Endocrine

, Volume 43, Issue 3, pp 514–528 | Cite as

Therapy of adrenal insufficiency: an update

  • Alberto Falorni
  • Viviana Minarelli
  • Silvia Morelli
Review

Abstract

Adrenal insufficiency may be caused by the destruction or altered function of the adrenal gland with a primary deficit in cortisol secretion (primary adrenal insufficiency) or by hypothalamic-pituitary pathologies determining a deficit of ACTH (secondary adrenal insufficiency). The clinical picture is determined by the glucocorticoid deficit, which may in some conditions be accompanied by a deficit of mineralcorticoids and adrenal androgens. The substitutive treatment is aimed at reducing the signs and symptoms of the disease as well as at preventing the development of an addisonian crisis, a clinical emergency characterized by hypovolemic shock. The oral substitutive treatment should attempt at mimicking the normal circadian profile of cortisol secretion, by using the lower possible doses able to guarantee an adequate quality of life to patients. The currently available hydrocortisone or cortisone acetate preparations do not allow an accurate reproduction of the physiological secretion pattern of cortisol. A novel dual-release formulation of hydrocortisone, recently approved by EMEA, represents an advancement in the optimization of the clinical management of patients with adrenal insufficiency. Future clinical trials of immunomodulation or immunoprevention will test the possibility to delay (or prevent) the autoimmune destruction of the adrenal gland in autoimmune Addison’s disease.

Keywords

21-Hydroxylase autoantibodies ACTH Addison’s disease Congenital adrenal hyperplasia Cortisone acetate Fludrocortisone Hydrocortisone 

References

  1. 1.
    W. Oelkers, Adrenal insufficiency. N. Engl. J. Med. 335, 1206–1212 (1996)PubMedCrossRefGoogle Scholar
  2. 2.
    S. Ten, M. New, N. Maclaren, Clinical review 130: Addison’s disease 2001. J. Clin. Endocrinol. Metab. 86, 2909–2922 (2001)PubMedCrossRefGoogle Scholar
  3. 3.
    T. Addison, On the constitutional and local effects of disease of the supra-renal capsules. 1855. Reproduced in Dr. Addison’s works. New Sydenham Soc. 36, 211–239 (1868)Google Scholar
  4. 4.
    P. Aubourg, The expanding world of primary adrenal insufficiencies. Eur. J. Endocrinol. 137, 10–12 (1997)PubMedCrossRefGoogle Scholar
  5. 5.
    S. Laureti, F. Santeusanio, A. Falorni, Recent advances in the diagnosis and therapy of primary adrenal insufficiency. Curr. Med. Chem. 2, 251–258 (2002)Google Scholar
  6. 6.
    A.S. Mason, T.W. Meade, J.A.H. Lee, J.N. Morris, Epidemiological and clinical picture of Addison’s disease. Lancet II, 744–747 (1968)CrossRefGoogle Scholar
  7. 7.
    J. Nerup, Addison’s disease—clinical studies. A report of 108 cases. Acta Endocrinol. (Copenh.) 76, 127–141 (1974)Google Scholar
  8. 8.
    S. Laureti, L. Vecchi, F. Santeusanio, A. Falorni, Is the prevalence of Addison’s disease underestimated? J. Clin. Endocrinol. Metab. 84, 1762 (1999)PubMedCrossRefGoogle Scholar
  9. 9.
    M.F. Kong, W. Jeffcoate, Eighty-six cases of Addison’s disease. Clin. Endocrinol. (Oxf.) 41, 757–761 (1994)CrossRefGoogle Scholar
  10. 10.
    A.C. Willis, F.P. Vince, The prevalence of Addison’s disease in Coventry, UK. Postgrad. Med. J. 73, 286–288 (1997)PubMedCrossRefGoogle Scholar
  11. 11.
    K. Løvas, E.S. Husebye, High prevalence and increasing incidence of Addison’s disease in western Norway. Clin. Endocrinol. (Oxf.) 56, 787–791 (2002)CrossRefGoogle Scholar
  12. 12.
    C. Betterle, C. Dal Pra, F. Mantero, R. Zanchetta, Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr. Rev. 23, 327–364 (2002)PubMedCrossRefGoogle Scholar
  13. 13.
    A. Falorni, A. Brozzetti, F. Calcinaro, S. Marzotti, F. Santeusanio, Recent advances in adrenal autoimmunity. Expert Rev. Clin. Endocrinol. Metab. 4, 333–348 (2009)CrossRefGoogle Scholar
  14. 14.
    O. Winqvist, F.A. Karlsson, O. Kämpe, 21-Hydroxylase, a major autoantigen in idiopathic Addison’s disease. Lancet 339, 1559–1562 (1992)PubMedCrossRefGoogle Scholar
  15. 15.
    A. Baumann-Antczak, N. Wedlock, J. Bednarek, Y. Kiso, H. Krishnan, S. Fowler, B. Rees Smith, J. Furmaniak, Autoimmune Addison’s disease and 21-hydroxylase. Lancet 340, 429–430 (1992)PubMedCrossRefGoogle Scholar
  16. 16.
    J. Bednarek, J. Furmaniak, N. Wedlock, Y. Kiso, A. Baumann-Antczak, S. Fowler, H. Krishnan, J.A. Craft, B. Rees Smith, Steroid 21-hydroxylase is a major autoantigen involved in adult onset autoimmune Addison’s disease. FEBS Lett. 309, 51–55 (1992)PubMedCrossRefGoogle Scholar
  17. 17.
    A. Falorni, A. Nikoshkov, S. Laureti et al., High diagnostic accuracy for idiopathic Addison’s disease with a sensitive radiobinding assay for autoantibodies against recombinant human 21-hydroxylase. J. Clin. Endocrinol. Metab. 80, 2752–2755 (1995)PubMedCrossRefGoogle Scholar
  18. 18.
    J. Colls, C. Betterle, M. Volpato, L. Prentice, B.R. Smith, J. Furmaniak, Immunoprecipitation assay for autoantibodies to steroid 21-hydroxylase in autoimmune adrenal diseases. Clin. Chem. 41, 375–380 (1995)PubMedGoogle Scholar
  19. 19.
    H. Tanaka, M.S. Perez, M. Powell et al., Steroid 21-hydroxylase autoantibodies: measurements with a new immunoprecipitation assay. J. Clin. Endocrinol. Metab. 82, 1440–1446 (1997)PubMedCrossRefGoogle Scholar
  20. 20.
    R. Nigam, E. Bhatia, D. Mei, L. Yu, A. Brozzetti, G.S. Eisenbarth, A. Falorni, Low prevalence of 21-hydroxylase antibodies in idiopathic Addison’s disease from India. Clin. Endocrinol. 59, 593–598 (2003)CrossRefGoogle Scholar
  21. 21.
    F. Kelestimur, The endocrinology of adrenal tuberculosis: the effects of tuberculosis on the hypothalamo-pituitary-adrenal axis and adrenocortical function. J. Endocrinol. Invest. 27, 380–386 (2004)PubMedGoogle Scholar
  22. 22.
    P. Aubourg, On the front of X-linked adrenoleukodystrophy. Neurochem. Res. 24, 515–520 (1999)PubMedCrossRefGoogle Scholar
  23. 23.
    E.R. McCabe, DAX1: increasing complexity in the roles of this novel nuclear receptor. Mol. Cell. Endocrinol. 265–266, 179–182 (2007)PubMedCrossRefGoogle Scholar
  24. 24.
    J.C. Achermann, M. Ito, M. Ito, P.C. Hindmarsch, J.L. Jameson, A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat. Genet. 22, 125–126 (1999)PubMedCrossRefGoogle Scholar
  25. 25.
    A.J. Clark, L. McLoughlin, A. Grossman, Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor. Lancet 341, 461–462 (1993)PubMedCrossRefGoogle Scholar
  26. 26.
    A. Weber, T.F. Wienker, M. Jung, D. Easton, H.J. Dean, C. Heinrichs, A. Reis, A.J. Clark, Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster. Hum. Mol. Genet. 5, 2061–2066 (1996)PubMedCrossRefGoogle Scholar
  27. 27.
    K. North, M.S. Korson, N. Krawiecki, J.M. Shoffner, I.A. Holm, Oxidative phosphorylation defect associated with primary adrenal insufficiency. J. Pediatrics 128, 688–692 (1996)CrossRefGoogle Scholar
  28. 28.
    H.C. Andersson, J. Frentz, J.E. Martínez, C.M. Tuck-Muller, J. Bellizaire, Adrenal insufficiency in Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 82, 382–384 (1999)PubMedCrossRefGoogle Scholar
  29. 29.
    R. Perry, O. Kecha, J. Paquette, C. Huot, G. Van Vliet, C. Deal, Primary adrenal insufficiency in children: twenty years experience at the Sainte-Justine Hospital, Montreal. J. Clin. Endocrinol. Metab. 92, 4602–4608 (2005)Google Scholar
  30. 30.
    C. Betterle, C. Scalici, F. Presotto et al., The natural history of adrenal function in autoimmune patients with adrenal autoantibodies. J. Endocrinol. 117, 467–475 (1988)PubMedCrossRefGoogle Scholar
  31. 31.
    A. De Bellis, A. Bizzarro, R. Rossi, V.A. Paglionico, T. Criscuolo, G. Lombardi, A. Bellastella, Remission of subclinical adrenocortical failure in subjects with adrenal autoantibodies. J. Clin. Endocrinol. Metab. 76, 1002–1007 (1993)PubMedCrossRefGoogle Scholar
  32. 32.
    C. Betterle, M. Volpato, B. Rees-Smith et al., I. Adrenal cortex and steroid 21-hydroxylase autoantibodies in adult patients with organ-specific autoimmune diseases: markers of low progression to clinical Addison’s disease. J. Clin. Endocrinol. Metab. 82, 932–938 (1997)PubMedCrossRefGoogle Scholar
  33. 33.
    C. Betterle, M. Volpato, B. Rees Smith, J. Furmaniak, S. Chen, R. Zanchetta, N.A. Greggio, B. Pedini, M. Boscaro, F. Presotto II, Adrenal cortex and steroid 21-hydroxylase autoantibodies in children with organ-specific autoimmune diseases: markers of high progression to clinical Addison’s disease. J. Clin. Endocrinol. Metab. 82, 939–942 (1997)PubMedCrossRefGoogle Scholar
  34. 34.
    S. Laureti, A. De Bellis, V.I. Muccitelli et al., Levels of adrenocortical autoantibodies correlate with the degree of adrenal dysfunction in subjects with preclinical Addison’s disease. J. Clin. Endocrinol. Metab. 83, 3507–3511 (1998)PubMedCrossRefGoogle Scholar
  35. 35.
    G. Coco, C. Dal Pra, F. Presotto et al., Estimated risk for developing autoimmune Addison’s disease in patients with adrenal cortex autoantibodies. J. Clin. Endocrinol. Metab. 91, 1637–1645 (2006)PubMedCrossRefGoogle Scholar
  36. 36.
    B. Jacobs, C. Papewalis, M. Ehlers, M. Schott, Endocrine organs under the control of the immune system: potential implications for cellular therapies. Horm. Metab. Res. 42, 912–917 (2010)PubMedCrossRefGoogle Scholar
  37. 37.
    K.I. Papadopoulos, B. Hallengren, Polyglandular autoimmune syndrome type II in patients with idiopathic Addison’s disease. Acta Endocrinol. (Copenh.) 122, 472–478 (1990)Google Scholar
  38. 38.
    A.A. Kasperlik-Zaluska, B. Migdalska, B. Czarnocka, J. Drac-Kaniewska, E. Niegowska, W. Czech, Association of Addison’s disease with autoimmune disorders—a long-term observation of 180 patients. Postgrad. Med. J. 67, 984–987 (1991)PubMedCrossRefGoogle Scholar
  39. 39.
    P.M. Zelissen, E.J. Bast, R.J. Croughs, Associated autoimmunity in Addison’s disease. J. Autoimmunity 8, 121–130 (1995)CrossRefGoogle Scholar
  40. 40.
    A. La Marca, A. Brozzetti, G. Sighinolfi, S. Marzotti, A. Volpe, A. Falorni, Primary ovarian insufficiency: autoimmune causes. Curr. Opin. Obstet. Gynecol. 22, 277–282 (2010)PubMedGoogle Scholar
  41. 41.
    G.S. Eisenbarth, P.A. Gottlieb, Autoimmune polyendocrine syndromes. N. Engl. J. Med. 350, 2068–2079 (2004)PubMedCrossRefGoogle Scholar
  42. 42.
    P. Peterson, J. Pitkänen, N. Sillanpää, K. Krohn, Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED): a model disease to study molecular aspects of endocrine autoimmunity. Clin. Exp. Immunol. 135, 348–357 (2004)PubMedCrossRefGoogle Scholar
  43. 43.
    A. Meager, K. Visvalingam, P. Peterson, K. Möll, A. Murumägi, K. Krohn, P. Eskelin, J. Perheentupa, E. Husebye, Y. Kadota, N. Willcox, Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. 3, e289 (2006)PubMedCrossRefGoogle Scholar
  44. 44.
    A. Meloni, M. Furcas, F. Cetani, C. Marcocci, A. Falorni, R. Perniola, M. Pura, A.S. Bøe Wolff, E. Husebye, D. Lilic, K.R. Ryan, A.R. Gennery, A.J. Cant, M. Abinun, G.P. Spickett, P.D. Arkwright, D. Denning, C. Costigan, M. Dominguez, V. McConnell, N. Willcox, A. Meager, Autoantibodies against type I Interferons as an additional diagnostic criteria for Autoimmune Polyendocrine Syndrome type 1. J. Clin. Endocrinol. Metab. 93, 4389–4397 (2008)PubMedCrossRefGoogle Scholar
  45. 45.
    A. Falorni, A. Brozzetti, D. La Torre, C. Tortoioli, G. Gambelunghe, The association of genetic polymorphisms and autoimmune Addison’s disease. Expert Rev. Clin. Immunol. 4, 441–456 (2008)PubMedCrossRefGoogle Scholar
  46. 46.
    P.W. Speiser, R. Azziz, L.S. Baskin, L. Ghizzoni, T.W. Hensle, D.P. Merke, H.F. Meyer-Bahlburg, W.L. Miller, V.M. Montori, S.E. Oberfield, M. Ritzen, P.C. White, Endocrine Society. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 95, 4133–4160 (2010)PubMedCrossRefGoogle Scholar
  47. 47.
    A. Nordenström, S. Ahmed, J. Jones, M. Coleman, D.A. Price, P.E. Clayton, C.M. Hall, Female preponderance in congenital adrenal hyperplasia due to CYP21 deficiency in England: implications for neonatal screening. Horm. Res. 63, 22–28 (2005)PubMedCrossRefGoogle Scholar
  48. 48.
    S. Pang, M.K. Shook, Current status of neonatal screening for congenital adrenal hyperplasia. Curr. Opin. Pediatr. 9, 419–423 (1997)PubMedCrossRefGoogle Scholar
  49. 49.
    B.L. Therrell, Newborn screening for congenital adrenal hyperplasia. Endocrinol. Metab. Clin. North Am. 30, 15–30 (2001)PubMedCrossRefGoogle Scholar
  50. 50.
    H.J. van der Kamp, J.M. Wit, Neonatal screening for congenital adrenal hyperplasia. Eur. J. Endocrinol. 151(Suppl 3), U71–U75 (2004)PubMedCrossRefGoogle Scholar
  51. 51.
    G. Reimondo, S. Bovio, B. Allasino, M. Terzolo, A. Angeli, Secondary hypoadrenalism. Pituitary 11, 147–154 (2008)PubMedCrossRefGoogle Scholar
  52. 52.
    P. Caturegli, C. Newschaffer, A. Olivi, M.G. Pomper, P.C. Burger, N.R. Rose, Auutoimmune hypophysitis. Endocr. Rev. 26, 599–614 (2005)PubMedCrossRefGoogle Scholar
  53. 53.
    M.S. Cooper, P.M. Stewart, Corticosteroid insufficiency in acutely ill patients. N. Engl. J. Med. 348, 727–734 (2003)PubMedCrossRefGoogle Scholar
  54. 54.
    E. Arvat, L. Di Vito, F. Lanfranco, M. Maccario, C. Baffoni, R. Rossetto, G. Aimaretti, F. Camanni, E. Ghigo, Stimulatory effect of adrenocorticotropin on cortisol, aldosterone, and dehydroepiandrosterone secretion in normal humans: dose-response study. J. Clin. Endocrinol. Metab. 85, 3141–3146 (2000)PubMedCrossRefGoogle Scholar
  55. 55.
    S. Laureti, E. Arvat, P. Candeloro, L. Di Vito, E. Ghigo, F. Santeusanio, A. Falorni, Low dose (1 microg) ACTH test in the evaluation of adrenal dysfunction in pre-clinical Addison’s disease. Clin. Endocrinol. (Oxf.) 53, 107–115 (2000)CrossRefGoogle Scholar
  56. 56.
    S. Laureti, P. Candeloro, M.C. Aglietti, R. Giordano, E. Arvat, E. Ghigo, F. Santeusanio, A. Falorni, Dehydroepiandrosterone, 17alpha-hydroxyprogesterone and aldosterone responses to the low-dose (1 micro g) ACTH test in subjects with preclinical adrenal autoimmunity. Clin. Endocrinol. (Oxf.) 57, 677–683 (2002)CrossRefGoogle Scholar
  57. 57.
    A. Falorni, S. Laureti, A. De Bellis et al., Italian Addison Network Study: update of diagnostic criteria for the etiological classification of primary adrenal insufficiency. J. Clin. Endocrinol. Metab. 89, 1598–1604 (2004)PubMedCrossRefGoogle Scholar
  58. 58.
    S. Laureti, P. Aubourg, F. Calcinaro, F. Rocchiccioli, G. Casucci, G. Angeletti, P. Brunetti, Å. Lernmark, F. Santeusanio, A. Falorni, Etiological diagnosis of primary adrenal insufficiency using an original flow-chart of immune and biochemical markers. J. Clin. Endocrinol. Metab. 83, 3163–3168 (1998)PubMedCrossRefGoogle Scholar
  59. 59.
    E.S. Husebye, J. Perheentupa, R. Rautemaa, O. Kämpe, Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J. Intern. Med. 265, 514–529 (2009)PubMedCrossRefGoogle Scholar
  60. 60.
    A. Falorni, S. Laureti, P. Candeloro et al., Steroid-cell autoantibodies are preferentially expressed in women with premature ovarian failure who have adrenal autoimmunity. Fertil. Steril. 78, 270–279 (2002)PubMedCrossRefGoogle Scholar
  61. 61.
    G. Reato, L. Morlin, S. Chen, J. Furmaniak, B.R. Smith, S. Masiero, M.P. Albergoni, S. Cervato, R. Zanchetta, C. Betterle, Premature ovarian failure in patients with autoimmune Addison’s disease: clinical, genetic, and immunological evaluation. J. Clin. Endocrinol. Metab. 96, E1255–E1261 (2011)PubMedCrossRefGoogle Scholar
  62. 62.
    A. Falorni, S. Chen, R. Zanchetta, L. Yu, C. Tiberti, M.L. Bacosi, J. Furmaniak, V. Bini, F. Dotta, G.S. Eisenbarth, B.R. Smith, C. Betterle, Measuring adrenal autoantibody response: interlaboratory concordance in the first international serum exchange for the determination of 21-hydroxylase autoantibodies. Clin. Immunol. 140, 291–299 (2011)PubMedCrossRefGoogle Scholar
  63. 63.
    K. Lovas, E.S. Husebye, Replacement therapy in Addison’s disease. Expert Opin. Pharmacother. 4, 2145–2149 (2003)PubMedCrossRefGoogle Scholar
  64. 64.
    W. Arlt, B. Allolio, Adrenal insufficiency. Lancet 361, 1881–1893 (2003)PubMedCrossRefGoogle Scholar
  65. 65.
    N.V. Esteban, T. Loughlin, A.L. Yergay, J.K. Zawadki, J.D. Booth, J.C. Winterer et al., Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J. Clin. Endocrinol. Metab. 72, 39–45 (1991)PubMedCrossRefGoogle Scholar
  66. 66.
    H. Filipsson, J.P. Monson, M. Koltowska-Häggström, A. Mattsson, G. Johansson, The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients. J. Clin. Endocrinol. Metab. 91, 3954–3961 (2006)PubMedCrossRefGoogle Scholar
  67. 67.
    R.M. Reynolds, P.M. Stewart, J.R. Seckl, P.L. Padfield, Assessing the HPA axis in patients with pituitary disease: a UK survey. Clin. Endocrinol. (Oxf) 64, 82–85 (2006)CrossRefGoogle Scholar
  68. 68.
    C.M. Feek, J.G. Ratcliffe, J. Seth, C.E. Gray, A.D. Toft, W.J. Irvine, Patterns of plasma cortisol and ACTH concentrations in patients with Addison’s disease treated with conventional corticosteroid replacement. Clin. Endocrinol. (Oxf.) 14, 451–458 (1981)CrossRefGoogle Scholar
  69. 69.
    R.S. Scott, R.A. Donald, E.A. Espiner, Plasma ACTH and cortisol profiles in Addisonian patients receiving conventional substitution therapy. Clin. Endocrinol. (Oxf.) 9, 571–576 (1978)CrossRefGoogle Scholar
  70. 70.
    W. Jeffcoate, Assessment of corticosteroid replacement therapy in adults with adrenal insufficiency. Ann. Clin. Biochem. 36(2), 151–157 (1999)PubMedGoogle Scholar
  71. 71.
    S. Laureti, A. Falorni, F. Santeusanio, Improvement of treatment of primary adrenal insufficiency by administration of cortisone acetate in three daily doses. J. Endocrinol. Invest. 26, 1071–1075 (2003)PubMedGoogle Scholar
  72. 72.
    W. Arlt, C. Rosenthal, S. Hahner, B. Allolio: Quality of glucocorticoid replacement in adrenal insufficiency: clinical assessment vs. timed serum cortisol measurements. Clin. Endocrinol. (Oxf.) 64, 384–389 (2006)Google Scholar
  73. 73.
    P.M. Mah, R.C. Jenkins, A. Rostami-Hodjegan, J. Newell-Price, A. Doane et al., Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clin. Endocrinol. (Oxf.) 61, 367–375 (2004)CrossRefGoogle Scholar
  74. 74.
    A.W. Meikle, J.D. Stringham, M.G. Woodward, D.T. Bishop, Heritability of variation of plasma cortisol levels. Metabolism 37, 514–517 (1988)PubMedCrossRefGoogle Scholar
  75. 75.
    A.L. Barbato, R.L. Landau, Serum cortisol appearance-disappearance in adrenal insufficiency after oral cortisone acetate. Acta Endocrinol. (Copenh.) 84, 600–604 (1977)Google Scholar
  76. 76.
    R.W. Groves, G.C. Toms, B.J. Hougthon, J.P. Monson, Corticosteroid replacement therapy: twice or thrice daily? J.R.Soc.Med. 81, 514–516 (1988)PubMedGoogle Scholar
  77. 77.
    L. Barbetta, C. Dall’Asta, T. Re, R. Libè, E. Costa, B. Ambrosi, Comparison of different regimens of glucocorticoid replacement therapy in patients with hypoadrenalism. J. Endocrinol. Invest. 28, 632–637 (2005)PubMedGoogle Scholar
  78. 78.
    T.A. Howlett, An assessment of optimal hydrocortisone replacement therapy. Clin. Endocrinol. (Oxf.) 46, 263–268 (1997)CrossRefGoogle Scholar
  79. 79.
    A.H. Thomson, M.C. Devers, A.M. Wallace, D. Grant, K. Campbell et al., Variability in hydrocortisone plasma and saliva pharmacokinetics following intravenous and oral administration to patients with adrenal insufficiency. Clin. Endocrinol. (Oxf.) 66, 789–796 (2007)CrossRefGoogle Scholar
  80. 80.
    E. Charmandari, A. Johnston, C.G. Brook, P.C. Hindmarsh, Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J. Endocrinol. 169, 65–70 (2001)PubMedCrossRefGoogle Scholar
  81. 81.
    B. Sauve, G. Koren, G. Walsh, S. Tokmakejian, S.H. Van Uum, Measurement of cortisol in human hair as a biomarker of systemic exposure. Clin. Invest. Med. 30, E183–E191 (2007)PubMedGoogle Scholar
  82. 82.
    L.F. Hofman, Human saliva as a diagnostic specimen. J. Nutr. 131, 1621S–1625S (2001)PubMedGoogle Scholar
  83. 83.
    A. Moreira, F. Arsati, de Oliveira Lima Arsati, Y.B., da Silva, D.A. de Araujo, V.C. Salivary cortisol in top-level professional soccer players. Eur. J. Appl. Physiol. 106, 25–30 (2009)PubMedCrossRefGoogle Scholar
  84. 84.
    D. Riad-Fahmy, G.F. Read, R.F. Walker, Salivary steroid assays for assessing variation in endocrine activity. J. Steroid Biochem. 19, 265–272 (1983)PubMedCrossRefGoogle Scholar
  85. 85.
    M. Groschl, Current status of salivary hormone analysis. Clin. Chem. 54, 1759–1769 (2008)PubMedCrossRefGoogle Scholar
  86. 86.
    I. Perogamvros, B.G. Keevil, D.W. Ray, P.J. Trainer, Salivary cortisone is a potential biomarker for serum free cortisol. J. Clin. Endocrinol. Metab. 95, 4951–4958 (2010)PubMedCrossRefGoogle Scholar
  87. 87.
    L.D. Dorn, J.F. Lucke, T.L. Loucks, S.L. Berga, Salivary cortisol reflects serum cortisol: analysis of circadian profiles. Ann. Clin. Biochem. 44, 281–284 (2007)PubMedCrossRefGoogle Scholar
  88. 88.
    J.G. Lewis, Steroid analysis in saliva: an overview. Clin. Biochem. Rev. 27, 139–146 (2006)PubMedGoogle Scholar
  89. 89.
    P. Wood, Salivary steroid assays – research or routine? Ann. Clin. Biochem. 46, 183–196 (2009)PubMedCrossRefGoogle Scholar
  90. 90.
    J.W. Findling, H. Raff, Cushing’s Syndrome: important issues in diagnosis and management. J. Clin. Endocrinol. Metab. 91, 3746–3753 (2006)PubMedCrossRefGoogle Scholar
  91. 91.
    H. Raff, Utility of salivary cortisol measurements in Cushing’s syndrome and adrenal insufficiency. J. Clin. Endocrinol. Metab. 94, 3647–3655 (2009)PubMedCrossRefGoogle Scholar
  92. 92.
    H. Raff, Salivary cortisol and the diagnosis of Cushing’s syndrome: a coming age. Endocrine 41, 353–354 (2012)PubMedCrossRefGoogle Scholar
  93. 93.
    E.M. Scott, H.H. McGarrigle, G.C. Lachelin, The increase in plasma and saliva cortisol levels in pregnancy is not due to the increase in corticosteroid-binding globulin levels. J. Clin. Endocrinol. Metab. 71, 639–644 (1990)PubMedCrossRefGoogle Scholar
  94. 94.
    A.M. Maguire, G.R. Ambler, B. Moore, M. McLean, M.G. Falleti, C.T. Cowell, Prolonged hypocortisolemia in hydrocortisone replacement regimens in adrenocorticotrophic hormone deficiency. Pediatrics 120, e164–e171 (2007)PubMedCrossRefGoogle Scholar
  95. 95.
    V. Wong, T. Yan, A. Donald, M. McLean, Saliva and bloodspot cortisol: novel sampling methods to assess hydrocortisone replacement therapy in hypoadrenal patients. Clin. Endocrinol. (Oxf.) 61, 131–137 (2004)CrossRefGoogle Scholar
  96. 96.
    K. Lovås, T.E. Thorsten, E.S. Husebye, Saliva cortisol measurement: simple and reliable assessment of the glucocorticoid replacement therapy in Addison’s disease. J. Endocrinol. Invest. 29, 727–731 (2006)PubMedGoogle Scholar
  97. 97.
    K. Lovås, E.S. Husebye, Continuous subcutaneous hydrocortisone infusion in Addison’s disease. Eur. J. Endocrinol. 157, 109–112 (2007)PubMedCrossRefGoogle Scholar
  98. 98.
    P. Restituto, J.C. Galofre, M.J. Gil, C. Mugueta, S. Santos et al., Advantage of salivary cortisol measurements in the diagnosis of glucocorticoid related disorders. Clin. Biochem. 41, 688–692 (2008)PubMedCrossRefGoogle Scholar
  99. 99.
    E. Badrick, C. Kirschbaum, M. Kumari, A. Steptoe, K. O’Donnell, M. Marmot, The relationship between smokling status and cortisol secretion. J. Clin. Endocrinol. Metab. 92, 819–824 (2007)PubMedCrossRefGoogle Scholar
  100. 100.
    A.M. Hansen, A.H. Garde, R. Persson, Sources of biological and methodological variation in salivary cortisol and their impact on measurement among healthy adults: a review. Scand. J. Clin. Lab. Invest. 68, 448–458 (2008)PubMedCrossRefGoogle Scholar
  101. 101.
    J. Vialard-Miguel, N. Belaidi, L. Lembeye, J.B. Corcuff, Lemon juice alters cortisol assays in saliva. Clin. Endocrinol. (Oxf.) 63, 478–479 (2005)CrossRefGoogle Scholar
  102. 102.
    M. Groschl, R. Wagner, M. Rauh, H.G. Dorr, Stability of salivary steroids: the influences of storage, food and dental care. Steroids 66, 737–741 (2001)PubMedCrossRefGoogle Scholar
  103. 103.
    M.C. Garcia, A. de Souza, G.P. Bella, D.M. Grassi-Kassisse, A.P. Tacla, R.C. Sapadari-Bratfisch, Salivary cortisol levels in Brazilian citizens of distintc socioeconomic and cultural levels. Ann.N.Y.Acad.Sci. 1148, 504–508 (2008)PubMedCrossRefGoogle Scholar
  104. 104.
    G.L. Brown, E.L. McGarvey, E.A. Schirtcliff, A. Keller, D.A. Granger, K. Flavin, Salivary cortisol, dehydroepiandrosterone, and testosterone interrelationships in healthy young males: a pilot study with implications for studies of aggressive behavior. Psychistry Res. 159, 67–76 (2008)CrossRefGoogle Scholar
  105. 105.
    S. Hahner, M. Loeefler, B. Bleicken, C. Drechsler, D. Milovanovic, M. Fassnacht, M. Ventz, M. Quinkler, B. Allolio, Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. Eur. J. Endocrinol. 162, 597–602 (2010)PubMedCrossRefGoogle Scholar
  106. 106.
    K. White, W. Arlt, Adrenal crisis in treated Addison’s disease: a predictable but under-managed event. Eur. J. Endocrinol. 162, 115–120 (2010)PubMedCrossRefGoogle Scholar
  107. 107.
    A.J. Chakera, B. Vaidya, Addison’s disease in adults: diagnosis and management. Am. J. Medicine 123, 409–413 (2010)CrossRefGoogle Scholar
  108. 108.
    W. Oelkers, Mineralocorticoid substitution in pregnant Addisonian women. J. Endocrinol. Invest. 27, 406 (2004)PubMedGoogle Scholar
  109. 109.
    P. Methlie, E.E. Husebye, S. Hustad, E.A. Lien, K. Løvås, Grapefruit juice and licorice increase cortisol availability in patients with Addison’s disease. Eur. J. Endocrinol. 165, 761–769 (2011)PubMedCrossRefGoogle Scholar
  110. 110.
    H. Cooper, B. Bhattacharya, V. Verma, A.J. McCulloch, W.S. Smellie, A.H. Heald, Liquorice and soy sauce, a life-saving concoction in a patient with Addison’s disease. Ann. Clin. Biochem. 44, 397–399 (2007)PubMedCrossRefGoogle Scholar
  111. 111.
    B. Ambrosi, L. Barbetta, L. Morricone, Diagnosis and management of Addison’s disease during pregnancy. J. Endocrinol. Invest. 26, 698–702 (2003)PubMedGoogle Scholar
  112. 112.
    E. Barrett-Connor, K.T. Khaw, S.S.C. Yen, A prospective study of dehydroepiandrosterone sulfate, mortality and cardiovascular disease. N. Engl. J. Med. 315, 1519–1524 (1986)PubMedCrossRefGoogle Scholar
  113. 113.
    P. Ebeling, V.A. Kiovisto, Physiological importance of dehydroepiandrosterone. Lancet 343, 1479–1481 (1994)PubMedCrossRefGoogle Scholar
  114. 114.
    P. Sambrook, J. Birmingham, D. Champion, P. Kelly, S. Kempler, J. Freund, J. Eisman, Postmenopausal bone loss in rheumatoid arthritis: effect of estrogens and androgens. J. Rheumatol. 19, 357–361 (1992)PubMedGoogle Scholar
  115. 115.
    R. Libè, L. Barbetta, C. Dall’Asta, F. Salvaggio, C. Gala, P. Beck-Peccoz, B. Ambrosi, Effects of dehydroepiandrosterone (DHEA) supplementation on hormonal, metabolic and behavioral status in patients with hypoadrenalism. J. Endocrinol. Invest. 27, 736–741 (2004)PubMedGoogle Scholar
  116. 116.
    W. Arlt, F. Callies, J.C. van Vlijmen, I. Koehler, M. Reincke, M. Bidlingmaier, D. Huebler, M. Oettel, M. Ernst, H.M. Schulte, B. Allolio, Dehydroepiandrosterone replacement in women with adrenal insufficiency. N. Engl. J. Med. 341, 1013–1020 (1999)PubMedCrossRefGoogle Scholar
  117. 117.
    P.J. Hunt, E.M. Gurnell, F.A. Huppert, C. Richards, A.T. Prevost, J.A. Wass, J. Herbert, V.K. Chatterjee, Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison’s disease in a randomized, double blind trial. J. Clin. Endocrinol. Metab. 85, 4650–4656 (2000)PubMedCrossRefGoogle Scholar
  118. 118.
    E.M. Gurnell, P.J. Hunt, S.E. Curran, C.L. Conway, E.M. Pullenayegum, F.A. Huppert, J.E. Compston, J. Herbert, V.K.K. Chatterjee, Long-term DHEA replacement in primary adrenal insufficiency: a randomized, controlled trial. J. Clin. Endocrinol. Metab. 93, 400–409 (2008)PubMedCrossRefGoogle Scholar
  119. 119.
    R. Bergthorsdottir, M. Leonsson-Zachrisson, A. Odén, G. Johannsson, Premature mortality in patients with Addison’s disease: a population-based study. J. Clin. Endocrinol. Metab. 91, 4849–4853 (2006)PubMedCrossRefGoogle Scholar
  120. 120.
    S. Bensing, L. Brandt, F. Tabaroj, O. Sjöberg, B. Nilsson, A. Ekbom, P. Blomqvist, O. Kämpe, Increased death risk and altered cancer incidence pattern in patients with isolated or combined autoimmune primary adrenocortical insufficiency. Clin. Endocrinol. (Oxf.) 69, 697–704 (2008)CrossRefGoogle Scholar
  121. 121.
    M.M. Erichsen, K. Løvås, K.J. Fougner, J. Svartberg, E.R. Hauge, J. Bollerslev, J.P. Berg, B. Mella, E.S. Husebye, Normal overall mortality rate in Addison’s disease, but young patients are at risk of premature death. Eur. J. Endocrinol. 160, 233–237 (2009)PubMedCrossRefGoogle Scholar
  122. 122.
    T. Rosén, B.A. Bengtsson, Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 336, 285–288 (1990)PubMedCrossRefGoogle Scholar
  123. 123.
    J.W. Tomlinson, N. Holden, R.K. Hills, K. Wheatley, R.N. Clayton, A.S. Bates, M.C. Sheppard, P.M. Stewart, Association between premature mortality and hypopituitarism. West Midlands Propsective Hypopituitary Study Group. Lancet 357, 425–431 (2001)PubMedCrossRefGoogle Scholar
  124. 124.
    J.L. Mills, L.B. Schonberger, D.K. Wysowski, P. Brown, S.J. Durako, C. Cox, F. Kong, J.E. Fradkin, Long-term mortality in the United States cohort of pituitary-derived growth hormone recipients. J. Pediatr. 144, 430–436 (2004)PubMedCrossRefGoogle Scholar
  125. 125.
    W.H. Ettinger, H.F. Klinefelter, P.O. Kwiterovitch, Effect of short-term, low-dose corticosteroids on plasma lipoprotein lipids. Atherosclerosis 63, 167–172 (1987)PubMedCrossRefGoogle Scholar
  126. 126.
    H.K. Choi, J.D. Seeger, Glucocorticoid use and serum lipid levels in US adults: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 53, 528–535 (2005)PubMedCrossRefGoogle Scholar
  127. 127.
    A.K. McDonough, J.R. Curtis, K.G. Saag, The epidemiology of glucocorticoid-associated adverse events. Curr. Opin. Rheumatol. 20, 131–137 (2008)PubMedCrossRefGoogle Scholar
  128. 128.
    I. Karp, M. Abrahamowicz, P.R. Fortin, L. Pilote, C. Neville, C. Pineau et al., Recent corticosteroid use and recent disease activity: independent determinants of coronary heart disease risk factors in systemic lupus erythematosus? Arthritis Rheum. 59, 169–175 (2008)PubMedCrossRefGoogle Scholar
  129. 129.
    D.H. van Raalte, D.M. Ouwens, M. Diamant, Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options? Eur. J. Clin. Invest. 39, 81–93 (2009)PubMedCrossRefGoogle Scholar
  130. 130.
    K. Walker-Bone, Recognizing and treating secondary osteoporosis. Nat. Rev. Rheumatol. 8, 480–492 (2012)PubMedCrossRefGoogle Scholar
  131. 131.
    G.P. Rossi, T.M. Seccia, C. Maniero, A.C. Pessina, Drug-related hypertension and resistance to antihypertensive treatment: a call for action. J. Hypertens. 29, 2295–2309 (2011)PubMedCrossRefGoogle Scholar
  132. 132.
    J.L. Beaudry, M.C. Riddell, Effects of glucocorticoids and exercise on pancreatic β cell function and diabetes development. Diabetes Metab. Res. Rev. doi: 10.1002/dmrr.2310 (2012)
  133. 133.
    M.N. Nanjee, N.E. Miller, Plasma lipoproteins and adrenocortical hormones in men—positive association of low density lipoprotein cholesterol with plasma cortisol concentration. Clin. Chim. Acta 180, 113–120 (1989)PubMedCrossRefGoogle Scholar
  134. 134.
    K.A. al-Shoumer, K.H. Cox, C.L. Hughes, W. Richmond, D.G. Johnston, Fasting and postprandial lipid abnormalities in hypopituitary women receiving conventional replacement therapy. J.Clin.Endocrinol.Metab. 82, 2653–2659 (1997)PubMedCrossRefGoogle Scholar
  135. 135.
    V. Markussis, S.A. Beshyah, C. Fisher, P. Sharp, A.N. Nicolaides, D.G. Johnston, Detection of premature atherosclerosis by high-resolution ultrasonography in symptom-free hypopituitary adults. Lancet 340, 1188–1192 (1992)PubMedCrossRefGoogle Scholar
  136. 136.
    R. Giordano, S. Marzotti, M. Balbo, S. Romagnoli, E. Marinazzo, R. Berardelli, G. Migliaretti, A. Benso, A. Falorni, E. Ghigo, E. Arvat, Metabolic and cardiovascular profile in patients with Addison’s disease under conventional glucocorticoid replacement. J. Endocrinol. Invest. 32, 917–923 (2009)PubMedGoogle Scholar
  137. 137.
    R. Giordano, S. Marzotti, R. Berardelli, I. Karamouzis, A. Brozzetti, V. D’Angelo, G. Mengozzi, G. Mandrile, D. Giachino, G. Migliaretti, V. Bini, A. Falorni, E. Ghigo, E. Arvat, BCLI polymorphism of the glucocorticoid receptor gene is associated with increased obesity, impaired glucose metabolism and dyslipidemia in patients with Addison’s disease. Clin. Endocrinol. (Oxf.). doi: 10.1111/j.1365-2265.2012.04439.x (2012)
  138. 138.
    J.P. Devogelaer, J. Crabbé, C. Nagant de Deuxchaisnes, Bone mineral density in Addison’s disease: evidence for an effect of adrenal androgens on bone mass. Br. Med. J. (Clin. Res. Ed.) 294, 798–800 (1987)Google Scholar
  139. 139.
    P.M. Zelissen, R.J. Croughs, P.P. van Rijk, J.A. Raymakers, Effect of glucocorticoid replacement therapy on bone mineral density in patients with Addison disease. Ann. Intern. Med. 120, 207–210 (1994)PubMedCrossRefGoogle Scholar
  140. 140.
    C.M. Florkowski, S.J. Holmes, J.R. Elliot, R.A. Donald, E.A. Espiner, Bone mineral density is reduced in female but not male subjects with Addison’s disease. N. Z. Med. J. 107, 52–53 (1994)PubMedGoogle Scholar
  141. 141.
    M.A. Valero, M. Leon, M.P. Ruiz Valdepeñas, L. Larrodera, M.B. Lopez, K. Papapietro, A. Jara, F. Hawkins, Bone density and turnover in Addison’s disease: effect of glucocorticoid treatment. Bone Miner. 26, 9–17 (1994)PubMedCrossRefGoogle Scholar
  142. 142.
    S.R. Peacey, C.Y. Guo, A.M. Robinson, A. Price, M.A. Giles, R. Eastell, A.P. Weetman, Glucocorticoid replacement therapy: are patients over treated and does it matter? Clin. Endocrinol. (Oxf.) 46, 255–261 (1997)CrossRefGoogle Scholar
  143. 143.
    G.D. Braatvedt, M. Joyce, M. Evans, J. Clearwater, I.R. Reid, Bone mineral density in patients with treated Addison’s disease. Osteoporos. Int. 10, 435–440 (1999)PubMedCrossRefGoogle Scholar
  144. 144.
    E. Jódar, M.P. Valdepeñas, G. Martinez, A. Jara, F. Hawkins, Long-term follow-up of bone mineral density in Addison’s disease. Clin. Endocrinol. (Oxf.) 58, 617–620 (2003)CrossRefGoogle Scholar
  145. 145.
    N. Chikada, T. Imaki, M. Hotta, K. Sato, K. Takano, An assessment of bone mineral density in patients with Addison’s disease and isolated ACTH deficiency treated with glucocorticoid. Endocr. J. 51, 355–360 (2004)PubMedCrossRefGoogle Scholar
  146. 146.
    G. Bassotti, D. Di Sarra, D. Pietrobono, R. Schiaffini, T. Battocletti, T. D’Amico, P. Gargiulo, Polyglandular autoimmune endocrine insufficiency complicated by severe osteoporosis. Minerva Endocrinol. 31, 289–296 (2006)PubMedGoogle Scholar
  147. 147.
    L. Leelarathna, L. Breen, J.K. Powrie, S.M. Thomas, R. Guzder, B. McGowan, P.V. Carroll, Co-morbidities, management and clinical outcome of auto-immune Addison’s disease. Endocrine 38, 113–117 (2010)PubMedCrossRefGoogle Scholar
  148. 148.
    K. Løvås, C.G. Gjesdal, M. Christensen, A.B. Wolff, B. Almås, J. Svartberg, K.J. Fougner, U. Syversen, J. Bollerslev, J.A. Falch, P.J. Hunt, V.K. Chatterjee, E.S. Husebye, Glucocorticoid replacement therapy and pharmacogenetics in Addison’s disease: effects on bone. Eur. J. Endocrinol. 160, 993–1002 (2009)PubMedCrossRefGoogle Scholar
  149. 149.
    S. Björnsdottir, M. Sääf, S. Bensing, O. Kämpe, K. Michaëlsson, J.F. Ludvigsson, Risk of hip fracture in Addison’s disease: a population-based cohort study. J. Intern. Med. 270, 187–195 (2011)PubMedCrossRefGoogle Scholar
  150. 150.
    K.R. Koetz, M. Ventz, S. Diederich, M. Quinkler, Bone mineral density is not significantly reduced in adult patients on low-dose glucocorticoid replacement therapy. J. Clin. Endocrinol. Metab. 97, 85–92 (2012)PubMedCrossRefGoogle Scholar
  151. 151.
    G. Mazziotti, T. Porcelli, A. Bianchi, V. Cimino, I. Patelli, C. Mejia, A. Fusco, A. Giampietro, L. De Marinis, A. Giustina, Glucocorticoid replacement therapy and vertebral fractures in hypopituitary adult males with GH deficiency. Eur. J. Endocrinol. 163, 15–20 (2010)PubMedCrossRefGoogle Scholar
  152. 152.
    K. Lovas, J.H. Loge, E.S. Husebye, Subjective health status in Norwegian patients with Addison’s disease. Clin. Endocrinol. (Oxf.) 56, 581–588 (2002)CrossRefGoogle Scholar
  153. 153.
    S. Hahner, M. Loeffler, M. Fassnacht, D. Weismann, A.C. Koschker, M. Quinkler 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)PubMedCrossRefGoogle Scholar
  154. 154.
    B. Bleicken, S. Hahner, M. Loeffler, M. Ventz, B. Allolio, M. Quinkler, Impaired subjective health status in chronic adrenal insufficiency: impact of different glucocorticoid replacement regimens. Eur. J. Endocrinol. 159, 811–817 (2008)PubMedCrossRefGoogle Scholar
  155. 155.
    K. Løvås, S. Curran, M. Oksnes, E.S. Husebye, F.A. Huppert, V.K. Chatterjee, Development of a disease-specific quality of life questionnaire in Addison’s disease. J. Clin. Endocrinol. Metab. 95, 545–551 (2010)PubMedCrossRefGoogle Scholar
  156. 156.
    M. Øksnes, S. Bensing, A.L. Hulting, O. Kämpe, A. Hackemann, G. Meyer, K. Badenhoop, C. Betterle, A. Parolo, R. Giordano, A. Falorni, L. Papierska, W. Jeske, A.A. Kasperlik-Zaluska, V.K. Chatterjee, E.S. Husebye, K. Løvås, Quality of life in European patients with Addison’s disease: validity of the disease-specific questionnaire AddiQoL. J. Clin. Endocrinol. Metab. 97, 568–576 (2012)PubMedCrossRefGoogle Scholar
  157. 157.
    M.F. Dallman, S.F. Akana, S. Bhatnagar, M.E. Bell, A.M. Strack, Bottomed out: metabolic significance of the circadian trough in glucocorticoid concentrations. Int. J. Obes. Relat. Metab. Disord. 24(Suppl 2), S40–S46 (2000)PubMedCrossRefGoogle Scholar
  158. 158.
    M. Debono, C. Ghobadi, A. Rostami-Hodjegan, H. Huatan, M.J. Campbell, J. Newell-Price, K. Darzy, D.P. Merke, W. Arlt, R.J. Ross, Modified-release hydrocortisone to provide circadian cortisol profiles. J. Clin. Endocrinol. Metab. 94, 1548–1554 (2009)PubMedCrossRefGoogle Scholar
  159. 159.
    S. Verma, C. Vanryzin, N. Sinaii, M.S. Kim, L.K. Nieman, S. Ravindran, K.A. Calis, W. Arlt, R.J. Ross, D.P. Merke, A pharmacokinetic and pharmacodynamic study of delayed- and extended-release hydrocortisone (Chronocort) vs. conventional hydrocortysone (Cortef) in the treatment of congenital adrenal hyperplasia. Clin. Endocrinol. (Oxf.) 72, 441–447 (2010)Google Scholar
  160. 160.
    E.M. McConnell, P.M. Bell, C. Ennis, D.R. Hadden, D.R. McCance, B. Sheridan, A.B. Atkinson, Effects of low-dose oral hydrocortisone replacement versus short-term reproduction of physiological serum cortisol concentrations on insulin action in adult-onset hypopituitarism. Clin. Endocrinol. (Oxf.) 56, 195–201 (2002)CrossRefGoogle Scholar
  161. 161.
    D. Garcia-Borreguero, T.A. Wehr, O. Larrosa, J.J. Granizo, D. Hardwick, G.P. Chrousos, T.C. Friedman, Glucocorticoid replacement is permissive for rapid eye movement sleep and sleep consolidation in patients with adrenal insufficiency. J. Clin. Endocrinol. Metab. 85, 4201–4206 (2000)PubMedCrossRefGoogle Scholar
  162. 162.
    G. Johannsson, R. Bergthorsdottir, A.G. Nilsson, H. Lennernas, T. Hedner, S. Skrtic, Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study. Eur. J. Endocrinol. 161, 119–130 (2009)PubMedCrossRefGoogle Scholar
  163. 163.
    G. Johansson, A.G. Nilsson, R. Bergthorsdottir, P. Burman, P. Dahlqvist, B. Ekman, B.E. Engstrom, T. Olsson, O. Ragnarsson, M. Ryberg, J. Wahlberg, B.M.K. Biller, J.P. Monson, P.M. Stewart, H. Lennernas, S. Skrtic, 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, 473–481 (2012)CrossRefGoogle Scholar
  164. 164.
    A.J. Coles, S. Thompson, A.L. Cox, S. Curran, E.M. Gurnell, V.K. Chatterjee, Dehydroepiandrosterone replacement in patients with Addison’s disease has a bimodal effect on regulatory (CD4 + CD25hi and CD4 + FoxP3 +) T cells. Eur. J. Immunol. 35, 3694–3703 (2005)PubMedCrossRefGoogle Scholar
  165. 165.
    S.H. Pearce, A.L. Mitchell, S. Bennett, P. King, S. Chandran, S. Nag, S. Chen, B.R. Smith, J.D. Isaacs, B. Vaidya, Adrenal steroidogenesis after b lymphocyte depletion therapy in new-onset Addison’s disease. J. Clin. Endocrinol. Metab. (2012). [Epub ahead of print]Google Scholar
  166. 166.
    A. De Bellis, A. Falorni, S. Laureti et al., Time course of 21-hydroxylase antibodies and long-term remission of subclinical autoimmune adrenalitis after corticosteroid therapy: case report. J. Clin. Endocrinol. Metab. 86, 675–678 (2001)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Alberto Falorni
    • 1
  • Viviana Minarelli
    • 1
  • Silvia Morelli
    • 1
  1. 1.Department of Internal Medicine, Section of Internal Medicine and Endocrine and Metabolic SciencesUniversity of PerugiaPerugiaItaly

Personalised recommendations