Download PDF
Horm Metab Res 2021; 53(08): 512-519
DOI: 10.1055/a-1539-6442
Endocrine Care

DHEAS and Differential Blood Counts as Indirect Signs of Glucocorticoid Excess in Adrenal Non-Producing Adenomas

Eliza P. Winzinger
1   Division of Endocrinology and Metabolism, Rostock University Medical Center, Rostock, Germany
,
Hana Jandikova
2   Third Department of Medicine – Clinic of Endocrinology and Metabolism, Charles University First Faculty of Medicine, Prague, Czech Republic
3   Division for Specific Endocrinology, University Hospital Dusseldorf, Medical Faculty HHU Dusseldorf, Dusseldorf, Germany
,
Matthias Haase
3   Division for Specific Endocrinology, University Hospital Dusseldorf, Medical Faculty HHU Dusseldorf, Dusseldorf, Germany
,
Andreas Knauerhase
1   Division of Endocrinology and Metabolism, Rostock University Medical Center, Rostock, Germany
,
Tudor Winzinger
1   Division of Endocrinology and Metabolism, Rostock University Medical Center, Rostock, Germany
,
Matthias Schott
3   Division for Specific Endocrinology, University Hospital Dusseldorf, Medical Faculty HHU Dusseldorf, Dusseldorf, Germany
,
Holger S. Willenberg 
1   Division of Endocrinology and Metabolism, Rostock University Medical Center, Rostock, Germany
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

The majority of incidentally discovered adrenal tumors are later characterized as non-producing adrenocortical adenomas (NPA). We asked whether laboratory abnormalities in parameters that reflect glucocorticoid action can be found in patients with NPA despite their nature of being clinically unapparent. Since glucocorticoids are potent immunosuppressants we studied blood counts and differential blood counts along with corticotropin and dehydroepiandrostenedione sulfate (DHEAS) blood concentrations, as well as cortisol values before and after an overnight 1 mg dexamethasone suppression test. We compared the results of normal individuals, of patients with adrenal adenomas and normal hormone profiles and with subclinical autonomous glucocorticoid hypersecretion, as well as overt cortisol excess. We found that almost all indices of the blood counts were significantly different between the patients groups. In particular, patients with adrenal non-producing adenomas already showed signs of glucocorticoid excess, including relative lymphocytopenia, lowered DHEAS, and ACTH concentrations than control individuals. We also found that the extent of lymphocytopenia correlated with the concentrations of DHEAS and ACTH, and DHEAS correlated well with ACTH. We conclude that the basal ACTH and DHEAS values along with the differential blood counts give good information on the extent of glucocorticoid excess and that silent adrenal adenomas seem to oversecrete glucocorticoids at concentrations that already alter these parameters.

Key words

adrenal - DHEAS - incidentaloma - cortisol - blood count


Publication History

Received: 14 November 2020

Accepted after revision: 23 June 2021

Article published online:
12 August 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Mansmann G, Lau J, Balk E. et al The clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev 2004; 25: 309-340
    CrossrefPubMedGoogle Scholar
  • 2 Terzolo M, Stigliano A, Chiodini I. et al AME position statement on adrenal incidentaloma. Eur J Endocrinol 2011; 164: 851-870
    CrossrefPubMedGoogle Scholar
  • 3 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
    CrossrefPubMedGoogle Scholar
  • 4 Farrugia FA, Misiakos E, Martikos G. et al A step by step approach in differential diagnosing of adrenal incidentaloma (epinephroma), (with comments on the new clinical practice guidelines of the European Society of Endocrinology). Rom J Intern Med 2017; 55: 188-197
    PubMedGoogle Scholar
  • 5 Nieman LK, Biller BMK, Findling JW. et al The diagnosis of Cushing’s syndrome: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93: 1526-1540
    CrossrefPubMedGoogle Scholar
  • 6 Vassilatou E, Vryonidou A, Michalopoulou S. et al Hormonal activity of adrenal incidentalomas: results from a long-term follow-up study. Clin Endocrinol 2009; 70: 674-679
    CrossrefPubMedGoogle Scholar
  • 7 Hammond GL. Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action. J Endocrinol 2016; 230: R13-R25
    CrossrefPubMedGoogle Scholar
  • 8 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
    CrossrefPubMedGoogle Scholar
  • 9 Bae YJ, Kratzsch J. Corticosteroid-binding globulin: modulating mechanisms of bioavailability of cortisol and its clinical implications. Best Pract Res Clin Endocrinol Metab 2015; 29: 761-772
    CrossrefPubMedGoogle Scholar
  • 10 Dhillo WS, Kong WM, Le Roux CW. et al Cortisol-binding globulin is important in the interpretation of dynamic tests of the hypothalamic--pituitary--adrenal axis. Eur J Endocrinol 2002; 146: 231-235
    CrossrefPubMedGoogle Scholar
  • 11 Popp KH, Kosilek RP, Frohner R. et al Computer vision technology in the differential diagnosis of Cushing's syndrome. Exp Clin Endocrinol Diabetes 2019; 127: 685-690
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Wei R, Jiang C, Gao J. et al Deep-learning approach to automatic identification of facial anomalies in endocrine disorders. Neuroendocrinology 2020; 110: 328-337
    CrossrefPubMedGoogle Scholar
  • 13 Leibowitz G, Tsur A, Chayen SD. et al Pre-clinical Cushing’s syndrome: an unexpected frequent cause of poor glycaemic control in obese diabetic patients. Clin Endocrinol 1996; 44: 717-722
    CrossrefPubMedGoogle Scholar
  • 14 Angeli A, Osella G, Reimondo G. et al Adrenal incidentalomas and subclinical Cushing’s syndrome: is there evidence for glucocorticoid-induced osteoporosis?. Front Horm Res 2002; 30: 73-85
    CrossrefPubMedGoogle Scholar
  • 15 Catargi B, Rigalleau V, Poussin A. et al Occult Cushing’s syndrome in type-2 diabetes. J Clin Endocrinol Metab 2003; 88: 5808-5813
    CrossrefPubMedGoogle Scholar
  • 16 Sippel RS, Chen H. Subclinical Cushing’s syndrome in adrenal incidentalomas. Surg Clin North Am 2004; 84: 875-885
    CrossrefPubMedGoogle Scholar
  • 17 Yener S, Cömlekci A, Yuksel F. et al Traditional and novel cardiovascular risk factors in non-functioning adrenal adenomas. Eur J Intern Med 2012; 23: 83-87
    CrossrefPubMedGoogle Scholar
  • 18 Carroll TB, Findling JW. The diagnosis of Cushing's syndrome. Rev Endocr Metab Disord 2010; 11: 147-153
    CrossrefPubMedGoogle Scholar
  • 19 Kannisto S, Laatikainen A, Taivainen A. et al Serum dehydroepiandrosterone sulfate concentration as an indicator of adrenocortical suppression during inhaled steroid therapy in adult asthmatic patients. Eur J Endocrinol 2004; 150: 687-690
    CrossrefPubMedGoogle Scholar
  • 20 Masjkur J, Gruber M, Peitzsch M. et al Plasma steroid profiles in subclinical compared with overt adrenal Cushing syndrome. J Clin Endocrinol Metab 2019; 104: 4331-4340
    CrossrefPubMedGoogle Scholar
  • 21 Ichijo T, Ueshiba H, Nawata H. et al A nationwide survey of adrenal incidentalomas in Japan: The first report of clinical and epidemiological features. Endocr J 2020; 67: 141-152
    CrossrefPubMedGoogle Scholar
  • 22 Ribeiro Cavalari EM, de Paula MP, Arruda M. et al Nonfunctioning adrenal incidentaloma: A novel predictive factor for metabolic syndrome. Clin Endocrinol 2018; 89: 586-595
    CrossrefPubMedGoogle Scholar
  • 23 Midorikawa S, Sanada H, Hashimoto S. et al The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection. Clin Endocrinol 2001; 54: 797-804
    CrossrefPubMedGoogle Scholar
  • 24 Reimondo G, Castellano E, Grosso M. et al Adrenal incidentalomas are tied to increased risk of diabetes: Findings from a prospective study. J Clin Endocrinol Metab 2020; 105 dgz284
    PubMedGoogle Scholar
  • 25 Di Dalmazi G, Pasquali R. Adrenal adenomas, subclinical hypercortisolism, and cardiovascular outcomes. Curr Opin Endocrinol Diabetes Obes 2015; 22: 163-168
    CrossrefPubMedGoogle Scholar
  • 26 Kim BY, Chun AR, Kim KJ. et al Clinical characteristics and metabolic features of patients with adrenal incidentalomas with or without subclinical Cushing's syndrome. Endocrinol Metab (Seoul) 2014; 29: 457-463
    CrossrefPubMedGoogle Scholar
  • 27 Arruda M, Cavalari MRE, de Paula PM. et al The presence of nonfunctioning adrenal incidentalomas increases arterial hypertension frequency and severity, and is associated with cortisol levels after dexamethasone suppression test. J Hum Hypertens 2017; 32: 3-11
    CrossrefPubMedGoogle Scholar
  • 28 Yener S, Ertilav S, Secil M. et al Increased risk of unfavorable metabolic outcome during short-term follow-up in subjects with nonfunctioning adrenal adenomas. Med Princ Pract 2012; 21: 429-434
    CrossrefPubMedGoogle Scholar
  • 29 Yener S, Comlekci A, Akinci B, Secil M, Demir T, Ertilav S, Yesil S. Non-functioning adrenal incidentalomas are associated with elevated D-dimer levels. J Endocrinol Invest 2009; 32: 338-343
    CrossrefPubMedGoogle Scholar
  • 30 Yener S, Baris M, Secil M. et al Is there an association between non-functioning adrenal adenoma and endothelial dysfunction?. J Endocrinol Invest 2011; 34: 265-270
    CrossrefPubMedGoogle Scholar
  • 31 Mantero F, Terzolo M, Arnaldi G. et al A survey on adrenal incidentaloma in Italy. Study group on adrenal tumors of the Italian society of endocrinology. J Clin Endocrinol Metab 2000; 85: 637-644
    PubMedGoogle Scholar
  • 32 Cavagnini F, Pecori Giraldi F. Adrenal causes of Cushing’s syndrome. Endocrinol: Adult and Pediatr 2016; e7: 1775-1809
    PubMedGoogle Scholar
  • 33 Harmon JM, Norman MR, Fowlkes BJ. et al Dexamethasone induces irreversible G1 arrest and death of a human lymphoid cell line. J Cell Physiol 1979; 98: 267-278
    CrossrefPubMedGoogle Scholar
  • 34 Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature. 1980; 284: 555-556
    CrossrefPubMedGoogle Scholar
  • 35 Herold MJ, McPherson KG, Reichardt HM. Glucocorticoids in T cell apoptosis and function. Cell Mol Life Sci 2006; 63: 60-72
    CrossrefPubMedGoogle Scholar
  • 36 Marchetti P, Castedo M, Susin SA. et al Mitochondrial permeability transition is a central coordinating event of apoptosis. J Exp Med 1996; 184: 1155-1160
    CrossrefPubMedGoogle Scholar
  • 37 Petit PX, Lecoeur H, Zorn E. Alterations in mitochondrial structure and function are early events of dexamethasone-induced thymocyte apoptosis. J Cell Biol 1995; 130: 157-167
    CrossrefPubMedGoogle Scholar
  • 38 Robertson NM, Zangriffi J, Fernandes-Alnemri T. et al Baculovirus P35 inhibits the glucocorticoid-mediated pathway of cell death. Cancer Res 1997; 57: 43-47
    PubMedGoogle Scholar
  • 39 Chandra J, Niemer I, Gilbreath J. et al Proteasome inhibitors induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemic lymphocytes. J Blood 1998; 92: 4220-4229
    CrossrefPubMedGoogle Scholar
  • 40 Baxter JD, Harrist AW, Tomkins GM. et al Glucocorticoid receptors in lymphoma cells in culture: relationship to glucocorticoid killing activity. Science 1971; 171: 189-191
    CrossrefPubMedGoogle Scholar
  • 41 Yuh YS, Thompson EB. Glucocorticoid effect on oncogene/growth gene expression in human T lymphoblastic leukemic cell line CCRF-CEM. Specific c-myc mRNA suppression by dexamethasone. J Biol Chem 1989; 264: 10904-10910
    CrossrefPubMedGoogle Scholar
  • 42 Almawi WY, Hess DA, Rieder MJ. Multiplicity of glucocorticoid action in inhibiting allograft rejection. Cell Transplant 1998; 7: 511-523
    CrossrefPubMedGoogle Scholar
  • 43 Mori A, Kaminuma O, Suko M. et al Two distinct pathways of interleukin-5 synthesis in allergen-specific human T-cell clones are suppressed by glucocorticoids. Blood 1997; 89: 2891-2900
    CrossrefPubMedGoogle Scholar
  • 44 Riccardi C, Bruscoli S, Ayroldi E. et al GILZ, a glucocorticoid hormone induced gene, modulates T lymphocytes activation and death through interaction with NF-kB. Adv Exp Med Biol 2001; 495: 31-39
    CrossrefPubMedGoogle Scholar
  • 45 Cannarile L, Zollo O, D'Adamio F. et al Cloning, chromosomal assignment and tissue distribution of human GILZ, a glucocorticoid hormone-induced gene. Cell Death Differ 2001; 8: 201-203
    CrossrefPubMedGoogle Scholar
  • 46 Bornstein SR, Stratakis CA, Chrousos GP. Adrenocortical tumors: recent advances in basic concepts and clinical management. Ann Intern Med 1999; 130: 759-771
    CrossrefPubMedGoogle Scholar
  • 47 Kasperlik-Zeluska AA, Rosłonowska E, Słowinska-Srzednicka J. et al Incidentally discovered adrenal mass (incidentaloma): investigation and management of 208 patients. Clin Endocrinol 1997; 46: 29-37
    CrossrefPubMedGoogle Scholar
  • 48 Arnaldi G, Masini AM, Giacchetti G. et al Adrenal incidentaloma. Braz J Med Biol Res. 2000; 33: 1177-1189
    CrossrefPubMedGoogle Scholar
  • 49 Bülow B, Jansson S, Juhlin C. et al Adrenal incidentaloma-follow-up results from a Swedish prospective study. Eur J Endocrinol 2006; 154: 419-423
    CrossrefPubMedGoogle Scholar
  • 50 Dennedy MC, Annamalai AK, Prankerd-Smith O. et al Low DHEAS: a sensitive and specific test for the detection of subclinical hypercortisolism in adrenal incidentalomas. J Clin Endocrinol Metab 2017; 102: 786-792
    PubMedGoogle Scholar
  • 51 Ueland GÅ, Grinde T, Methlie P. et al Diagnostic testing of autonomous cortisol secretion in adrenal incidentalomas. Endocr Connect 2020; 9: 963-970
    CrossrefPubMedGoogle Scholar
  • 52 Huayllas MKP, Netzel BC, Singh RJ. et al Serum cortisol levels via radioimmunoassay vs liquid chromatography mass spectrophotometry in healthy control subjects and patients with adrenal incidentalomas. Lab Med 2018; 49: 259-267
    PubMedGoogle Scholar
  • 53 Constantinescu G, Bidlingmaier M, Gruber M. et al Mass spectrometry reveals misdiagnosis of primary aldosteronism with scheduling for adrenalectomy due to immunoassay interference. Clin Chim Acta 2020; 507: 98-103
    CrossrefPubMedGoogle Scholar
  • 54 Nandakumar V, Paul Theobald J, Algeciras-Schimnich A. Evaluation of plasma ACTH stability using the Roche Elecsys immunoassay. Clin Biochem 2020; 81: 59-62
    CrossrefPubMedGoogle Scholar
  • 55 Ye YL, Yuan XX, Chen MK. et al Management of adrenal incidentaloma: the role of adrenalectomy may be underestimated. BMC Surg 2016; 16: 41
    CrossrefPubMedGoogle Scholar
  • 56 Nishikawa T, Saito J, Omura M. Mini review: surgical indications for adrenal incidentaloma. Biomed Pharmacother 2002; 56: 145s-148s
    CrossrefPubMedGoogle Scholar
  • 57 Papierska L, Cichocki A, Sankowski AJ. et al Adrenal incidentaloma imaging-the first steps in therapeutic management. Pol J Radiol 2013; 78: 47-55
    CrossrefPubMedGoogle Scholar
  • 58 Zeiger MA, Siegelman SS, Hamrahian AH. Medical and surgical evaluation and treatment of adrenal incidentalomas. J Clin Endocrinol Metab 2011; 96: 2004-2015
    CrossrefPubMedGoogle Scholar
  • 59 Vassiliadi DA, Tsagarakis S. Endocrine incidentalomas--challenges imposed by incidentally discovered lesions. Nat Rev Endocrinol 2011; 7: 668-680
    CrossrefPubMedGoogle Scholar
  • 60 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
    CrossrefPubMedGoogle Scholar
  • 61 Thomas AZ, Blute ML, Seitz C. et al Management of the Incidental Adrenal Mass. Eur Urol Focus 2016; 1: 223-230
    CrossrefPubMedGoogle Scholar