One hundred and seventy-two patients with partial or complete hypopituitarism diagnosed between 1967 and 1994 were studied retrospectively. Those with acromegaly or Cushing's disease were excluded. One hundred and two patients were male (median age at, diagnosis, 53 yr; range, 12-78 yr) and 70 female (median age at diagnosis, 51 yr; range, 1-74 yr). In 131 patients the cause of hypopituitarism was a pituitary tumor or the effects of its treatment, as the majority underwent surgery and/or radiotherapy. In 22, the cause was an extrapituitary tumor, 14 were termed idiopathic, 2 developed hypopituitarism as a result of basal sarcoid, 2 were due to trauma, and 1 was the result of Sheehan's syndrome. The patients were treated with standard replacement therapy. Mortality due to all causes was higher than expected in an age- and sex-matched control population (ratio of observed/expected deaths, 1.73; 95% confidence interval, 1.28-2.28; P < 0.01). Females tended to have a worse prognosis (ratio of observed/expected deaths, 2.29; 95% confidence interval, 1.37-3.58; P < 0.01) than their male counterparts (ratio of observed/expected deaths, 1.50; 95% confidence interval, 1.02-2.13; P < 0.01). There was a small but nonsignificant increase in the number of deaths due to vascular disease (ratio of observed/expected deaths, 1.35; 95% confidence interval, 0.84-2.07; P = 0.11). The only significant independent predictive factors for survival were age at diagnosis and hypogonadism. The majority of the male hypogonadal cohort received replacement therapy (79%), but fewer of the females did so (27%). Hypogonadal patients had a better prognosis than their eugonadal counterparts (log rank, 6.85; P < 0.01). Our data confirmed that mortality in patients with hypopituitarism is significantly increased. However, the contribution of vascular disease to this poor prognosis was not as great as previously reported, and overall, our results favor a multifactorial explanation of the poor long term outcome.

Radiotherapy and ACTH deficiency are significantly associated with increased mortality in patients with acromegaly. In ACTH-deficient patients, a daily dose of more than 25 mg hydrocortisone is associated with increased mortality compared to lower doses. These results have important implications for the treatment of patients with acromegaly and also raise issues as to the optimum hydrocortisone treatment regimens for ACTH-deficient patients.

There is still uncertainty about what is the most appropriate test for assessment of the integrity of the hypothalamo-pituitary-adrenal (HPA) axis. Many advocate the insulin tolerance test (ITT), but this is unpleasant and resource intensive, and may occasionally give misleading results. The conventional [250 microg tetracosactrin, ACTH-(1-24)] short synacthen test (SST) has been used as a simple alternative to the ITT, but it has produced some falsely reassuring results with potentially serious consequences. A low dose [1 microg tetracosactrin, ACTH-(1-24)] short synacthen test (LDSST) has recently been advocated as a more reliable and safer alternative to ITT. Some studies, however, have failed to demonstrate any difference between SST and LDSST. The purpose of this study was to assess the clinical usefulness of LDSST compared to SST and ITT in patients with pituitary disease. We studied 64 patients with suspected or proven pituitary disease. All patients underwent SST and LDSST. Forty-two patients underwent ITT. There was a high correlation between the ITT and LDSST peak cortisol responses (r = 0.89; P < 0.0001), the ITT and SST 30 min cortisol levels (r = 0.83; P < 0.0001), and the LDSST peak cortisol response and the SST 30 min cortisol level (r = 0.85; P < 0.0001). In the LDSST, all but six patients achieved maximal cortisol response by 30 min. A plasma cortisol cut-off of 600 nmol/L is more helpful than 500 nmol/L for clinical decision-making using either the SST 30 min cortisol level or the LDSST peak cortisol response. The sensitivity of the LDSST was 100% (cortisol response of >600 nmol/L indicates intact HPA axis), with no falsely reassuring results. SST (pass cortisol level, >600 nmol/L) was less sensitive than LDSST, it produced 2 of 64 (3%) falsely reassuring results. Even the ITT (pass cortisol level, >500 nmol/L) failed to identify one patient with clinically evident cortisol deficiency. The results of this study indicate that both SST and LDSST, at a cortisol cut-off of 600 nmol/L, are safe for the purpose of clinical decision-making with regard to steroid replacement therapy in patients with pituitary disease. As the LDSST produced no falsely reassuring decisions, we suggest that this could replace the SST and ITT for initial evaluation of the HPA axis in patients with pituitary disease. We suggest administering 1 microg tetracosactrin, i.v., with sampling at 0, 20, and 30 min.

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Research Articles: "Doc2b is a high-affi nity Ca 2+ sensor for spontaneous neurotransmitter release" by A. J. Groffen et al. (26 March, p. 1614). Several author affi liations were not footnoted properly; three corrected affi liations follow.