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ACTH Deficiency, Higher Doses of Hydrocortisone Replacement, and Radiotherapy Are Independent Predictors of Mortality in Patients with Acromegaly

Centre for Endocrinology, Diabetes and Metabolism (M.S., A.A.A., J.A., M.C.S., P.M.S.), School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TH, United Kingdom; Centre for Childhood Cancer Survivor Studies (R.C.R., M.M.H.), Department of Public Health and Epidemiology, University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Postgraduate Medicine (R.N.C.), University of Keele, Hartshill, Stoke-on-Trent ST4 7QB, United Kingdom; and Birmingham Heartlands and Solihull National Health Service Trust (A.S.B.), Birmingham B9 5SS, United Kingdom

Address all correspondence and requests for reprints to: Professor Paul M. Stewart, Institute of Biomedical Research, Division of Medical Sciences, University of Birmingham, Birmingham B15 2TH, United Kingdom. E-mail: P.M.Stewart{at}bham.ac.uk.

Context: A number of retrospective studies report that patients with acromegaly have increased morbidity and premature mortality, with standardized mortality ratios (SMR) of 1.3–3. Many patients with acromegaly develop hypopituitarism as a result of the pituitary adenoma itself or therapies such as surgery and radiotherapy. Pituitary radiotherapy and hypopituitarism have also been associated with an increased SMR.

Methods: Using the West Midlands Acromegaly database (n = 501; 275 female), we assessed the influence of prior radiotherapy and hypopituitarism (and replacement therapy) on mortality in patients with acromegaly. Median duration of follow-up was 14.0 yr (interquartile range, 7.9–21 yr).

Results: All-cause mortality was elevated [SMR, 1.7 (1.4, 2.0); P < 0.001]. On external analysis, prior radiotherapy, ACTH, and gonadotropin deficiency were associated with an elevated SMR [radiotherapy SMR, 2.1 (1.7–2.6); P = 0.006; ACTH deficiency SMR, 2.5 (1.9–3.2); P < 0.0005; and gonadotropin deficiency SMR, 2.1 (1.6–2.7); P = 0.037].

On internal analysis, the relative risk (RR) of mortality was increased in the radiotherapy [RR, 1.8 (1.2–2.8); P = 0.008] and ACTH-deficiency groups [RR, 1.7 (1.2–2.5); P = 0.004], but not in the gonadotropin- or TSH-deficiency groups. In the ACTH-deficient group, increased replacement doses of hydrocortisone greater than 25 mg/d were associated with increased mortality compared to lower doses.

Conclusions: 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.