The glucagon test in diagnosis of secondary adrenal insufficiency after craniospinal irradiation: the feasibility of application, the features of performing the test, and its diagnostic informativity

BACKGROUND: The glucagon test (GT) is a promising alternative to the insulin hypoglycemia test (IHT) in diagnosis of secondary adrenal insufficiency (SAI).

AIM: To study the feasibility of using the GT in patients after craniospinal irradiation and to determine the cut-off value to rule out SAI.

METHODS: A total of 28 patients (14 males and 14 females) with the median age of 19 years (17; 23) who had undergone combination treatment (surgery, craniospinal irradiation (35 Gy) with boost to the tumor bed, and polychemotherapy) of extrapituitary brain tumors no later than 2 years before study initiation and 10 healthy volunteers of matching sex and age were examined. All the subjects underwent the GT and IHT with an interval of at least 5–7 days. The cortisol, ACTH, and glucose levels were measured.

RESULTS: Twelve out of 28 patients were diagnosed with SAI according to the IHT results. ROC analysis revealed that cortisol release during the GT >499 nmol/L ruled out SAI [100% sensitivity (Se); 62% specificity (Sp)], while the absence of a rise >340 nmol/l verified SAI (Sp 100%; 55% Se). For GT, the area under a curve (AUC) was 93.6%, which corresponds to a very good diagnostic informativity. In 19 patients, the IHT and GT results were concordant (in ten patients, the release of cortisol occurred above the cut-off value in both tests; no release was detected in nine patients). In nine cases, the results were discordant: the maximum cortisol level detected in the GT was ≤500 nmol/l, but the IHT results ruled out SAI (the GT yielded a false positive outcome). Contrariwise, in three (10.7%) patients the release of cortisol detected in the GT was adequate, while being insufficient in the IHT test. Adverse events (nausea) were reported during the GT test in 9 (25%) subjects; one patient had hypoglycemia (1.8 mmol/l).

CONCLUSION: GT is highly informative and can be used as a first-level stimulation test for ruling out SAI in patients exposed to craniospinal irradiation performed to manage brain tumors. The cortisol level of 500 nmol/L is the best cut-off value for ruling out SAI according to the GT results. The insulin hypoglycemia test is used as the second-level supporting test in patients with positive GT results.

adrenal insufficiency, the hypothalamic–pituitary–adrenal axis, glucagon, young adults, radiation therapy, brain tumors, long-term sequelae

1. Schmiegelow M, Feldt-Rasmussen U, Rasmussen AK, et al. Assessment of the hypothalamo-pituitary-adrenal axis in patients treated with radiotherapy and chemotherapy for childhood brain tumor. J Clin Endocrinol Metab. 2003;88(7):3149–3154. doi: https://doi.org/10.1210/jc.2002-021994

2. Pfeifer M, Kanc K, Verhovec R, Kocijancic A. Reproducibility of the insulin tolerance test (ITT) for assessment of growth hormone and cortisol secretion in normal and hypopituitary adult men. Clin Endocrinol (Oxf). 2001;54(1):17–22. doi: https://doi.org/10.1046/j.1365-2265.2001.01179.x

3. Vestergaard P, Hoeck HC, Jakobsen PE, Laurberg P. Reproducibility of growth hormone and cortisol responses to the insulin tolerance test and the short ACTH test in normal adults. Horm Metab Res. 1997;29(3):106–110. doi: https://doi.org/10.1055/s-2007-979000

4. Grossman AB. The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010;95(11):4855–4863. doi: https://doi.org/10.1210/jc.2010-0982

5. Желудкова О.Г., Поляков В.Г., Рыков М.Ю. и др. Клинические проявления онкологических заболеваний у детей: практические рекомендации. / Под ред. В.Г. Полякова, М.Ю. Рыкова. – СПб.: Типография Михаила Фурсова, 2017. – 52 с. [Zheludkova OG, Polyakov VG, Rykov MYu. Klinicheskie proyavleniya onkologicheskikh zabolevanii u detei: practicheskie rekomendatsii. Ed. by Polyakov VG, Rykov MYu. St. Petersburg: Tipografiya Mikhaila Fursova; 2017. 52 p. (In Russ).]

6. Agha A, Sherlock M, Brennan S, et al. Hypothalamic-pituitary dysfunction after irradiation of nonpituitary brain tumors in adults. J Clin Endocrinol Metab. 2005;90(12):6355–6360. doi: https://doi.org/10.1210/jc.2005-1525

7. Leong KS, Walker AB, Martin I, et al. An audit of 500 subcutaneous glucagon stimulation tests to assess growth hormone and ACTH secretion in patients with hypothalamic-pituitary disease. Clin Endocrinol (Oxf). 2001;54(4):463–468. doi: https://doi.org/10.1046/j.1365-2265.2001.01169.x

8. Yuen KC, Biller BM, Katznelson L, et al. Clinical characteristics, timing of peak responses and safety aspects of two dosing regimens of the glucagon stimulation test in evaluating growth hormone and cortisol secretion in adults. Pituitary. 2013;16(2):220–230. doi: https://doi.org/10.1007/s11102-012-0407-7

9. Cegla J, Jones B, Seyani L, et al. Comparison of the overnight metyrapone and glucagon stimulation tests in the assessment of secondary hypoadrenalism. Clin Endocrinol (Oxf). 2013;78(5):738–742. doi: https://doi.org/10.1111/cen.12043

10. Berg C, Meinel T, Lahner H, et al. Diagnostic utility of the glucagon stimulation test in comparison to the insulin tolerance test in patients following pituitary surgery. Eur J Endocrinol. 2010;162(3): 477–482. doi: https://doi.org/10.1530/EJE-09-0824

11. di Iorgi N, Napoli F, Allegri A, et al. The accuracy of the glucagon test compared to the insulin tolerance test in the diagnosis of adrenal insufficiency in young children with growth hormone deficiency. J Clin Endocrinol Metab. 2010;95(5):2132–2139. doi: https://doi.org/10.1210/jc.2009-2697

12. Эндокринология: Национальное руководство. / Под ред. Дедова И.И., Мельниченко Г.А. 2-е изд., перераб. и доп. – М.: ГЭОТАР-Медиа, 2016. – 1142 c. [Dedov II, Melnichenko GA, editors. Endocrinology: National guidelines. 2nd ed., revised and enlarged. Moscow: GEOTAR-Media; 2016. 1142 p. (In Russ).]

13. Karaca Z, Lale A, Tanriverdi F, et al. The comparison of low and standard dose ACTH and glucagon stimulation tests in the evaluation of hypothalamo-pituitary-adrenal axis in healthy adults. Pituitary. 2011;14(2):134–140. doi: https://doi.org/10.1007/s11102-010-0270-3

14. Böttner A, Kratzsch J, Liebermann S, et al. Comparison of adrenal function tests in children – the glucagon stimulation test allows the simultaneous assessment of adrenal function and growth hormone response in children. J Pediatr Endocrinol Metab. 2005;18(5):433–442. doi: https://doi.org/10.1515/jpem.2005.18.5.433

15. Ach T, Yosra H, Jihen M, et al. Cortisol cut-points for the glucagon stimulation test in the evaluation of hypothalamic pituitary adrenal axis. Endocr J. 2018;65(9):935–942. doi: https://doi.org/10.1507/endocrj.EJ18-0147

16. Hamrahian AH, Yuen KC, Gordon MB, et al. Revised GH and cortisol cut-points for the glucagon stimulation test in the evaluation of GH and hypothalamic–pituitary–adrenal axes in adults: results from a prospective randomized multicenter study. Pituitary. 2016;19(3):332–341. doi: https://doi.org/10.1007/s11102-016-0712-7

17. Tenenbaum A, Phillip M, de Vries L. The intramuscular glucagon stimulation test does not provide good discrimination between normal and inadequate ACTH reserve when used in the investigation of short healthy children. Horm Res Paediatr. 2014;82(3):194–200. doi: https://doi.org/10.1159/000365190.

18. Simsek Y, Karaca Z, Tanriverdi F, et al. A comparison of low-dose ACTH, glucagon stimulation and insulin tolerance test in patients with pituitary disorders. Clin Endocrinol (Oxf). 2015;82(1):45–52. doi: https://doi.org/10.1111/cen.12528

19. Fleseriu M, Hashim I, Karavitaki N, et al. Hormonal replacement in hypopituitarism in adults: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(11):3888–3921. doi: https://doi.org/110.1210/jc.2016-2118