Absence of adrenocorticotropin (ACTH) neurosecretory dysfunction but increased cortisol concentrations and production rates in ACTH-replete adult cancer survivors after cranial irradiation for nonpituitary brain tumors

Context: For the first time, physiological cortisol secretion has been studied in ACTH-replete adult cancer survivors to explore any discrepancy between stimulated ( during insulin-induced hypoglycemia) and spontaneous cortisol secretion and, in particular, the possible existence of ACTH neurosecretory dysfunction that might explain the excessive fatigue suffered by some cancer survivors. Study Subjects: Cortisol profiling at 20-min intervals over 24 h during the fed state was undertaken in 34 patients ( 10 females), aged 17-53.7 yr ( median, 21.5 yr), 2 - 29 yr ( median, 11.5 yr) after receiving conventional cranial irradiation for nonpituitary brain tumors or leukemia (n = 5) and in 33 age-, gender-, and body mass index-matched normal controls, of whom 23 patients and 17 controls were also profiled in the last 24 h of a 33-h fast. Results: The fed profile mean cortisol concentration (mean +/- SEM) was significantly increased (by 14 %) in the patients compared with that in normal subjects (213 +/- 6.9 vs. 187 +/- 6.7 nmol/liter; P = 0.009), with all individual values above the lowest seen in normal subjects. Multiparameter deconvolution analysis revealed a parallel increase (by 20 %) in cortisol secretion rates (1.8 +/- 0.09 vs. 1.5 +/- 0.08 nmol/ liter(.)min; P = 0.03) due to selective augmentation of the cortisol mass released per burst with no changes in burst frequency (12/24 h) or half-life. No significant differences were observed between males and females, after short-term fasting, or between female patients and normal females. Thus, in the light of total group comparisons, male patients had even higher values than normal males, and more so during fasting ( mean cortisol and cortisol secretion increased by 20 and 29 % in the fed state and by 41 and 32 % in the fasting state, respectively; P < 0.05). Conclusions: This study has demonstrated that radiation-induced ACTH neurosecretory dysfunction does not exist and, thus, resolved the clinical dilemma as to whether cortisol replacement should be considered in those patients with excessive fatigue and normal stimulated cortisol responses. On the contrary, cranial irradiation causes activation of the corticotrope-adrenal axis, and in the absence of ACTH deficiency, this activation is manifested by parallel increases in circulating cortisol levels and cortisol production rates without any change in cortisol half-life. The lack of cortisol increase in female patients may be attributed to the adverse effect of their higher body mass index on cortisol secretion or may reflect a genuine gender dichotomy.