Horm Metab Res 2013; 45(01): 62-68
DOI: 10.1055/s-0032-1321855
Humans, Clinical
© Georg Thieme Verlag KG Stuttgart · New York

Salivary Cortisol Day Curves in Addison’s Disease in Patients on Hydrocortisone Replacement

I. L. Ross
1   Division of Endocrinology, Department of Medicine University of Cape Town, South Africa
,
N. S. Levitt
1   Division of Endocrinology, Department of Medicine University of Cape Town, South Africa
,
J. S. Van der Walt
2   Division of Pharmacology, University of Cape Town, South Africa
3   University of Uppsala, Uppsala, Sweden
,
D. A. Schatz
4   Department of Paediatrics, University of Florida, Gainsville, Florida, USA
,
G. Johannsson
5   Department of Endocrinology, Institute of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Sweden
,
D. H. Haarburger
6   Division of Chemical Pathology, University of Cape Town and NHLS, Groote Schuur, South Africa
,
T. S. Pillay
6   Division of Chemical Pathology, University of Cape Town and NHLS, Groote Schuur, South Africa
7   Department of Chemical Pathology, University of KwaZulu Natal, NHLS, IALCH, South Africa
› Author Affiliations
Further Information

Publication History

received 04 April 2012

accepted 02 July 2012

Publication Date:
14 August 2012 (online)

Abstract

Using salivary cortisol (SC) measurements, cortisol exposure in Addison’s disease patients on hydrocortisone replacement was determined and compared with healthy controls. Cortisol pharmacokinetics was assessed in 31 patients with Addison’s disease on replacement hydrocortisone doses (median daily dose 20 mg; range 5–50 mg) and 30 healthy control subjects. Saliva samples (n=16) were collected between 08:00 and 00:00 h in 1 day, using a passive drool technique. Cortisol exposure was evaluated by noncompartmental approach. In the patients, cortisol exposure was significantly higher than in controls: median inter-quartile range (IQR) peak cortisol (Cmax) 174.5 (59.3–837.0) vs. 6.50 (4.7–19.3) nmol/l, p=0.0001; area under the curve (AUC) 390.1 (177.1–928.9) vs. 21.4 (14.6–28.4) minutes*nmol/l, p=0.0001, trough cortisol level (Cmin) 0.49 (0.49–0.96) vs. 0.49 (0.49–0.49) nmol/l, p=0.02, occurring at 480.0 (0.1–660.0) vs. 405.0 (180.0–570.0) min, p=0.56. First peak cortisol was 174.5 (53.0–754.7) vs. 6.27 (3.90–8.47) nmol/l, p=0.0001 and second peak cortisol 18.90 (5.22–76.9) vs. 3.12 (1.76–4.79) nmol/l, p=0.0001. The time to first peak cortisol differed between the 2 groups, 30 (30–75) vs. 0.1 (0.1–30) minutes; p=0.0001. At doses studied, hydrocortisone replacement therapy results in cortisol pharmacokinetics being markedly different from endogenous cortisol profiles in healthy control subjects. Addison’s disease patients had significantly higher SC levels compared to healthy control subjects.

 
  • References

  • 1 Simon N, Castinetti F, Ouliac F, Lesavre N, Brue T, Oliver C. Pharmacokinetic evidence for suboptimal treatment of adrenal insufficiency with currently available hydrocortisone tablets. Clin Pharmacokinet 2010; 49: 455-463
  • 2 Arlt W, Rosenthal C, Hahner S, Allolio B. Quality of glucocorticoid replacement in adrenal insufficiency: clinical assessment vs. timed serum cortisol measurements. Clinical Endocrinology 2006; 64: 384-389
  • 3 Moreira A, Arsati F, de Oliveira Lima Arsati YB, da Silva DA, de Araujo VC. Salivary cortisol in top-level professional soccer players. Eur J Appl Physiol 2009; 106: 25-30
  • 4 Hofman LF. Human saliva as a diagnostic specimen. J Nutr 2001; 131: 1621S-1625S
  • 5 Restituto P, Galofre JC, Gil MJ, Mugueta C, Santos S, Monreal JI, Varo N. Advantage of salivary cortisol measurements in the diagnosis of glucocorticoid related disorders. Clin Biochem 2008; 41: 688-692
  • 6 Lovas K, Husebye ES. Continuous subcutaneous hydrocortisone infusion in Addison’s disease. Eur J Endocrinol 2007; 157: 109-112
  • 7 Wong V, Yan T, Donald A, McLean M. Saliva and bloodspot cortisol: novel sampling methods to assess hydrocortisone replacement therapy in hypoadrenal patients. Clin Endocrinol (Oxf) 2004; 61: 131-137
  • 8 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
  • 9 Thomson AH, Devers MC, Wallace AM, Grant D, Campbell K, Freel M, Connell JM. Variability in hydrocortisone plasma and saliva pharmacokinetics following intravenous and oral administration to patients with adrenal insufficiency. Clin Endocrinol (Oxf) 2007; 66: 789-796
  • 10 Rosmond R, Dallman MF, Bjorntorp P. Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities. J Clin Endocrinol Metab 1998; 83: 1853-1859
  • 11 Bjorntorp P, Holm G, Rosmond R. Hypothalamic arousal, insulin resistance and Type 2 diabetes mellitus. Diabet Med 1999; 16: 373-383
  • 12 Wood P. Salivary steroid assays – research or routine?. Ann Clin Biochem 2009; 46: 183-196
  • 13 Oltmanns KM, Dodt B, Schultes B, Raspe HH, Schweiger U, Born J, Fehm HL, Peters A. Cortisol correlates with metabolic disturbances in a population study of type 2 diabetic patients. Eur J Endocrinol 2006; 154: 325-331
  • 14 Danilowicz K, Bruno OD, Manavela M, Gomez RM, Barkan A. Correction of cortisol overreplacement ameliorates morbidities in patients with hypopituitarism: a pilot study. Pituitary 2008; 11: 279-285
  • 15 Ross I, Boulle A, Soule S, Levitt N, Pirie F, Karlsson A, Mienie J, Yang P, Wang H, She JX, Winter W, Schatz D. Autoimmunity predominates in a large South African cohort with Addison’s disease of mainly European descent despite long-standing disease and is associated with HLA DQB*0201. Clin Endocrinol (Oxf) 2010; 73: 291-298
  • 16 Alderling M, Theorell T, de la Torre B, Lundberg I. The demand control model and circadian saliva cortisol variations in a Swedish population based sample (The PART study). BMC Public Health 2006; 6: 288
  • 17 Krouwer JS, Garber CC, Goldschmidt HM, Kroll MH, Linnet K, Meier K, Rabinowitz M, Kennedy JW. Method comparison and bias estimation using patient samples; approved guidelines-second edition. Wayne, Pennsylvania clinical and laboratory standards Institute (formerly NCCLS) 2002; 25-32
  • 18 van Aken MO, Romijn JA, Miltenburg JA, Lentjes EG. Automated measurement of salivary cortisol. Clin Chem 2003; 49: 1408-1409
  • 19 Zhao ZY, Xie Y, Fu YR, Li YY, Bogdan A, Touitou Y. Circadian rhythm characteristics of serum cortisol and dehydroepiandrosterone sulfate in healthy Chinese men aged 30 to 60 years. A cross-sectional study. Steroids 2003; 68: 133-138
  • 20 Scaglione F, Mouton JW, Mattina R, Fraschini F. Pharmacodynamics of levofloxacin and ciprofloxacin in a murine pneumonia model: peak concentration/MIC versus area under the curve/MIC ratios. Antimicrob Agents Chemother 2003; 47: 2749-2755
  • 21 Takeuchi H, Matsuno N, Senuma K, Hirano T, Yokoyama T, Taira S, Kihara Y, Kuzuoka K, Konno O, Jojima Y, Mejit A, Akashi I, Nakamura Y, Iwamoto H, Hama K, Iwahori T, Ashizawa T, Nagao T, Toraishi T, Okuyama K, Oka K, Unezaki S. Evidence of different pharmacokinetics including relationship among AUC, peak, and trough levels between cyclosporine and tacrolimus in renal transplant recipients using new pharmacokinetic parameter – why cyclosporine is monitored by C(2) level and tacrolimus by trough level. Biol Pharm Bull 2008; 31: 90-94
  • 22 Fournier C, Vennin P, Hecquet B. Correlation between free platinum AUC and total platinum measurement 24 h after i. v. bolus injection of cisplatin in humans. Cancer Chemother Pharmacol 1988; 21: 75-77
  • 23 Esteban NV, Loughlin T, Yergey AL, Zawadzki JK, Booth JD, Winterer JC, Loriaux DL. Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J Clin Endocrinol Metab 1991; 72: 39-45
  • 24 Maguire AM, Ambler GR, Moore B, McLean M, Falleti MG, Cowell CT. Prolonged hypocortisolemia in hydrocortisone replacement regimens in adrenocorticotrophic hormone deficiency. Pediatrics 2007; 120: e164-e171
  • 25 Perogamvros I, Keevil BG, Ray DW, Trainer PJ. Salivary cortisone is a potential biomarker for serum free cortisol. J Clin Endocrinol Metab 2010; 95: 4951-4958
  • 26 Aanderud S, Myking OL. Plasma cortisol concentrations after oral substitution of cortisone in the fasting and non-fasting state. Acta Med Scand 1981; 210: 157-161
  • 27 Barbhaiya RH, Welling PG. Influence of food on the absorption of hydrocortisone from the gastrointestinal tract. Drug Nutr Interact 1982; 1: 103-112
  • 28 Lennernas H, Skrtic S, Johannsson G. Replacement therapy of oral hydrocortisone in adrenal insufficiency: the influence of gastrointestinal factors. Expert Opin Drug Metab Toxicol 2008; 4: 749-758
  • 29 Howlett TA. An assessment of optimal hydrocortisone replacement therapy. Clin Endocrinol (Oxf) 1997; 46: 263-268
  • 30 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
  • 31 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
  • 32 Nater UM, Maloney E, Boneva RS, Gurbaxani BM, Lin JM, Jones JF, Reeves WC, Heim C. Attenuated morning salivary cortisol concentrations in a population-based study of persons with chronic fatigue syndrome and well controls. J Clin Endocrinol Metab 2008; 93: 703-709
  • 33 Keedwell PA, Poon L, Papadopoulos AS, Marshall EJ, Checkley SA. Salivary cortisol measurements during a medically assisted alcohol withdrawal. Addict Biol 2001; 6: 247-256
  • 34 Misra M, Miller KK, Almazan C, Ramaswamy K, Lapcharoensap W, Worley M, Neubauer G, Herzog DB, Klibanski A. Alterations in cortisol secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab 2004; 89: 4972-4980
  • 35 Smans LC, Zelissen PM. Partial recovery of adrenal function in a patient with autoimmune Addison’s disease. J Endocrinol Invest 2008; 31: 672-674
  • 36 Peacey SR, Guo CY, Robinson AM, Price A, Giles MA, Eastell R, Weetman AP. Glucocorticoid replacement therapy: are patients over treated and does it matter?. Clin Endocrinol (Oxf) 1997; 46: 255-261
  • 37 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
  • 38 Johannsson G, Nilsson AG, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, Engstrom BE, Olsson T, Ragnarsson O, Ryberg M, Wahlberg J, Biller BM, Monson JP, Stewart PM, Lennernas H, Skrtic S. 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 2012; 97: 473-481
  • 39 Lee BK, Glass TA, McAtee MJ, Wand GS, Bandeen-Roche K, Bolla KI, Schwartz BS. Associations of salivary cortisol with cognitive function in the Baltimore memory study. Arch Gen Psychiatry 2007; 64: 810-818
  • 40 Dekker MJ, Koper JW, van Aken MO, Pols HA, Hofman A, de Jong FH, Kirschbaum C, Witteman JC, Lamberts SW, Tiemeier H. Salivary cortisol is related to atherosclerosis of carotid arteries. J Clin Endocrinol Metab 2008; 93: 3741-3747
  • 41 Hansen AM, Garde AH, Persson R. Sources of biological and methodological variation in salivary cortisol and their impact on measurement among healthy adults: a review. Scand J Clin Lab Invest 2008; 68: 448-458