Examination of the Dose-Effect Relationship of Radiation-Induced Hypopituitarism: Results of a Case-Control Study

Previous reports have documented a dose-effect relationship for radiation-induced hypopituitarism in patients receiving therapy near or at the base of the skull. We aimed to characterize this long-term endocrinopathy further by examining the effect of dose on both the incidence and severity of toxicity, as well as exploring a possible dose threshold for this effect. Out of an initial 346 patients who had received radiation therapy to the base of the skull, 53 patients with adequate endocrine evaluation were found. Of these, 19 patients who subsequently developed at least 1 endocrinopathy (cases) as well as 17 patients who did not (controls) were identified, for a total of 36. Patients’ charts were reviewed, and endocrinologic laboratory tests recorded. Treatment plans were reviewed and doses to the hypothalamus and pituitary gland were calculated. One-way analysis of variance was used to determine differences between cases and controls, and Pearson's correlation coefficient was used to relate mean pituitary dose to serum free thyroxine, insulin-like growth factor 1, prolactin, cortisol, and luteinizing hormone. There were 20 men and 16 women, with a median age of 58. Median follow-up was 32 months (range, 18- 85 months). Median total plan dose delivered was 54 Gy (range, 50.4-70 Gy). Independent sample t tests as well as univariate analysis showed a significantly greater dose to the hypothalamus and pituitary of the cases compared with the controls, while other factors were not significantly different between the 2 groups. There was a statistically significant negative correlation (Pearson's correlation coefficient = -0.65, P = .001) between the mean dose to the pituitary gland and the serum free thyroxine. No case of endocrine toxicity was observed at a mean dose to the pituitary below 30 Gy. Our results suggest that late endocrinopathy is a true deterministic effect, with a dose threshold, and with both the incidence and severity of toxicity being related to the dose.