Assessment of Plasma-Free Cortisol Concentrations by LC-MS/MS in Patients with Autonomous Cortisol Secretion

Abstract

Autonomous cortisol secretion (ACS) of an adrenal incidentaloma (AI) is associated with mild cortisol excess that could result in poor metabolic and cardiovascular outcomes. The biological activity of glucocorticoids depends on the unbound, free fraction. We aimed to evaluate plasma free cortisol (FC) concentrations in patients with ACS in this cross-sectional study. One hundred and ten AI patients in 3 groups; non-functioning (NFA, n=33), possible ACS (n=65), ACS (n=12) were enrolled. Following measurements were conducted: Clinical data and total serum cortisol (TC), plasma corticotrophin (ACTH), serum dehydroepiandrosterone sulfate (DHEA-S), cortisol after 1 mg dexamethasone by both immunoassay and LC-MS/MS (DexF), serum corticosteroid binding globulin (CBG), plasma dexamethasone concentration [DEX] and plasma FC by LC-MS/MS. Patients with ACS featured an unfavorable metabolic profile. Plasma [DEX] and serum CBG levels were similar between groups. Plasma FC was significantly higher in ACS when compared to NFA and possible ACS groups p<0.05 and p<0.01, respectively. In multiple regression analysis DexF (beta=0.402, p<0.001) and CBG (beta=−0.257, p=0.03) remained as the independent predictors of plasma FC while age, sex, BMI, smoking habit, and existing cardiovascular disease did not make a significant contribution to the regression model. In conclusion, the magnitude of cortisol excess in ACS could lead to increased plasma FC concentrations. Further studies in AI patients are needed to demonstrate whether any alterations of cortisol affinity for CBG exist and to establish whether plasma FC concentrations predict the unfavorable metabolic profile in ACS.

Key words

adrenal incidentaloma - autonomous cortisol secretion - free cortisol - LC-MS/MS

Publication History

Received: 12 July 2021

Accepted after revision: 27 September 2021

Article published online:
05 November 2021

• References

• 1 Di Dalmazi G, Pasquali R, Beuschlein F. et al Subclinical hypercortisolism: a state, A syndrome, or a disease?. Eur J Endocrinol 2015; 173: M61-M71
• 2 Fassnacht M, Arlt W, Bancos I. et al Management of adrenal incidentalomas: European society of endocrinology clinical practice guideline in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol 2016; 175: G1-G34
• 3 Lewis JG, Bagley CJ, Elder PA. et al Plasma free cortisol fraction reflects levels of functioning corticosteroid-binding globulin. Clin Chim Acta 2005; 359: 189-194
• 4 Beishuizen A, Thijs LG, Vermes I. Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma. Intensive Care Med 2001; 27: 1584-1591
• 5 Hammond GL, Smith CL, Underhill DA. Molecular studies of corticosteroid binding globulin structure, biosynthesis and function. J Steroid Biochem Mol Biol 1991; 40: 755-762
• 6 Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med 2004; 350: 1629-1638
• 7 Ho JT, Al-Musalhi H, Chapman MJ. et al Septic shock and sepsis: A comparison of total and free plasma cortisol levels. J Clin Endocrinol Metab 2006; 91: 105-114
• 8 Jung C, Ho JT, Torpy DJ. et al A longitudinal study of plasma and urinary cortisol in pregnancy and postpartum. J Clin Endocrinol Metab 2011; 96: 1533-1540
• 9 le Roux CW, Chapman GA, Kong WM. et al Free cortisol index is better than serum total cortisol in determining hypothalamic-pituitary-adrenal status in patients undergoing surgery. J Clin Endocrinol Metab 2003; 88: 2045-2048
• 10 Loriaux DL. Diagnosis and Differential Diagnosis of Cushing’s Syndrome. N Engl J Med 2017; 377: e3
• 11 Mancia G, De Backer G, Dominiczak A. et al 2007 ESH-ESC practice guidelines for the management of arterial hypertension: ESH-ESC task force on the management of arterial hypertension. J Hypertens 2007; 25: 1751-1762
• 12 American Diabetes A 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2019. Diabetes Care 2019; 42: S13-S28
• 13 Huang W, Kalhorn TF, Baillie M. et al Determination of free and total cortisol in plasma and urine by liquid chromatography-tandem mass spectrometry. Ther Drug Monit 2007; 29: 215-224
• 14 Ray JA, Kushnir MM, Rockwood AL. et al Analysis of cortisol, cortisone and dexamethasone in human serum using liquid chromatography tandem mass spectrometry and assessment of cortisol: cortisone ratios in patients with impaired kidney function. Clin Chim Acta 2011; 412: 1221-1228
• 15 Breuner CW, Beyl HE, Malisch JL. Corticosteroid-binding globulins: Lessons from biomedical research. Mol Cell Endocrinol 2020; 514: 110857
• 16 Faix JD. Principles and pitfalls of free hormone measurements. Best Pract Res Clin Endocrinol Metab 2013; 27: 631-645
• 17 Qian X, Droste SK, Gutierrez-Mecinas M. et al A rapid release of corticosteroid-binding globulin from the liver restrains the glucocorticoid hormone response to acute stress. Endocrinology 2011; 152: 3738-3748
• 18 Dichtel LE, Schorr M, Loures de Assis C. et al Plasma free cortisol in states of normal and altered binding globulins: implications for adrenal insufficiency diagnosis. J Clin Endocrinol Metab 2019; 104: 4827-4836
• 19 Bendel S, Karlsson S, Pettila V. et al Free cortisol in sepsis and septic shock. Anesth Analg 2008; 106: 1813-1819
• 20 Poomthavorn P, Lertbunrian R, Preutthipan A. et al Serum free cortisol index, free cortisol, and total cortisol in critically ill children. Intensive Care Med 2009; 35: 1281-1285
• 21 Cohen J, Smith ML, Deans RV. et al Serial changes in plasma total cortisol, plasma free cortisol, and tissue cortisol activity in patients with septic shock: An observational study. Shock 2012; 37: 28-33
• 22 Perogamvros I, Ray DW, Trainer PJ. Regulation of cortisol bioavailability--effects on hormone measurement and action. Nat Rev Endocrinol 2012; 8: 717-727
• 23 Nieman LK, Biller BM, Findling JW. et al The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93: 1526-1540
• 24 Palmieri S, Morelli V, Polledri E. et al The role of salivary cortisol measured by liquid chromatography-tandem mass spectrometry in the diagnosis of subclinical hypercortisolism. Eur J Endocrinol 2013; 168: 289-296
• 25 Ceccato F, Barbot M, Albiger N. et al Daily salivary cortisol and cortisone rhythm in patients with adrenal incidentaloma. Endocrine 2018; 59: 510-519
• 26 Di Dalmazi G, Vicennati V, Garelli S. et al Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing’s syndrome: A 15-year retrospective study. Lancet Diabetes Endocrinol 2014; 2: 396-405