The assessment of the hypothalamo-pituitary-adrenal axis in pituitary disease: are there short cuts?

The main task of the hypothalamo-pituitary-adrenal (HPA) axis is to enable sufficient cortisol release under regular and stressful situations. Therefore, to prove its being intact in pituitary disease, stimulation tests are usually needed. Cortisol level has to be shown to exceed a threshold level, which has to be defined on normal subjects in each lab, as results may differ greatly. Insulin tolerance test (ITT) is considered the "gold standard". Hypoglycemia induces a severe stress, which stimulates the HPA axis maximally. However, for regularly accepted cut-off points (18-20 microg/dl, 500-550 nmol/l), false positive results are documented, even in normal volunteers, and reproducibility is far from perfect. The metyrapone test, by blocking cortisol production, stimulates ACTH release to overcome the blockade. In this test 11-DOC levels are usually measured, and a cut-off point of 7.0 microg/dl (200 nmol/l) used. Measuring ACTH and/or cortisol + 11-DOC levels may improve the test, both in reasoning and reliability. The CRH test yields unsatisfactory results, and its use is usually saved for differential diagnosis of hypercortisolism. The ACTH test is the easiest to perform, and usually used as a screening test. Abnormal responses should be considered diagnostic, while normal responses, especially in newly onset or recent pituitary disease, should be followed by either ITT or metyrapone test. Most studies show superiority of the 1.0 microg (so called "low dose") ACTH test over the high dose (250 microg) test. The physiologic dose test should replace the pharmacologic dose test whenever ACTH test is considered. In every test there are limitations and pitfalls. Knowing them, and using best clinical judgment, will reduce and minimalize mistakes.