to the timing of intake. Tailoring of GS should be attempted in all patients—by experts—on a case-by-case basis. The Panel identified specific subgroups of AI patients that could be help by this process. Long-term studies are needed to confirm the short-term benefits associated with the modified-release GCs. The impact of GC tailoring has yet to be proven in terms of hospitalization rate, morbidity and mortality.

Keywords

Adrenal insufficiency Glucocorticoid Addison Hydrocortisone Cortisone acetate Prednisone 

Notes

Acknowledgements

The authors thank Marie-Hélène Hayles for her medical writing assistance during the preparation of the manuscript.

Funding

No funding was used to produce this manuscript.

Compliance with ethical standards

Conflict of interest

AM.I. has received grants and advisory fees from Takeda and Novartis. G.A. has been Principal Investigator of Research Studies for Novartis; has received research grants from Novartis and Shire; has received speaker fees from Novartis; and has received consulting fees from Novartis and Pfizer, Inc. as board member. M.B. has been Principal Investigator of Research Studies for Novartis; has been Investigator of Research Studies for Novartis, HRA Pharma and ViroPharma; and has received consulting fees from Novartis as board member. AF declares that he has received a speaker honorarium from Shire Italy S.p.A. C.G. has been Principal Investigator of Research Studies for Novo Nordisk and Lilly USA, LLC; has received research grants from Novo Nordisk and Lilly USA, LLC; has been an occasional consultant for Novartis, Pfizer, Inc., Ipsen and Shire; and has received speaker fees from Novo Nordisk, Lilly USA, LLC and Novartis. R.G. has been occasional consultant for Shire. R.P. has been Principal Investigator of Research Studies for Novartis, HRA Pharma, Ipsen, Shire, Corcept Therapeutics, Cortendo AB; Co-investigator of Research Studies for Pfizer; received research grants from Novartis, Pfzer, Ipsen, HRA Pharma, Shire, IBSA; has been an occasional consultant for Novartis, Ipsen, Pfzer, Shire, HRA Pharma, Cortendo AB, Ferring and Italfarmaco; and has received fees and honoraria for presentations from Novartis, Shire. C.S. has been occasional consultant for Shire and Ipsen. C.S. has been Principal Investigator of Research Studies for Novartis, Otsuka and Pfizer, Inc.; has been Co-investigator of Research Studies for Novartis and Lilly USA, LLC; has received research grants from Novartis, Lilly USA, LLC, Otsuka and Pfizer, Inc.; has been an occasional consultant for Novartis and Otsuka; and has received speaker fees for presentations from Otsuka and Lilly USA, LLC. A.L. has received grants and advisory fees from Takeda and Novartis. C.P. and E.S. have no conflicts of interest.

Ethical approval

It is an Expert Opinion, with no original experimental or clinical data, and thus no requirement for ethical approval.

Informed consent

For this type of study formal consent is not required.

Supplementary material

40618_2019_1146_MOESM1_ESM.docx (62 kb)
Supplementary material 1 (PDF 61 kb)

References

  1. 1.
    Arlt W, Allolio B (2003) Adrenal insufficiency. Lancet 361(9372):1881–1893PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Ekman B, Fitts D, Marelli C, Murray RD, Quinkler M, Zelissen PM (2014) European Adrenal Insufficiency Registry (EU-AIR): a comparative observational study of glucocorticoid replacement therapy. BMC Endocr Disord 14:40PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Murray RD, Ekman B, Uddin S, Marelli C, Quinkler M, Zelissen PM et al (2017) Management of glucocorticoid replacement in adrenal insufficiency shows notable heterogeneity data from the EU-AIR. Clin Endocrinol (Oxf) 86(3):340–346CrossRefGoogle Scholar
  4. 4.
    Erichsen MM, Lovas K, Skinningsrud B, Wolff AB, Undlien DE, Svartberg J et al (2009) Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. J Clin Endocrinol Metab 94(12):4882–4890PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Bjornsdottir S, Sundstrom A, Ludvigsson JF, Blomqvist P, Kampe O, Bensing S (2013) Drug prescription patterns in patients with Addison’s disease: a Swedish population-based cohort study. J Clin Endocrinol Metab 98(5):2009–2018PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Hong AR, Ryu OH, Kim SY, Kim SW, Korean Adrenal G, Endocrine Hypertension Study Group KES (2017) Characteristics of Korean patients with primary adrenal insufficiency: a registry-based nationwide survey in Korea. Endocrinol Metab (Seoul) 32(4):466–474CrossRefGoogle Scholar
  7. 7.
    OCEBM Table of Evidence Working Group (2011) “The Oxford 2011 Levels of Evidence”. Oxford Centre for Evidence-Based Medicine. http://www.cebm.net/index.aspx?o=5653
  8. 8.
    Mason AS, Meade TW, Lee JA, Morris JN (1968) Epidemiological and clinical picture of Addison’s disease. Lancet 2(7571):744–747PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Nerup J (1974) Addison’s disease–clinical studies. A report fo 108 cases. Acta Endocrinol (Copenh) 76(1):127–141CrossRefGoogle Scholar
  10. 10.
    Meyer G, Neumann K, Badenhoop K, Linder R (2014) Increasing prevalence of Addison’s disease in German females: health insurance data 2008-2012. Eur J Endocrinol 170(3):367–373PubMedCrossRefGoogle Scholar
  11. 11.
    Betterle C, Morlin L (2011) Autoimmune Addison’s disease. Endocr Dev 20:161–172PubMedCrossRefGoogle Scholar
  12. 12.
    Willis AC, Vince FP (1997) The prevalence of Addison’s disease in Coventry. UK. Postgrad Med J 73(859):286–288PubMedCrossRefGoogle Scholar
  13. 13.
    Lovas K, Husebye ES (2002) High prevalence and increasing incidence of Addison’s disease in western Norway. Clin Endocrinol (Oxf) 56(6):787–791CrossRefGoogle Scholar
  14. 14.
    Laureti S, Vecchi L, Santeusanio F, Falorni A (1999) Is the prevalence of Addison’s disease underestimated? J Clin Endocrinol Metab 84(5):1762PubMedGoogle Scholar
  15. 15.
    Graziadio C, Hasenmajer V, Venneri MA, Gianfrilli D, Isidori AM, Sbardella E (2018) Glycometabolic alterations in secondary adrenal insufficiency: does replacement therapy play a role? Front Endocrinol (Lausanne). 9:434PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Tomlinson JW, Holden N, Hills RK, Wheatley K, Clayton RN, Bates AS et al (2001) Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet 357(9254):425–431PubMedCrossRefGoogle Scholar
  17. 17.
    Nilsson B, Gustavasson-Kadaka E, Bengtsson BA, Jonsson B (2000) Pituitary adenomas in Sweden between 1958 and 1991: incidence, survival, and mortality. J Clin Endocrinol Metab 85(4):1420–1425PubMedGoogle Scholar
  18. 18.
    Regal M, Paramo C, Sierra SM, Garcia-Mayor RV (2001) Prevalence and incidence of hypopituitarism in an adult Caucasian population in northwestern Spain. Clin Endocrinol (Oxf) 55(6):735–740CrossRefGoogle Scholar
  19. 19.
    Gomez MT, Magiakou MA, Mastorakos G, Chrousos GP (1993) The pituitary corticotroph is not the rate limiting step in the postoperative recovery of the hypothalamic-pituitary-adrenal axis in patients with Cushing syndrome. J Clin Endocrinol Metab 77(1):173–177PubMedGoogle Scholar
  20. 20.
    Giordano R, Guaraldi F, Mazzoli M, Ghigo E (2017) Do glucocorticoids induce addiction in humans? J Endocrinol Invest 40(8):881–883PubMedCrossRefGoogle Scholar
  21. 21.
    Pofi R, Feliciano C, Sbardella E, Argese N, Woods CP, Grossman AB et al (2018) The short synacthen (corticotropin) test can be used to predict recovery of hypothalamo-pituitary-adrenal axis function. J Clin Endocrinol Metab 103(8):3050–3059PubMedCrossRefGoogle Scholar
  22. 22.
    Sbardella E, Isidori AM, Woods CP, Argese N, Tomlinson JW, Shine B et al (2017) Baseline morning cortisol level as a predictor of pituitary-adrenal reserve: a comparison across three assays. Clin Endocrinol (Oxf) 86(2):177–184CrossRefGoogle Scholar
  23. 23.
    Boonen E, Bornstein SR, Van den Berghe G (2015) New insights into the controversy of adrenal function during critical illness. Lancet Diabetes Endocrinol 3(10):805–815PubMedCrossRefGoogle Scholar
  24. 24.
    Krieger DT, Allen W, Rizzo F, Krieger HP (1971) Characterization of the normal temporal pattern of plasma corticosteroid levels. J Clin Endocrinol Metab 32(2):266–284PubMedCrossRefGoogle Scholar
  25. 25.
    Spiegel K, Leproult R, Van Cauter E (1999) Impact of sleep debt on metabolic and endocrine function. Lancet 354(9188):1435–1439PubMedCrossRefGoogle Scholar
  26. 26.
    Oster H, Challet E, Ott V, Arvat E, Ronald de Kloet E, Dijk DJ et al (2017) The functional and clinical significance of the 24-hour rhythm of circulating glucocorticoids. Endocr Rev 38(1):3–45PubMedGoogle Scholar
  27. 27.
    Van Cauter E, Polonsky KS, Scheen AJ (1997) Roles of circadian rhythmicity and sleep in human glucose regulation. Endocr Rev 18(5):716–738PubMedGoogle Scholar
  28. 28.
    Spiegel K, Knutson K, Leproult R, Tasali E, Van Cauter E (2005) Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes. J Appl Physiol 99(5):2008–2019PubMedCrossRefGoogle Scholar
  29. 29.
    Oelkers W, Diederich S, Bahr V (2001) Therapeutic strategies in adrenal insufficiency. Ann Endocrinol (Paris). 62(2):212–216PubMedGoogle Scholar
  30. 30.
    Falorni A, Minarelli V, Morelli S (2013) Therapy of adrenal insufficiency: an update. Endocrine 43(3):514–528PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Charmandari E, Nicolaides NC, Chrousos GP (2014) Adrenal insufficiency. Lancet 383(9935):2152–2167PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Crowley RK, Argese N, Tomlinson JW, Stewart PM (2014) Central hypoadrenalism. J Clin Endocrinol Metab 99(11):4027–4036PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD et al (2016) Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 101(2):364–389PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R et al (2016) Hormonal replacement in hypopituitarism in adults: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 101(11):3888–3921PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Besser GM, Jeffcoate WJ (1976) Endocrine and metabolic diseases. Adrenal diseases. Br Med J 1(6007):448–451PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Esteban NV, Loughlin T, Yergey AL, Zawadzki JK, Booth JD, Winterer JC et al (1991) Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J Clin Endocrinol Metab 72(1):39–45PubMedCrossRefGoogle Scholar
  37. 37.
    Cope CL, Black E (1958) The production rate of cortisol in man. Br Med J 1(5078):1020–1024PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Lovas K, Loge JH, Husebye ES (2002) Subjective health status in Norwegian patients with Addison’s disease. Clin Endocrinol (Oxf) 56(5):581–588CrossRefGoogle Scholar
  39. 39.
    Bergthorsdottir R, Leonsson-Zachrisson M, Oden A, Johannsson G (2006) Premature mortality in patients with Addison’s disease: a population-based study. J Clin Endocrinol Metab 91(12):4849–4853PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Bensing S, Brandt L, Tabaroj F, Sjoberg O, Nilsson B, Ekbom A et al (2008) Increased death risk and altered cancer incidence pattern in patients with isolated or combined autoimmune primary adrenocortical insufficiency. Clin Endocrinol (Oxf) 69(5):697–704CrossRefGoogle Scholar
  41. 41.
    Hahner S, Loeffler M, Fassnacht M, Weismann D, Koschker AC, Quinkler M et al (2007) Impaired subjective health status in 256 patients with adrenal insufficiency on standard therapy based on cross-sectional analysis. J Clin Endocrinol Metab 92(10):3912–3922PubMedCrossRefGoogle Scholar
  42. 42.
    Bleicken B, Hahner S, Loeffler M, Ventz M, Decker O, Allolio B et al (2010) Influence of hydrocortisone dosage scheme on health-related quality of life in patients with adrenal insufficiency. Clin Endocrinol (Oxf) 72(3):297–304CrossRefGoogle Scholar
  43. 43.
    Oksnes M, Bensing S, Hulting AL, Kampe O, Hackemann A, Meyer G et al (2012) Quality of life in European patients with Addison’s disease: validity of the disease-specific questionnaire AddiQoL. J Clin Endocrinol Metab 97(2):568–576PubMedCrossRefGoogle Scholar
  44. 44.
    Lovas K, Curran S, Oksnes M, Husebye ES, Huppert FA, Chatterjee VK (2010) Development of a disease-specific quality of life questionnaire in Addison’s disease. J Clin Endocrinol Metab 95(2):545–551PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Mah PM, Jenkins RC, Rostami-Hodjegan A, Newell-Price J, Doane A, Ibbotson V et al (2004) Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clin Endocrinol (Oxf) 61(3):367–375CrossRefGoogle Scholar
  46. 46.
    Simon N, Castinetti F, Ouliac F, Lesavre N, Brue T, Oliver C (2010) Pharmacokinetic evidence for suboptimal treatment of adrenal insufficiency with currently available hydrocortisone tablets. Clin Pharmacokinet 49(7):455–463PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Moeller H (1985) Chronopharmacology of hydrocortisone and 9 alpha-fluorhydrocortisone in the treatment for congenital adrenal hyperplasia. Eur J Pediatr 144(4):370–373PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Husebye ES, Allolio B, Arlt W, Badenhoop K, Bensing S, Betterle C et al (2014) Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J Intern Med 275(2):104–115PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Johannsson G, Nilsson AG, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B et al (2012) Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation. J Clin Endocrinol Metab 97(2):473–481PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Mallappa A, Sinaii N, Kumar P, Whitaker MJ, Daley LA, Digweed D et al (2015) 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(3):1137–1145PubMedCrossRefGoogle Scholar
  51. 51.
    Williams EL, Choudhury S, Tan T, Meeran K (2016) Prednisolone replacement therapy mimics the circadian rhythm more closely than other glucocorticoids. J Appl Lab Med 1(2):152–161CrossRefGoogle Scholar
  52. 52.
    Stavreva DA, Wiench M, John S, Conway-Campbell BL, McKenna MA, Pooley JR et al (2009) Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription. Nat Cell Biol 11(9):1093–1102PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Plat L, Leproult R, L’Hermite-Baleriaux M, Fery F, Mockel J, Polonsky KS et al (1999) Metabolic effects of short-term elevations of plasma cortisol are more pronounced in the evening than in the morning. J Clin Endocrinol Metab 84(9):3082–3092PubMedGoogle Scholar
  54. 54.
    Amin A, Sam AH, Meeran K (2014) Glucocorticoid Replace. BMJ 349:g4843PubMedCrossRefGoogle Scholar
  55. 55.
    Pearce SH (2014) Insufficient evidence to favour prednisolone over hydrocortisone in glucocorticoid replacement. BMJ 349:g5510PubMedCrossRefGoogle Scholar
  56. 56.
    Bleicken B, Hahner S, Loeffler M, Ventz M, Allolio B, Quinkler M (2008) Impaired subjective health status in chronic adrenal insufficiency: impact of different glucocorticoid replacement regimens. Eur J Endocrinol 159(6):811–817PubMedCrossRefGoogle Scholar
  57. 57.
    Quinkler M, Ekman B, Marelli C, Uddin S, Zelissen P, Murray RD et al (2017) Prednisolone is associated with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency. Endocr Connect 6(1):1–8PubMedCrossRefGoogle Scholar
  58. 58.
    Smith DJF, Prabhudev H, Choudhury S, Meeran K (2017) Prednisolone has the same cardiovascular risk profile as hydrocortisone in glucocorticoid replacement. Endocr Connect. 6(8):766–772PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Frey KR, Kienitz T, Schulz J, Ventz M, Zopf K, Quinkler M (2018) Prednisolone is associated with a worse bone mineral density in primary adrenal insufficiency. Endocr Connect. 7(6):811–818PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Johannsson G, Falorni A, Skrtic S, Lennernas H, Quinkler M, Monson JP et al (2015) Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy. Clin Endocrinol (Oxf) 82(1):2–11CrossRefGoogle Scholar
  61. 61.
    Groves RW, Toms GC, Houghton BJ, Monson JP (1988) Corticosteroid replacement therapy: twice or thrice daily? J R Soc Med 81(9):514–516PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Derendorf H, Mollmann H, Barth J, Mollmann C, Tunn S, Krieg M (1991) Pharmacokinetics and oral bioavailability of hydrocortisone. J Clin Pharmacol 31(5):473–476PubMedCrossRefGoogle Scholar
  63. 63.
    Rushworth RL, Torpy DJ (2015) Adrenal insufficiency in australia: is it possible that the use of lower dose, short-acting glucocorticoids has increased the risk of adrenal crises? Horm Metab Res 47(6):427–432PubMedCrossRefGoogle Scholar
  64. 64.
    Nordenstrom A, Marcus C, Axelson M, Wedell A, Ritzen EM (1999) Failure of cortisone acetate treatment in congenital adrenal hyperplasia because of defective 11beta-hydroxysteroid dehydrogenase reductase activity. J Clin Endocrinol Metab 84(4):1210–1213PubMedGoogle Scholar
  65. 65.
    Filipsson H, Monson JP, Koltowska-Haggstrom M, Mattsson A, Johannsson G (2006) The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. J Clin Endocrinol Metab 91(10):3954–3961PubMedCrossRefGoogle Scholar
  66. 66.
    Fariss BL, Hane S, Shinsako J, Forsham PH (1978) Comparison of absorption of cortisone acetate and hydrocortisone hemisuccinate. J Clin Endocrinol Metab 47(5):1137–1140PubMedCrossRefGoogle Scholar
  67. 67.
    Feek CM, Ratcliffe JG, Seth J, Gray CE, Toft AD, Irvine WJ (1981) Patterns of plasma cortisol and ACTH concentrations in patients with Addison’s disease treated with conventional corticosteroid replacement. Clin Endocrinol (Oxf) 14(5):451–458CrossRefGoogle Scholar
  68. 68.
    Nickelsen T, Schulz F, Demisch K (1983) Studies on cortisol substitution therapy in patients with adrenal insufficiency. Exp Clin Endocrinol 82(1):35–41PubMedGoogle Scholar
  69. 69.
    Laureti S, Falorni A, Santeusanio F (2003) Improvement of treatment of primary adrenal insufficiency by administration of cortisone acetate in three daily doses. J Endocrinol Invest 26(11):1071–1075PubMedCrossRefGoogle Scholar
  70. 70.
    Barbetta L, Dall’Asta C, Re T, Libe R, Costa E, Ambrosi B (2005) Comparison of different regimens of glucocorticoid replacement therapy in patients with hypoadrenalism. J Endocrinol Invest 28(7):632–637PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Cardini F, Torlone E, Bini V, Falorni A (2019) Continuous subcutaneous hydrocortisone infusion in a woman with secondary adrenal insufficiency. Endocrine 63(2):398–400PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Lovas K, Husebye ES (2007) Continuous subcutaneous hydrocortisone infusion in Addison’s disease. Eur J Endocrinol 157(1):109–112PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Johannsson G, Bergthorsdottir R, Nilsson AG, Lennernas H, Hedner T, Skrtic S (2009) Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study. Eur J Endocrinol 161(1):119–130PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Oksnes M, Ross R, Lovas K (2015) Optimal glucocorticoid replacement in adrenal insufficiency. Best Pract Res Clin Endocrinol Metab 29(1):3–15PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Quinkler M, Miodini Nilsen R, Zopf K, Ventz M, Oksnes M (2015) Modified-release hydrocortisone decreases BMI and HbA1c in patients with primary and secondary adrenal insufficiency. Eur J Endocrinol 172(5):619–626PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Giordano R, Guaraldi F, Marinazzo E, Fumarola F, Rampino A, Berardelli R et al (2016) Improvement of anthropometric and metabolic parameters, and quality of life following treatment with dual-release hydrocortisone in patients with Addison’s disease. Endocrine 51(2):360–368PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Nilsson AG, Marelli C, Fitts D, Bergthorsdottir R, Burman P, Dahlqvist P et al (2014) Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency. Eur J Endocrinol 171(3):369–377PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Bergthorsdottir R, Nilsson AG, Gillberg P, Ekman B, Wahlberg J (2015) Health-related quality of life in patients with adrenal insufficiency receiving plenadren compared with immediate-release hydrocortisone. Value Health 18(7):A616CrossRefGoogle Scholar
  79. 79.
    Mongioi LM, Condorelli RA, La Vignera S, Calogero AE (2018) Dual-release hydrocortisone treatment: glycometabolic profile and health-related quality of life. Endocr Connect 7(1):211–219PubMedCrossRefGoogle Scholar
  80. 80.
    Isidori AM, Venneri MA, Graziadio C, Simeoli C, Fiore D, Hasenmajer V et al (2018) 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(3):173–185PubMedCrossRefGoogle Scholar
  81. 81.
    Venneri MA, Hasenmajer V, Fiore D, Sbardella E, Pofi R, Graziadio C et al (2018) Circadian rhythm of glucocorticoid administration entrains clock genes in immune cells: a DREAM trial ancillary study. J Clin Endocrinol Metab 103(8):2998–3009PubMedCrossRefGoogle Scholar
  82. 82.
    Frara S, Chiloiro S, Porcelli T, Giampietro A, Mazziotti G, De Marinis L et al (2018) Bone safety of dual-release hydrocortisone in patients with hypopituitarism. Endocrine 60(3):528–531PubMedCrossRefGoogle Scholar
  83. 83.
    Ceccato F, Selmin E, Sabbadin C, Dalla Costa M, Antonelli G, Plebani M et al (2018) Improved salivary cortisol rhythm with dual-release hydrocortisone. Endocr Connect 7(9):965–974PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Newell-Price J, Whiteman M, Rostami-Hodjegan A, Darzy K, Shalet S, Tucker GT et al (2008) Modified-release hydrocortisone for circadian therapy: a proof-of-principle study in dexamethasone-suppressed normal volunteers. Clin Endocrinol (Oxf) 68(1):130–135CrossRefGoogle Scholar
  85. 85.
    Debono M, Ghobadi C, Rostami-Hodjegan A, Huatan H, Campbell MJ, Newell-Price J et al (2009) Modified-release hydrocortisone to provide circadian cortisol profiles. J Clin Endocrinol Metab 94(5):1548–1554PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Verma S, Vanryzin C, Sinaii N, Kim MS, Nieman LK, Ravindran S et al (2010) A pharmacokinetic and pharmacodynamic study of delayed- and extended-release hydrocortisone (Chronocort) vs. conventional hydrocortisone (Cortef) in the treatment of congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 72(4):441–447PubMedCrossRefGoogle Scholar
  87. 87.
    Whitaker MJ, Debono M, Huatan H, Merke DP, Arlt W, Ross RJ (2014) An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure. Clin Endocrinol (Oxf) 80(4):554–561CrossRefGoogle Scholar
  88. 88.
    Neumann U, Whitaker MJ, Wiegand S, Krude H, Porter J, Davies M et al (2018) Absorption and tolerability of taste-masked hydrocortisone granules in neonates, infants and children under 6 years of age with adrenal insufficiency. Clin Endocrinol (Oxf) 88(1):21–29CrossRefGoogle Scholar
  89. 89.
    Porter J, Withe M, Ross RJ (2018) Immediate-release granule formulation of hydrocortisone, Alkindi(R), for treatment of paediatric adrenal insufficiency (Infacort development programme). Expert Rev Endocrinol Metab 13(3):119–124PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Hahner S, Spinnler C, Fassnacht M, Burger-Stritt S, Lang K, Milovanovic D et al (2015) High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. J Clin Endocrinol Metab 100(2):407–416PubMedCrossRefGoogle Scholar
  91. 91.
    Guarnotta V, Ciresi A, Pillitteri G, Giordano C (2018) Improved insulin sensitivity and secretion in prediabetic patients with adrenal insufficiency on dual-release hydrocortisone treatment: a 36-month retrospective analysis. Clin Endocrinol (Oxf) 88(5):665–672CrossRefGoogle Scholar
  92. 92.
    Sbardella E, Pozza C, Isidori AM, Grossman AB (2019) Endocrinology and adolescence: dealing with transition in young patients with pituitary disorders. Eur J Endocrinol 181(4):R155–R171CrossRefGoogle Scholar
  93. 93.
    Alexandraki KI, Kaltsas GA, Isidori AM, Storr HL, Afshar F, Sabin I et al (2013) Long-term remission and recurrence rates in Cushing’s disease: predictive factors in a single-centre study. Eur J Endocrinol 168(4):639–648CrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2019

Authors and Affiliations

  • A. M. Isidori
    • 1
    Email author
  • G. Arnaldi
    • 2
  • M. Boscaro
    • 3
  • A. Falorni
    • 4
  • C. Giordano
    • 5
  • R. Giordano
    • 6
  • R. Pivonello
    • 7
  • C. Pozza
    • 1
  • E. Sbardella
    • 1
  • C. Simeoli
    • 7
  • C. Scaroni
    • 3
  • A. Lenzi
    • 1
  • On behalf of the Italian Society of Endocrinology
  1. 1.Department of Experimental MedicineSapienza University of RomeRomeItaly
  2. 2.Clinica di Endocrinologia e Malattie del MetabolismoAzienda Ospedaliero-Universitaria, Università Politecnica delle MarcheAnconaItaly
  3. 3.UOC Endocrinologia, Dipartimento di Medicina DIMEDAzienda Ospedaliera-Università di PadovaPaduaItaly
  4. 4.Dipartimento di MedicinaUniversità di PerugiaPerugiaItaly
  5. 5.Section of Diabetology, Endocrinology and Metabolism, PROMISEUniversity of PalermoPalermoItaly
  6. 6.Department of Clinical and Biological Sciences, Division of Endocrinology, Diabetes and Metabolism-Department of Medical SciencesUniversity of TurinTurinItaly
  7. 7.Dipartimento di Medicina Clinica e Chirurgia, Sezione di EndocrinologiaUniversità Federico II di NapoliNaplesItaly

Personalised recommendations