Objectives: Patients with organic growth hormone deficiency (GHD) or with structural hypothalamicpituitary abnormalities may have additional anterior pituitary hormone deficits, and are at risk of developing complete or partial corticotropin (ACTH) deficiency. Evaluation of the integrity of the hypothalamic -pituitary -adrenal axis (HPA) is essential in these patients because, although clinically asymptomatic, their HPA cannot appropriately react to stressful stimuli with potentially life-threatening consequences. Design and methods: In this study we evaluated the integrity of the HPA in 24 patients (age 4.2 -31 years at the time of the study) with an established diagnosis of GHD and compared the reliability of the insulin tolerance test (ITT), short synacthen test (SST), low-dose SST (LDSST), and corticotropin releasing hormone (CRH) test in the diagnosis of adrenal insufficiency. Results: At a cortisol cut-off for a normal response of 550 nmol/l (20 mg/dl), the response to ITT was subnormal in 11 subjects, 6 with congenital and 5 with acquired GHD. Four patients had overt adrenal insufficiency, with morning cortisol concentrations ranging between 66.2 -135.2 nmol/l (2.4-4.9 mg/dl) and typical clinical symptoms and laboratory findings. In all these patients, a subnormal cortisol response to ITT was confirmed by LDSST and by CRH tests. SST failed to identify one of the patients as adrenal insufficient. In the seven asymptomatic patients with a subnormal cortisol response to ITT, the diagnosis of adrenal insufficiency was confirmed in one by LDSST, in none by SST, and in five by CRH tests. The five patients with a normal cortisol response to ITT exhibited a normal response also after LDSST and SST. Only two of them had a normal response after a CRH test. In the seven patients with asymptomatic adrenal insufficiency mean morning cortisol concentration was significantly higher than in the patients with overt adrenal insufficiency. ITT was contraindicated in eight patients, and none of them had clinical symptoms of overt adrenal insufficiency. One of these patients had a subnormal cortisol response to LDSST, SST, and CRH, and three exhibited a subnormal response to CRH but normal responses to LDSST and to SST. Conclusion: We conclude that none of these tests can be considered completely reliable for establishing or excluding the presence of secondary or tertiary adrenal insufficiency. Consequently, clinical judgment remains one of the most important issues for deciding which patients need assessment or re -assessment of adrenal function. European Journal of Endocrinology 152 735-741

Objective: A consensus exists that severe growth hormone deficiency (GHD) in adults is defined by a peak GH response to insulin-induced hypoglycemia (insulin tolerance test, ITT) of less than 3 mg/l based on a cohort of subjects with a mean age of 45 years. Design and methods: By considering one of the following two criteria for the diagnosis of probable permanent GHD, i.e. the severity of GHD (suggested by the presence of multiple pituitary hormone deficiencies (MPHD)) or the magnetic resonance (MR) imaging identification of structural hypothalamic -pituitary abnormalities, 26 patients (17 males, 9 females, mean age 20.8^2.3 years, range 17 -25 years) were selected for re-evaluation of the GH response to ITT and their IGF-I concentration. Eight subjects had isolated GHD (IGHD) and 18 had MPHD. Normative data for peak GH were obtained after ITT in 39 healthy subjects (mean age 21.2^4.4 years, range 15.1 -30.0 years) and the reference range for IGF-I was calculated using normative data from 117 healthy individuals. Results: Mean peak GH response to ITT was significantly lower in the 26 patients (1.8^2.0 mg/l, range 0.1-6.1 mg/l) compared with the 39 controls (18.5^15.5 mg/l, range 6.1-84.0 mg/l; P , 0.0001). One subject with septo-optic dysplasia had a peak GH response of 6.1 mg/l that overlapped the lowest peak GH response obtained in normal subjects. There was an overlap for IGF-I SDS between subjects with IGHD and MPHD, as well as with normal controls. The diagnostic accuracy of a peak GH response of 6.1 mg/l showed a 96% sensitivity with 100% specificity. The maximum diagnostic accuracy with IGF-I SDS was obtained with a cut-off of 2 1.7 SDS (sensitivity 77%, specificity 100%) while an IGF-I # 2 2.0 SDS showed a sensitivity of 62%. Conclusion: Our data show that the cut-off value of the peak GH response to ITT of less than 3 mg/l or 5 mg/l and of IGF-I of less than 22.0 SDS are too restrictive for the diagnosis of permanent GH deficiency in the transition period. We suggest that permanent GHD could be investigated more accurately by means of an integrated analysis of clinical history, the presence of MPHD, IGF-I concentration and the MR imaging findings of structural hypothalamic -pituitary abnormalities.

These observations reveal two novel HESX1 mutations in a so-far-undescribed disease phenotype characterized by a life-threatening neonatal condition associated with anterior pituitary aplasia, in the absence of ectopic posterior pituitary and optic nerve abnormalities, two features classically associated with HESX1 defects.

The adopted peak GH to ITT below 5.62 microg/liter is an accurate diagnostic cutoff point for HLGHD in young adults with COGHD. In addition, IGF-I is a reliable marker providing information about the severity of GHD. Careful follow-up is required for subjects with discordant ITT and IGF-I results.

This study shows that glucagon is an accurate and safe diagnostic test for adrenal function in young children who are at risk for adrenal insufficiency.