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Horm Metab Res 2010; 42(13): 961-966
DOI: 10.1055/s-0030-1265218
Humans, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Variable Sensitivity to the Glucocorticoid Activity of Cortisol in Patients with Primary Adrenal Insufficiency: Assessment with ACTH Profiles

B. Ekman1 , J. Blomgren2 , P.-O. Andersson2 , M. Carlsson3 , H. J. Arnqvist4
  • 1Department of Medicine and Health Sciences, Division of Internal Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden
  • 2Internal Medicine County Hospital, Eksjö, Sweden
  • 3Internal Medicine County Hospital, Kalmar, Sweden
  • 4Department of Clinical and Experimental Medicine, Division of Cellbiology, Faculty of Health Sciences, Linköping University, Linköping, Sweden
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Publication History

received 30.04.2010

accepted 23.08.2010

Publication Date:
05 October 2010 (online)

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Abstract

Our aim was to investigate the usefulness of circulating levels of adrenocorticotropic hormone (ACTH) and also salivary cortisol to monitor cortisone substitution in patients with Addison's disease. 13 patients with primary adrenal insufficiency (8 women and 5 men, age 44±11 years) received 12.5 mg cortisone acetate orally at 16:00 h and 25 mg at 07:00 h. Blood samples for cortisol and ACTH analysis were drawn every hour for 24 h, and also every half hour between 07:00 and 12:00 h. Samples for salivary cortisol were collected in parallel. Total ACTH levels showed large inter-individual variations and a diurnal rhythm with a nadir in the early evening at 19:00 (median 19 ng/l, range 2–434 ng/l) and high levels in the early morning, with a peak around 07:30 (median 844 ng/l, range 45–2 249 ng/l). Plasma cortisol concentrations showed 2 peaks distinct in time, but variable in height, 1–2 h after intake of cortisone. Plasma cortisol correlated significantly with ln(ACTH) at 17:00 h (r=–0.56), at 10:00 h (r=–0.51), and at 10.30 h (r=–0.57). When tested at different time points, ln(ACTH) at 10:00 to 12:00 h was negatively correlated with plasma cortisol between 08:30 and 12:00 h. Plasma cortisol was highly correlated to ln(salivary cortisol) most of the time points measured, but 30–60 min after intake of cortisone acetate the correlation disappeared. In conclusion, the large interindividual variation in ACTH levels most likely indicates varying sensitivity to cortisol with a need for individualized dosing schemes. Furthermore ACTH-determinations may be useful for dose titration of cortisol.

Key words

cortisol - cortisone - ACTH - adrenal insufficiency

References

  • 1 Oelkers W, Diederich S, Bahr V. Diagnosis and therapy surveillance in Addison's disease: rapid adrenocorticotropin (ACTH) test and measurement of plasma ACTH, renin activity, and aldosterone.  J Clin Endocrinol Metab. 1992;  75 259-264
    Google Scholar
  • 2 Besser GM, Jeffcoate WJ. Endocrine and metabolic diseases. Adrenal diseases.  Br Med J. 1976;  1 448-451
    Google Scholar
  • 3 Oelkers W. Adrenal insufficiency.  N Engl J Med. 1996;  335 1206-1212
    Google Scholar
  • 4 Arlt W, Allolio B. Adrenal insufficiency.  Lancet. 2003;  361 1881-1893
    Google Scholar
  • 5 Ten S, New M, Maclaren N. Clinical review 130: Addison's disease 2001.  J Clin Endocrinol Metab. 2001;  86 2909-2922
    Google Scholar
  • 6 Debono M, Ross RJ, Newell-Price J. Inadequacies of glucocorticoid replacement and improvements by physiological circadian therapy.  Eur J Endocrinol. 2009;  160 719-729
    Google Scholar
  • 7 Feek CM, Ratcliffe JG, Seth J, Gray CE, Toft AD, Irvine WJ. Patterns of plasma cortisol and ACTH concentrations in patients with Addison's disease treated with conventional corticosteroid replacement.  Clin Endocrinol (Oxf). 1981;  14 451-458
    Google Scholar
  • 8 Laureti S, Falorni A, Santeusanio F. Improvement of treatment of primary adrenal insufficiency by administration of cortisone acetate in 3 daily doses.  J Endocrinol Invest. 2003;  26 1071-1075
    Google Scholar
  • 9 Scott RS, Donald RA, Espiner EA. Plasma ACTH and cortisol profiles in Addisonian patients receiving conventional substitution therapy.  Clin Endocrinol (Oxf). 1978;  9 571-576
    Google Scholar
  • 10 Lewis JG, Mopert B, Shand BI, Doogue MP, Soule SG, Frampton CM, Elder PA. Plasma variation of corticosteroid-binding globulin and sex hormone-binding globulin.  Horm Metab Res. 2006;  38 241-245
    Google Scholar
  • 11 Rosner W. Plasma steroid-binding proteins.  Endocrinol Metab Clin North Am. 1991;  20 697-720
    Google Scholar
  • 12 Holder G. Measurement of glucocorticoids in biological fluids.  Methods Mol Biol. 2006;  324 141-157
    Google Scholar
  • 13 Hiramatsu R. Direct assay of cortisol in human saliva by solid phase radioimmunoassay and its clinical applications.  Clin Chim Acta. 1981;  117 239-249
    Google Scholar
  • 14 Read GF, Walker RF, Wilson DW, Griffiths K. Steroid analysis in saliva for the assessment of endocrine function.  Ann N Y Acad Sci. 1990;  595 260-274
    Google Scholar
  • 15 Holdaway IM. Suppression of plasma ACTH levels with corticosteroids in Addison's disease.  Clin Endocrinol (Oxf). 1973;  2 37-42
    Google Scholar
  • 16 Baid SK, Rubino D, Sinaii N, Ramsey S, Frank A, Nieman LK. Specificity of screening tests for Cushing's syndrome in an overweight and obese population.  J Clin Endocrinol Metab. 2009;  94 3857-3864
    Google Scholar
  • 17 Blomgren J, Ekman B, Andersson PO, Arnqvist HJ. Non-physiological levels of circulating cortisol in growth hormone-treated hypopituitary adults after conventional cortisone substitution.  Scand J Clin Lab Invest. 2004;  64 132-139
    Google Scholar
  • 18 Jenkins JS, Sampson PA. Conversion of cortisone to cortisol and prednisone to prednisolone.  Br Med J. 1967;  2 205-207
    Google Scholar
  • 19 Colburn WA, DiSanto AR, Stubbs SS, Monovich RE, DeSante KA. Pharmacokinetic interpretation of plasma cortisol and cortisone concentrations following a single oral administration of cortisone acetate to human subjects.  J Clin Pharmacol. 1980;  20 428-436
    Google Scholar
  • 20 Srivastava LS, Werk Jr EE, Thrasher K, Sholiton LJ, Kozera R, Nolten W, Knowles HC, Jr. Plasma cortisone concentration as measured by radioimmunoassay.  J Clin Endocrinol Metab. 1973;  36 937-943
    Google Scholar
  • 21 Turner AK, Carroll CJ, Pinkus JL, Charles D, Chattoraj SC. Simultaneous competitive protein binding assay for cortisol, cortisone, and prednisolone in plasma, and its clinical application.  Clin Chem. 1973;  19 731-736
    Google Scholar
  • 22 Heazelwood VJ, Galligan JP, Cannell GR, Bochner F, Mortimer RH. Plasma cortisol delivery from oral cortisol and cortisone acetate: relative bioavailability.  Br J Clin Pharmacol. 1984;  17 55-59
    Google Scholar
  • 23 Purnell JQ, Brandon DD, Isabelle LM, Loriaux DL, Samuels MH. Association of 24-h cortisol production rates, cortisol-binding globulin, and plasma-free cortisol levels with body composition, leptin levels, and aging in adult men and women.  J Clin Endocrinol Metab. 2004;  89 281-287
    Google Scholar
  • 24 Mah PM, Jenkins RC, Rostami-Hodjegan A, Newell-Price J, Doane A, Ibbotson V, Tucker GT, Ross RJ. Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency.  Clin Endocrinol (Oxf). 2004;  61 367-375
    Google Scholar
  • 25 Kivlighan KT, Granger DA, Schwartz EB, Nelson V, Curran M, Shirtcliff EA. Quantifying blood leakage into the oral mucosa and its effects on the measurement of cortisol, dehydroepiandrosterone, and testosterone in saliva.  Horm Behav. 2004;  46 39-46
    Google Scholar
  • 26 Lovas K, Thorsen TE, Husebye ES. Saliva cortisol measurement: simple and reliable assessment of the glucocorticoid replacement therapy in Addison's disease.  J Endocrinol Invest. 2006;  29 727-731
    Google Scholar
  • 27 Lovas K, Loge JH, Husebye ES. Subjective health status in Norwegian patients with Addison's disease.  Clin Endocrinol (Oxf). 2002;  56 581-588
    Google Scholar
  • 28 Bergthorsdottir R, Leonsson-Zachrisson M, Oden A, Johannsson G. Premature mortality in patients with Addison's disease: a population-based study.  J Clin Endocrinol Metab. 2006;  91 4849-4853
    Google Scholar
  • 29 Debono M, Ghobadi C, Rostami-Hodjegan A, Huatan H, Campbell MJ, Newell-Price J, Darzy K, Merke DP, Arlt W, Ross RJ. Modified-release hydrocortisone to provide circadian cortisol profiles.  J Clin Endocrinol Metab. 2009;  94 1548-1554
    Google Scholar
  • 30 Johannsson G, Bergthorsdottir R, Nilsson A, Lennemas H, Hedner T, Skrtic S. Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study.  Eur J Endocrinol. 2009;  161 119-130
    Google Scholar

Correspondence

H. J. Arnqvist MD, PhD 

Department of Endocrinology

and Diabetology

University Hospital

581 85 Linköping

Sweden

Phone: +46/13/222 000

Fax: +46/13/223 502

Email: Hans.Arnqvist@liu.se