ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This study identifies a reliable cut-off value for the glucagon stimulation test, which may be used as an alternative to the insulin tolerance test (ITT) in the diagnosis of growth hormone deficiency (GHD) in transition age.

Many patients with childhood-onset growth hormone deficiency (GHD) show normal GH secretion when re-tested at the end of growth, especially those with isolated GHD and normal or small pituitary gland (1). ITT is recognized as the gold standard test for the diagnosis of GHD in transition age, with a cut-off value ≤ 6 μg/L (2). However, ITT should be avoided in patients with epilepsy, cerebral or cardiovascular diseases (3); in such cases, the glucagon stimulation test (GST) is a valid alternative to ITT. For the diagnosis of adult GHD, the American Association of Clinical Endocrinologists (AACE) recommend using a GH cut-off of 3 μg/L for normal and overweight patients with a high pretest probability of GHD or 1 μg/L for overweight and obese patients with a low pretest probability of GHD (4). However, these cut-off values are not been established in clinical practice for the transition phase.

This study evaluated the accuracy of the glucagon stimulation test (GST) compared to ITT in the diagnosis of GHD in young adults with childhood-onset GHD in 97 patients (median age, 17.39 years) who underwent ITT, GST, and IGF-1 testing. Patients were affected by a) idiopathic isolated GHD ( n =44); b) moderate organic GHD, with congenital anomalies (pituitary stalk interruption syndrome and other cerebral midline defects), organic hypothalamic-pituitary disease (secondary to brain surgery, craniospinal and total body irradiation, or infiltrative disease of the hypothalamus and pituitary stalk), with 1 or 2 pituitary defects ( n =35) and severe organic GHD (≥3 hormone deficiencies, n =18).

ROC curve analysis of GST showed a GH peak value of 7.3 μg/L as the optimal cutoff (95% CI 4.15-8.91; sensitivity 95.7%, specificity 88.2%) to correctly classify 91.8% of the entire cohort. Subgroup analyses were possible only in moderate organic GHD patients (highly likelihood GHD), due to the insufficient sample size in the severe organic GHD group. The proportion of correctly classified patients at the optimal threshold (91.4%) was obtained for a GH peak cutoff of 5.8 μg/L (95% CI 3.16-7.39; sensitivity, 96.0%, specificity 80.0%). A strong concordance between GST and ITT was reported, as demonstrated by an intraclass correlation coefficient around 92%.

GST is a safe alternative to ITT for assessing GH secretion in young adults with childhood-onset GHD. Patients with a GH peak < 5.8 μg/L are candidates to restart rhGH therapy.

References: 1. Laurer E, Sirovina A, Blaschitz A, et al. The landscape of retesting in childhood-onset idiopathic growth hormone deficiency and its reversibility: a systematic review and meta-analysis. Eur J Endocrinol. 2022;187(2):265-278.2. Ho KKY; 2007 GH Deficiency Consensus Workshop Participants. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Eur J Endocrinol. 2007;157(6):695-700.3. Yeoh P, Dwyer AA, Anghel E, et al. A comparison of the blood glucose, growth hormone, and cortisol responses to two doses of insulin (0.15 U/kg vs. 0.10 U/kg) in the insulin tolerance test: a single-centre audit of 174 cases. Int J Endocrinol. 2022;2022: 7360282.4. Yuen KCJ, Biller BMK, Radovick S, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of growth hormone deficiency in adults and patients transitioning from pediatric to adult care. Endocr Pract. 2019;25(11):1191-1232.