Hair Cortisol Measurement in Mitotane-Treated Adrenocortical Cancer Patients

L. Manenschijn; M. Quinkler; E. F. C. van Rossum

doi:10.1055/s-0034-1370961

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2014; 46(04): 299-304
DOI: 10.1055/s-0034-1370961

Endocrine Care

Hair Cortisol Measurement in Mitotane-Treated Adrenocortical Cancer Patients

L. Manenschijn^*

¹Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands

,

M. Quinkler^*

²Department of Clinical Endocrinology, Charité Campus Mitte, Charité University Medicine Berlin, Berlin, Germany

,

E. F. C. van Rossum

¹Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands

› Author Affiliations

Abstract

The only approved drug for the treatment of adrenocortical cancer (ACC) is mitotane. Mitotane is adrenolytic and therefore, hydrocortisone replacement therapy is necessary. Since mitotane increases cortisol binding globulin (CBG) and induces CYP3A4 activity, high doses of hydrocortisone are thought to be required. Evaluation of hydrocortisone therapy in mitotane-treated patients has been difficult since there is no good marker to evaluate hydrocortisone therapy. Measurement of cortisol in scalp hair is a novel method that offers the opportunity to measure long-term cortisol levels. Our aim was to evaluate whether hair cortisol measurements could be useful in evaluating recent hydrocortisone treatment in mitotane-treated ACC patients. Hair cortisol levels were measured in 15 mitotane-treated ACC patients on hydrocortisone substitution and 96 healthy individuals. Cortisol levels were measured in 3 cm hair segments, corresponding to a period of 3 months. Hair cortisol levels were higher in ACC patients compared to healthy individuals (p<0.0001). Seven ACC patients (47%) had hair cortisol levels above the reference range. None of the patients had hair cortisol levels below normal. In contrast to hydrocortisone doses (β=0.03, p=0.93), hair cortisol levels were associated with BMI (β=0.53, p=0.042). There was no correlation between hair cortisol levels and hydrocortisone doses (β=0.41, p=0.13). Almost half of the ACC patients had high hair cortisol levels, suggesting long-term over-substitution of hydrocortisone in some of the patients, whereas none of the patients was under-substituted. Hair cortisol measurements might be useful in long-term monitoring hydrocortisone treatment in mitotane-treated ACC patients.

Key words

hair cortisol - adrenal insufficiency - glucocorticoid replacement therapy - cortisol

Full Text

References

References
1 Soreide JA, Brabrand K, Thoresen SO. Adrenal cortical carcinoma in Norway, 1970–1984. World J Surg 1992; 16: 663-667
2 Brennan MF. Adrenocortical carcinoma. CA Cancer J Clin 1987; 37: 348-365
3 Lafemina J, Brennan MF. Adrenocortical carcinoma: Past, present and future. J Surg Oncol 2012; 106: 586-594
4 Sullivan M, Boileau M, Hodges CV. Adrenal cortical carcinoma. J Urol 1978; 120: 660-665
5 Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, Rossetto R, Buci L, Sperone P, Grossrubatscher E, Reimondo G, Bollito E, Papotti M, Saeger W, Hahner S, Koschker AC, Arvat E, Ambrosi B, Loli P, Lombardi G, Mannelli M, Bruzzi P, Mantero F, Allolio B, Dogliotti L, Berruti A. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 2007; 356: 2372-2380
6 Bertherat J, Coste J, Bertagna X. Adjuvant mitotane in adrenocortical carcinoma. N Engl J Med 2007; 357: 1256-1257
7 Dickstein G, Shechner C, Nativ O. Adjuvant mitotane in adrenocortical carcinoma. N Engl J Med 2007; 357: 1257-1258
8 Lee JE. Adjuvant mitotane in adrenocortical carcinoma. N Engl J Med 2007; 357: 1258
9 Schteingart DE. Adjuvant mitotane therapy of adrenal cancer – use and controversy. N Engl J Med 2007; 356: 2415-2418
10 Berruti A, Fassnacht M, Baudin E, Hammer G, Haak H, Leboulleux S, Skogseid B, Allolio B, Terzolo M. Adjuvant therapy in patients with adrenocortical carcinoma: a position of an international panel. J Clin Oncol 2010; 28: e401-e402
11 Cai W, Benitez R, Counsell RE, Djanegara T, Schteingart DE, Sinsheimer JE, Wotring LL. Bovine adrenal cortex transformations of mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane; o,p′-DDD] and its p,p′- and m,p′-isomers. Biochem Pharmacol 1995; 49: 1483-1489
12 Hermsen IG, Fassnacht M, Terzolo M, Houterman S, den HJ, Leboulleux S, Daffara F, Berruti A, Chadarevian R, Schlumberger M, Allolio B, Haak HR, Baudin E. Plasma concentrations of o,p’DDD, o,p’DDA, and o,p’DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: results of a retrospective ENS@T multicenter study. J Clin Endo Metabol 2011; 96: 1844-1851
13 Schteingart DE, Doherty GM, Gauger PG, Giordano TJ, Hammer GD, Korobkin M, Worden FP. Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer 2005; 12: 667-680
14 Watson AD, Rijnberk A, Moolenaar AJ. Systemic availability of o,p’-DDD in normal dogs, fasted and fed, and in dogs with hyperadrenocorticism. Res Vet Sci 1987; 43: 160-165
15 Alexandraki KI, Kaltsas GA, le Roux CW, Fassnacht M, Ajodha S, Christ-Crain M, Akker SA, Drake WM, Edwards R, Allolio B, Grossman AB. Assessment of serum-free cortisol levels in patients with adrenocortical carcinoma treated with mitotane: a pilot study. Clin Endocrinol (Oxf) 2010; 72: 305-311
16 Daffara F, De FS, Reimondo G, Zaggia B, Aroasio E, Porpiglia F, Volante M, Termine A, Di CF, Dogliotti L, Angeli A, Berruti A, Terzolo M. Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly. Endocr Relat Cancer 2008; 15: 1043-1053
17 van Erp NP, Guchelaar HJ, Ploeger BA, Romijn JA, Hartigh J, Gelderblom H. Mitotane has a strong and a durable inducing effect on CYP3A4 activity. Eur J Endocrinol 2011; 164: 621-626
18 Chortis V, Taylor AE, Schneider P, Tomlinson JW, Hughes BA, O’Neil DM, Libe R, Allolio B, Bertagna X, Bertherat J, Beuschlein F, Fassnacht M, Karavitaki N, Mannelli M, Mantero F, Opocher G, Porfiri E, Quinkler M, Sherlock M, Terzolo M, Nightingale P, Shackleton CH, Stewart PM, Hahner S, Arlt W. Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5alpha-reductase, explaining the need for personalized glucocorticoid and androgen replacement. J Clin Endo Metabol 2013; 98: 161-171
19 Allolio B, Fassnacht M. Adrenocortical Carcinoma: Clinical Update. J Clin Endocrinol Metab 2006; 91: 2027-2037
20 Haak HR, Hermans J, van der Velde CJ, Lentjes EG, Goslings BM, Fleuren GJ, Krans HM. Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 1994; 69: 947-951
21 Hague RV, May W, Cullen DR. Hepatic microsomal enzyme induction and adrenal crisis due to o,p′DDD therapy for metastatic adrenocortical carcinoma. Clin Endocrinol (Oxf) 1989; 31: 51-57
22 Kroiss M, Quinkler M, Lutz WK, Allolio B, Fassnacht M. Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma. Clin Endocrinol (Oxf) 2011; 75: 585-591
23 Van Seters AP, Moolenaar AJ. Mitotane increases the blood levels of hormone-binding proteins. Acta Endocrinol (Copenh) 1991; 124: 526-533
24 Quinkler M, Hahner S. What is the best long-term management strategy for patients with primary adrenal insufficiency?. Clin Endocrinol (Oxf) 2012; 76: 21-25
25 Robinson BG, Hales IB, Henniker AJ, Ho K, Luttrell BM, Smee IR, Stiel JN. The effect of o,p’-DDD on adrenal steroid replacement therapy requirements. Clin Endocrinol 1987; 27: 437-444
26 Sauve B, Koren G, Walsh G, Tokmakejian S, van Uum SH. Measurement of cortisol in human hair as a biomarker of systemic exposure. Clin Invest Med 2007; 30: E183-E191
27 Dettenborn L, Tietze A, Kirschbaum C, Stalder T. The assessment of cortisol in human hair – associations with sociodemographic variables and potential confounders. Stress 2012; 15: 578-588
28 Kirschbaum C, Tietze A, Skoluda N, Dettenborn L. Hair as a retrospective calendar of cortisol production-Increased cortisol incorporation into hair in the third trimester of pregnancy. Psychoneuroendocrinology 2009; 34: 32-37
29 Manenschijn L, Koper JW. Lamberts SW, van Rossum EF. Evaluation of a method to measure long term cortisol levels. Steroids 2011; 76: 1032-1036
30 Stalder T, Steudte S, Miller R, Skoluda N, Dettenborn L, Kirschbaum C. Intraindividual stability of hair cortisol concentrations. Psychoneuroendocrinology 2012; 37: 602-610
31 van Uum SH, Sauve B, Fraser LA, Morley-Forster P, Paul TL, Koren G. Elevated content of cortisol in hair of patients with severe chronic pain: a novel biomarker for stress. Stress 2008; 11: 483-488
32 Meyer JS, Novak MA. Minireview: Hair cortisol: a novel biomarker of hypothalamic-pituitary-adrenocortical activity. Endocrinology 2012; 153: 4120-4127
33 Manenschijn L, Koper JW, van den Akker EL, de Heide LJ, Geerdink EA, de Jong FH, Feelders RA, van Rossum EF. A Novel Tool in the Diagnosis and Follow-Up of (Cyclic) Cushing’s Syndrome: Measurement of Long-Term Cortisol in Scalp Hair. J Clin Endo Metabol 2012; 97: E1836-E1843
34 Thomson S, Koren G, Fraser LA, Rieder M, Friedman TC, van Uum SH. Hair analysis provides a historical record of cortisol levels in Cushing’s syndrome. Exp Clin Endocrinol Diabetes 2010; 118: 133-138
35 Gow R, Koren G, Rieder M, Van US. Hair cortisol content in patients with adrenal insufficiency on hydrocortisone replacement therapy. Clin Endocrinol 2011; 74: 687-693
36 Manenschijn L, van Kruysbergen RG, de Jong FH, Koper JW, van Rossum EF. Shift work at young age is associated with elevated long-term cortisol levels and body mass index. J Clin Endo Metabol 2011; 96: E1862-E1865
37 Stalder T, Steudte S, Alexander N, Miller R, Gao W, Dettenborn L, Kirschbaum C. Cortisol in hair, body mass index and stress-related measures. Biol Psychol 2012; 90: 218-223
38 Dettenborn L, Tietze A, Bruckner F, Kirschbaum C. Higher cortisol content in hair among long-term unemployed individuals compared to controls. Psychoneuroendocrinology 2010; 35: 1404-1409
39 Vilar L, Freitas MC, Faria M, Montenegro R, Casulari LA, Naves L, Bruno OD. Pitfalls in the diagnosis of Cushing’s syndrome. Arq Bras Endocrinol Metabol 2007; 51: 1207-1216
40 Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA, Findling JW, Gaillard RC, Grossman AB, Kola B, Lacroix A, Mancini T, Mantero F, Newell-Price J, Nieman LK, Sonino N, Vance ML, Giustina A, Boscaro M. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endo Metabl 2003; 88: 5593-5602
41 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
42 Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endo Metabol 2008; 93: 1526-1540
43 Manenschijn L, Schaap L, van Schoor NM, van der Pas S, Peeters GM, Lips P, Koper JW, van Rossum EF. High Long-Term Cortisol Levels, Measured in Scalp Hair, Are Associated With a History of Cardiovascular Disease. J Clin Endo Metabol 2013; 98: 2078-2083
44 Stalder T, Kirschbaum C, Alexander N, Bornstein SR, Gao W, Miller R, Stark S, Bosch JA, Fischer JE. Cortisol in hair and the metabolic syndrome. J Clin Endo Metabol 2013; 98: 2573-2580