Skip to main content

Advertisement

Log in

Secondary hypoadrenalism

  • Published:
Pituitary Aims and scope Submit manuscript

Abstract

Secondary adrenal insufficiency (SAI) is a clinical disorder that results from hypothalamic or hypophyseal damage or from prolonged administration of supraphysiological doses of glucocorticoids. Since glucocorticoids are widely used for a variety of diseases, the prevalence of SAI is by far exceeding that of primary adrenal insufficiency. Although the presentation of adrenal insufficiency may be insidious and difficult to recognize, an appropriate adrenocortical hormone replacement could lead to a normal quality of life and longevity can be achieved. The spectrum of adrenal insufficiency ranges from overt adrenal crises to subtle dysfunctions in asymptomatic patients who may be at risk of developing acute adrenal insufficiency since their hypothalamic-pituitary-adrenal (HPA) axis cannot appropriately react to stress. Thus, identification of patients with subtle abnormalities of the HPA is mandatory for avoiding this life–threatening event in stressful conditions. The optimal tests and the optimal testing sequence for adrenal insufficiency are still matter of debate. Insulin tolerance test (ITT) could be the gold standard, as it tests the whole HPA axis, but there are some patients who pass the ITT failing the ACTH test. Various alternatives to the ITT, including the standard cosyntropin stimulation test (SST) and low-dose SST, have been proposed since the adrenal gland in SAI loses the capacity for a prompt response to ACTH stimulation. The standard ACTH dose, but not the 1 μg dose, increases adrenal blood flow and this may contribute to produce an early cortisol response of greater magnitude. Moreover, the loss of the early cortisol response to ACTH stimulation could be a specific property of adrenal insufficiency, thus being a sensitive and early marker of failing adrenal function. While the results of the SSTs are often positive in patients with long-standing and severe disease, in patients with mild or recent-onset SAI these tests, using either 250 μg or 1 μg ACTH, tend to give normal results; thus, a negative cosyntropin test result does not rule out the possibility of SAI. Further studies with a systematic comparison of the different tests in large series of patients submitted to a prolonged follow-up are needed to solve the controversy of the optimal diagnostic strategy of SAI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Dorin RI, Qualls CR, Crapo LM (2003) Diagnosis of adrenal insufficiency. Ann Intern Med 139:194–204.

    PubMed  Google Scholar 

  2. Andrioli M, Pecori Giraldi F, Cavagnini F (2006) Isolated corticotrophin deficiency. Pituitary 9:289–295. doi:10.1007/s11102-006-0408-5

    Article  PubMed  CAS  Google Scholar 

  3. Watts NB, Tindall GT (1988) Rapid assessment of corticotropin reserve after pituitary surgery. JAMA 259:708–711. doi:10.1001/jama.259.5.708

    Article  PubMed  CAS  Google Scholar 

  4. Auchus RJ, Shewbridge RK, Shepherd MD (1997) Which patients benefit from provocative adrenal testing after transsphenoidal pituitary surgery? Clin Endocrinol (Oxf) 46:21–27. doi:10.1046/j.1365-2265.1997.d01-1748.x

    Article  CAS  Google Scholar 

  5. Hurel SJ, Thompson CJ, Watson MJ, Harris MM, Baylis PH, Kendall-Taylor P (1996) The short Synacthen and insulin stress tests in the assessment of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol (Oxf) 44:141–146. doi:10.1046/j.1365-2265.1996.555381.x

    Article  CAS  Google Scholar 

  6. Rasmuson S, Olsson T, Hagg E (1996) A low-dose ACTH test to assess the function of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol (Oxf) 44:151–156. doi:10.1046/j.1365-2265.1996.600482.x

    Article  CAS  Google Scholar 

  7. Hagg E, Asplund K, Lithner F (1987) Value of basal plasma cortisol assays in the assessment of pituitary adrenal insufficiency. Clin Endocrinol (Oxf) 26:221–226.

    Article  CAS  Google Scholar 

  8. Jones SI, Trainer PJ, Perr L, Wass J, Besser GM, Groosman A (1994) An audit of the insulin tolerance test in adult subjects in an acute investigation unit over one year. Clin Endocrinol (Oxf) 41:123–128.

    Article  CAS  Google Scholar 

  9. Dokmetas HS, Colak R, Kelestimur F, Selcuklu A, Unluhizarci K, Bayram F (2000) A comparison between the 1-mg adrenocorticotropin (ACTH) test, the short ACTH (250 mg) test, and the insulin tolerance test in the assessment of hypothalamo-pituitary-adrenal axis immediately after pituitary surgery. J Clin Endocrinol Metab 85:3713–3719. doi:10.1210/jc.85.10.3713

    Article  PubMed  CAS  Google Scholar 

  10. Plumpton FS, Besser GM (1969) The adrenocortical response to surgery and insulin-induced hypoglycaemia in corticosteroid-treated and normal subjects. Br J Surg 56:216–219. doi:10.1002/bjs.1800560315

    Article  PubMed  CAS  Google Scholar 

  11. Nieman LK (2003) Dynamic evaluation of adrenal hypofunction. J Endocrinol Invest 26:74–82.

    PubMed  CAS  Google Scholar 

  12. Salvatori R (2005) Adrenal insufficiency. JAMA 294:2481–2488. doi:10.1001/jama.294.19.2481

    Article  PubMed  CAS  Google Scholar 

  13. Nelson JC, Tindall DJ (1978) A comparison of the adrenal response to hypoglicemia, metyrapone and ACTH. Am J Med Sci 275:165–172. doi:10.1097/00000441-197803000-00006

    Article  PubMed  CAS  Google Scholar 

  14. Lindholm J, Kehlet H (1987) Reevaluation of the clinical value of the 30 min ACTH test in assessing the hypotalamic-pituitaryadrenocortical function. Clin Endocrinol (Oxf) 26:53–59.

    Article  CAS  Google Scholar 

  15. Tsatsoulis A, Shalet SM, Harrison J, Ratcliffe WA, Beardwell CG, Robinson EL (1998) ACTH deficiency undetected by standard dynamic tests of hypotalamic-pituitary-adrenal axis. Clin Endocrinol (Oxf) 28:225–232

    Article  Google Scholar 

  16. Semakula C, Damberg G, Kendall D, Seaquist ER (1999) The use of the hypoglycaemic clamp in the assessment of pituitary function. Clin Endocrinol 51:709–714. doi:10.1046/j.1365-2265.1999.00866.x

    Article  PubMed  CAS  Google Scholar 

  17. Staub JJ, Noelpp B, Girard J, Baumann JB, Graf S, Ratcliff JG (1979) The short metyrapone test: comparison of the plasma ACTH response to metyrapone and insulin induced hypoglycaemia. Clin Endocrinol 10:595–601.

    Article  PubMed  CAS  Google Scholar 

  18. Fiad TM, Kirby JM, Cunningham SK, McKenna TJ (1994) The overnight single-dose metyrapone test is a simple and reliable index of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol 40:603–609.

    Article  PubMed  CAS  Google Scholar 

  19. Courtney CH, McAllister AS, McCance DR et al (2000) The insulin hypoglycaemia and overnight metyrapone tests in the assessment of the hypothalamic-pituitary-adrenal axis following pituitary surgery. Clin Endocrinol 53:309–312. doi:10.1046/j.1365-2265.2000.01093.x

    Article  CAS  Google Scholar 

  20. Wood JB, James VH, Frankland AW, Landon J (1965) A rapid test of adrenocortical function. Lancet 1:243–245. doi:10.1016/S0140-6736(65)91526-6

    Article  PubMed  CAS  Google Scholar 

  21. Vestergaard P, Hoeck HC, Jakobsen PE, Laurberg P (1997) Reproducibility of growth hormone and cortisol responses to the insulin tolerance test and the short ACTH test in normal adults. Horm Metab Res 29:106–110.

    PubMed  CAS  Google Scholar 

  22. Mayenknecht J, Diederich S, Bahr V, Plockinger U, Oelkers W (1998) Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab 83:1558–1562. doi:10.1210/jc.83.5.1558

    Article  PubMed  CAS  Google Scholar 

  23. Weintrob N, Sprecher E, Josefsberg Z et al (1998) Standard and low-dose short adrenocorticotropin test compared with insulin-induced hypoglycemia for assessment of the hypothalamic-pituitaryadrenal axis in children with idiopathic multiple pituitary hormone deficiencies. J Clin Endocrinol Metab 83:88–92. doi:10.1210/jc.83.1.88

    Article  PubMed  CAS  Google Scholar 

  24. Gonzalez-Gonzalez JG, De la Garza-Hernandez NE, Mancillas-Adame LG, Montes-Villarreal J, Villarreal-Perez JZ (1998) A high-sensitivity test in the assessment of adrenocortical insufficiency: 10 microg vs 250 microg cosyntropin dose assessment of adrenocortical insufficiency. J Endocrinol 159:275–280. doi:10.1677/joe.0.1590275

    Article  PubMed  CAS  Google Scholar 

  25. Laureti S, Arvat E, Candeloro P et al (2000) Low dose (1 microg) ACTH test in the evaluation of adrenal dysfunction in pre-clinical Addison’s disease. Clin Endocrinol (Oxf) 53:107–115. doi:10.1046/j.1365-2265.2000.01050.x

    Article  CAS  Google Scholar 

  26. Clark PM, Neylon I, Raggatt PR, Sheppard MC, Stewart PM (1998) Defining the normal cortisol response to the short Synacthen test: implications for the investigation of hypothalamic-pituitary disorders. Clin Endocrinol (Oxf) 49:287–292. doi:10.1046/j.1365-2265.1998.00555.x

    Article  CAS  Google Scholar 

  27. McGill PE, Greig WR, Browning MC, Boyle JA (1967) Plasma cortisol response to synacthen (beta-1-24 Ciba) at different times of the day in patients with rheumatic diseases. Ann Rheum Dis 26:123–126.

    Article  PubMed  CAS  Google Scholar 

  28. Greig WR, Maxwell JD, Boyle JA, Lindsay RM, Browning MC (1969) Criteria for distinguishing normal from subnormal adrenocortical function using the Synacthen test. Postgrad Med J 45:307–313.

    PubMed  CAS  Google Scholar 

  29. Kehlet H, Binder C (1973) Value of an ACTH test in assessing hypothalamic-pituitary- adrenocortical function in glucocorticoid-treated patients. BMJ 2:147–149.

    PubMed  CAS  Google Scholar 

  30. Dluhy RG, Himathongkam T, Greenfield M (1974) Rapid ACTH test with plasma aldosterone levels. Improved diagnostic discrimination. Ann Intern Med 80:693–696.

    PubMed  CAS  Google Scholar 

  31. Stewart PM, Corrie J, Seckl JR, Edwards CRW, Padfield PL (1988) A rational approach for assessing the hypothalamic-pituitary-adrenal axis. Lancet 1:1208–1210. doi:10.1016/S0140-6736(88)92020-X

    Article  PubMed  CAS  Google Scholar 

  32. Clayton RN (1996) Short synacthen test versus insulin stress test for assessment of the hypothalamo-pituitary-adrenal axis: controversy revisited. Clin Endocrinol (Oxf) 44:147–149. doi:10.1046/j.1365-2265.1996.666478.x

    Article  CAS  Google Scholar 

  33. Kane KF, Emery P, Sheppard MC, Stewart PM (1995) Assessing the hypothalamo-pituitary-adrenal axis in patients on long-term glucocorticoid therapy: the short Synacthen versus the insulin tolerance test. QJM 88:263–267.

    PubMed  CAS  Google Scholar 

  34. Abdu TA, Elhadd TA, Neary R, Clayton RN (1999) Comparison of the low-dose SST (1 mg), the conventional-dose SST (250 mg), and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease. J Clin Endocrinol Metab 84:838–843. doi:10.1210/jc.84.3.838

    Article  PubMed  CAS  Google Scholar 

  35. Bangar V, Clayton RN (1998) How reliable is the short Synacthen test for the investigation of the hypothalamic-pituitary-adrenal axis? Eur J Endocrinol 139:580–583. doi:10.1530/eje.0.1390580

    Article  PubMed  CAS  Google Scholar 

  36. Courtney CH, McAllister AS, Bell PM et al (2004) Low- and standard-dose corticotropin and insulin hypoglycaemia testing in the assessment of hypothalamic-pituitary adrenal function after pituitary surgery. J Clin Endocrinol Metab 89:1712–1717. doi:10.1210/jc.2003-031577

    Article  PubMed  CAS  Google Scholar 

  37. Pfeifer M, Kanc K, Verhovec R. Kocijancic (2001) A Reproducibility of the insulin tolerance test (ITT) for assessment of growth hormone and cortisol secretion in normal and hypopituitary adult men. Clin Endocrinol (Oxf) 54:17–22. doi:10.1046/j.1365-2265.2001.01179.x

    Article  CAS  Google Scholar 

  38. Tordjman K, Jaffe A, Grazas N, Apter C, Stern N (1995) The role of the low dose (1 microgram) adrenocorticotropin test in the evaluation of patients with pituitary diseases. J Clin Endocrinol Metab 80:1301–1305. doi:10.1210/jc.80.4.1301

    Article  PubMed  CAS  Google Scholar 

  39. Landon J, James VHT, Wharton MJ, Friedman M (1967) Threshold adrenocortical sensitivity in man and its possible application to corticotrophin bioassay. Lancet 2:697–700. doi:10.1016/S0140-6736(67)90976-2

    Article  PubMed  CAS  Google Scholar 

  40. Soule SG, Fahie-Wilson M, Tomlinson S (1996) Failure of the short ACTH test to unequivocally diagnose long-standing symptomatic secondary hypoadrenalism. Clin Endocrinol (Oxf) 44:137–140. doi:10.1046/j.1365-2265.1996.540363.x

    Article  CAS  Google Scholar 

  41. Agha A, Tomlinson JW, Clark PM, Holder G, Stewart PM (2006) 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. doi:10.1210/jc.2005-1131

    Article  PubMed  CAS  Google Scholar 

  42. Gleeson HK, Walker BR, Seckl JR, Padfield PL (2003) Ten years on: safety of short Synacthen tests in assessing adrenocorticotropin deficiency in clinical practice. J Clin Endocrinol Metab 88:2106–2111. doi:10.1210/jc.2002-020969

    Article  PubMed  CAS  Google Scholar 

  43. Dickstein G, Shechner C, Nicholson WE (1991) ACTH test: effect of basal cortisol level, time of day and suggested new sensitive low dose test. J Clin Endocrinol Metab 72:773–778.

    PubMed  CAS  Google Scholar 

  44. Broide J, Soferman R, Kivity S et al (1995) Low-dose adrenocorticotropin test reveals impaired adrenal function in patients taking inhaled corticosteroids. J Clin Endocrinol Metab 80:1243–1246. doi:10.1210/jc.80.4.1243

    Article  PubMed  CAS  Google Scholar 

  45. Daidoh H, Morita H, Mune T, Hanafusa H, Shibata T, Yasuda K (1995) Responses of plasma adrenocortical steroids to low dose ACTH in normal subjects. Clin Endocrinol (Oxf) 43:311–315.

    Article  CAS  Google Scholar 

  46. Nye EJ, Hockings GI, Grice JE, Strakosch CR, Torpy DJ, Jackson RV (1999) The use of naloxone for investigating disorders of the hypothalamic-pituitary-adrenal axis. Endocrinologist 9:161–182. doi:10.1097/00019616-199905000-00003

    Article  Google Scholar 

  47. Crowley S, Hindmarsh PC, Holownia P, Honour JW, Brook CG (1991) The use of low doses of ACTH in the investigation of adrenal function in man. J Endocrinol 130:475–479.

    PubMed  CAS  Google Scholar 

  48. Crowley S, Hindmarsh PC, Honour JW, Brook CG (1993) Reproducibility of the cortisol response to stimulation with a low dose of ACTH(1–24): the effect of basal cortisol levels and comparison of low-dose with high-dose secretory dynamics. J Endocrinol 136:167–172.

    Article  PubMed  CAS  Google Scholar 

  49. Dickstein G, Arad E, Schechner C (1997) Low-dose ACTH stimulation test. Endocrinologist 7:285–293

    Article  Google Scholar 

  50. Graybeal ML, Fang VS (1985) Physiological dosing of exogenous ACTH. Acta Endocrinol (Copenh) 108:401–406.

    CAS  Google Scholar 

  51. Oelkers W, Boelke T, Ba¨hr V (1988) Dose–response relationships between plasma adrenocorticotropin, cortisol, aldosterone, and 18-OH-hydroxycorticosterone after injection of ACTH (1–39) or human CRH in man. J Clin Endocrinol Metab 66:181–186.

    Article  PubMed  CAS  Google Scholar 

  52. Tordjman K, Jaffe A, Trostanetsky Y, Greenman Y, Limor R, Stern N (2000) Low-dose (1 microgram) adrenocorticotrophin (ACTH) stimulation as a screening test for impaired hypothalamo-pituitary-adrenal axis function: sensitivity, specificity and accuracy in comparison with the high-dose (250 microgram) test. Clin Endocrinol (Oxf) 52:633–640. doi:10.1046/j.1365-2265.2000.00984.x

    Article  CAS  Google Scholar 

  53. Talwar V, Lodha S, Dash RJ (1998) Assessing the hypothalamo-pituitary-adrenocortical axis using physiological doses of adrenocorticotropic hormone. QJM 91:285–290. doi:10.1093/qjmed/91.4.285

    Article  PubMed  CAS  Google Scholar 

  54. Suliman AM, Smith TP, Labib M, Fiad TM, McKenna TJ (2002) The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency. Clin Endocrinol (Oxf) 56:533–539. doi:10.1046/j.1365-2265.2002.01509.x

    Article  CAS  Google Scholar 

  55. Ambrosi B, Barbetta L, Re T, Passini E, Faglia G (1998) The one microgram adrenocorticotropin test in the assessment of hypothalamic-pituitary-adrenal function. Eur J Endocrinol 139:575–579. doi:10.1530/eje.0.1390575

    Article  PubMed  CAS  Google Scholar 

  56. Soule S, Van Zyl Smit C, Parolis G et al (2000) The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoadrenalism. Clin Endocrinol (Oxf) 53:221–227. doi:10.1046/j.1365-2265.2000.01057.x

    Article  CAS  Google Scholar 

  57. Zarkovic M, Ciric J, Stojanovic M et al (1999) Optimizing the diagnostic criteria for standard (250-microg) and low dose (1-microg) adrenocorticotropin tests in the assessment of adrenal function. J Clin Endocrinol Metab 84:3170–3173. doi:10.1210/jc.84.9.3170

    Article  PubMed  CAS  Google Scholar 

  58. Oelkers W (1998) The role of high- and low-dose corticotropin tests in the diagnosis of secondary adrenal insufficiency. Eur J Endocrinol 139:567–570. doi:10.1530/eje.0.1390567

    Article  PubMed  CAS  Google Scholar 

  59. Nye EJ, Grice JE, Hockings GI et al (2001) Adrenocorticotropin stimulation tests in patients with hypothalamic-pituitary disease: low dose, standard high dose and 8-h infusion tests. Clin Endocrinol (Oxf) 55:625–633. doi:10.1046/j.1365-2265.2001.01389.x

    Article  CAS  Google Scholar 

  60. Gandhi PG, Shah NS, Khandelwal AG, Chauhan P, Menon PS (2002) Evaluation of low dose ACTH stimulation test in suspected secondary adrenocortical insufficiency. J Postgrad Med 48:280–282.

    PubMed  CAS  Google Scholar 

  61. Thaler LM, Blevins LS Jr (1998) The low dose (1-microg) adrenocorticotropin stimulation test in the evaluation of patients with suspected central adrenal insufficiency. J Clin Endocrinol Metab 83:2726–2729. doi:10.1210/jc.83.8.2726

    Article  PubMed  CAS  Google Scholar 

  62. Streeten DH (1999) Shortcomings in the low-dose (1 microg) ACTH test for the diagnosis of ACTH deficiency states [Editorial]. J Clin Endocrinol Metab 84:835–837. doi:10.1210/jc.84.3.835

    Article  PubMed  CAS  Google Scholar 

  63. Agwu JC, Spoudeas H, Hindmarsh PC, Pringle PJ, Brook CG (1999) Tests of adrenal insufficiency. Arch Dis Child 80:330–333.

    PubMed  CAS  Google Scholar 

  64. Luthold WW, Marcondes JA, Wajchenberg BL (1985) Salivary cortisol for the evaluation of Cushing’s syndrome. Clin Chim Acta 151:33–39. doi:10.1016/0009-8981(85)90232-3

    Article  PubMed  CAS  Google Scholar 

  65. Raff H, Raff JL, Findling JW (1998) Late-night salivary cortisol as a screening test for Cushing’s syndrome. J Clin Endocrinol Metab 83:2681–2686. doi:10.1210/jc.83.8.2681

    Article  PubMed  CAS  Google Scholar 

  66. Castro M, Elias PC, Quidute AR, Halah FP, Moreira AC (1999) Out-patient screening for Cushing’s syndrome: the sensitivity of the combination of circadian rhythm and overnight dexamethasone suppression salivary cortisol tests. J Clin Endocrinol Metab 84:878–882. doi:10.1210/jc.84.3.878

    Article  PubMed  CAS  Google Scholar 

  67. Contreras LN, Arregger AL, Persi GG, Gonzalez NS, Cardoso EM (2004) A new less-invasive and more informative low-dose ACTH test: salivary steroids in response to intramuscular corticotrophin. Clin Endocrinol (Oxf) 61:675–682. doi:10.1111/j.1365-2265.2004.02144.x

    Article  CAS  Google Scholar 

  68. Marcus-Perlman Y, Tordjman K, Greenman Y et al (2006) Low-dose ACTH (1 μg) salivary test: a potential alternative to the classical blood test. Clin Endocrinol (Oxf) 64:215–218. doi:10.1111/j.1365-2265.2006.02451.x

    Article  CAS  Google Scholar 

  69. Grinspoon SK, Biller BM (1994) Clinical review 62: Laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab 79:923–931. doi:10.1210/jc.79.4.923

    Article  PubMed  CAS  Google Scholar 

  70. Maghnie M, Uga E, Temperini F et al (2005) Evaluation of adrenal function in patients with growth hormone deficiency and hypothalamic–pituitary disorders: comparison between insulin-induced hypoglycemia, low-dose ACTH, standard ACTH and CRH stimulation tests. Eur J Endocrinol 152:735–741. doi:10.1530/eje.1.01911

    Article  PubMed  CAS  Google Scholar 

  71. Orme SM, Peacey SR, Barth JH, Belchetz PE (1996) Comparison of tests of stress-released cortisol secretion in pituitary disease. Clin Endocrinol (Oxf) 45:135–140. doi:10.1046/j.1365-2265.1996.d01-1562.x

    Article  CAS  Google Scholar 

  72. Ammari F, Issa BG, Millward E, Scanion MF (1996) A comparison between short ACTH and insulin stress tests for assessing hypothalamo-pituitary-adrenal function. Clin Endocrinol (Oxf) 44:473–476. doi:10.1046/j.1365-2265.1996.712533.x

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Massimo Terzolo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reimondo, G., Bovio, S., Allasino, B. et al. Secondary hypoadrenalism. Pituitary 11, 147–154 (2008). https://doi.org/10.1007/s11102-008-0108-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11102-008-0108-4

Keywords

Navigation