Low-dose (1 microgram) adrenocorticotrophin (ACTH) stimulation as a screening test for impaired hypothalamo-pituitary-adrenal axis function: sensitivity, specificity and accuracy in comparison with the high-dose (250 microgram) test.

OBJECTIVE: We have shown previously that in contrast to the standard high-dose 250-microgram ACTH test, a low-dose 1-microgram ACTH stimulation test correctly identified all patients with pituitary disease who had impaired hypothalamo-pituitary-adrenal (HPA) function. In this study we further compared the performances of these two tests as screening procedures for possible HPA impairment. DESIGN: A comparison of the 1-microgram and the 250-microgram ACTH stimulation tests in healthy controls and in patients with pituitary disease whose HPA axis status was characterized formally by a gold standard test. SUBJECTS: A total of 89 subjects were investigated: 27 healthy normal controls, 43 patients with pituitary disease and normal HPA function, and 19 patients with various pituitary diseases and impaired HPA function. MEASURES: All 89 subjects underwent stimulation with 1 microgram ACTH; 80 also underwent the high-dose 250-microgram ACTH test. A receiver operating characteristic analysis (ROC) was performed to compare the tests. RESULTS: Using a stimulated cortisol > 500 nmol/l as the criterion for a normal response, the 1-microgram ACTH stimulation identified 18 of the 19 subjects with impaired HPA function (94.7% sensitivity with a likelihood ratio of 0.0588 for a negative test). In contrast, 15/16 passed the high-dose test (a 6.2% sensitivity with a likelihood ratio of 0.875 for a negative test). All normal controls, and 36/43 patients with preserved HPA function, passed the 1-microgram ACTH test (90% specificity). This degree of accuracy was unrivalled by the high dose test at all the cut-off levels considered. CONCLUSIONS: More sensitive and accurate, the low-dose 1-microgram ACTH test is as simple and safe as the standard 250-microgram test. We suggest it should replace it in screening for adrenal insufficiency.

Effect of TRH on beta-gonadotropin subunits in patients with pituitary microincidentalomas.

OBJECTIVE: To explore the hypothesis that most of the pituitary abnormalities compatible with the diagnosis of microadenoma, and detected in about 10% of the normal adult population, represent asymptomatic gonadotropinomas. DESIGN: Patients diagnosed with pituitary microincidentalomas at the Institute of Endocrinology of the Tel Aviv Medical Center were evaluated. Circulating beta-subunits of gonadotropin hormones were measured before and 30, 45, 60 and 90 min after the intravenous injection of 400 microgram TRH. PATIENTS: Twenty-two patients with pituitary incidentaloma and 16 normal volunteers were tested. RESULTS: In 16 of the 22 patients, an abnormal beta-subunit response was detected after the TRH challenge. Three patients had an abnormal increase in both beta-FSH and beta-LH after TRH administration. Isolated pathological beta-FSH or beta-LH responses were demonstrated in five and eight patients respectively. Six patients had normal basal and stimulated gonadotropin subunit values, raising the possibility that their lesions were not pituitary microadenomas. There was a significant overall difference between the response to TRH of the patient and control groups. In the gonadotropin positive group, comprising 16 patients, serum beta-FSH increased from 6.4+/-1.6 ng/ml to 9.2+/-1.3 ng/ml (P=0.042) 1 h after TRH stimulation, whereas no changes were detected in the control group after TRH injection (basal: 4.1+/-0.8 ng/ml, peak: 5.1+/-0.8 ng/ml; P=0.15). Serum beta-LH increased from 10.5+/-3.2 ng/ml to 23.4+/-4.9 ng/ml (P=0.0037) at this time, in contrast to a lack of response in controls (basal: 6.4+/-1.5 ng/ml, peak: 8.2+/-2.3 ng/ml; P=0.24). CONCLUSION: In about 73% of patients with pituitary incidentalomas smaller than 10 mm, TRH elicits an increase in gonadotropin beta-subunits. This observation raises the possibility that non-functioning pituitary micro- and macroadenomas, which share a similar response to TRH, originate in a common ancestor cell type, probably a pituitary gonadotrope.