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THE UNIVERSITY OF MANCHESTER ABSTRACT OF THESIS submitted by Ken Darzy for the Degree of M.D. and entitled 'Pharmacological and physiological studies of anterior pituitary hormones secretion (GH, ACTH and TSH) in cranially irradiated adult cancer survivors with radiation-induced hypothalamic-pituitary dysfunction'. Month and Year of submission: June 2008. This thesis describes the dynamics of GH, ACTH/Cortisol and TSH/T4 secretion in adult cancer survivors irradiated for non-pituitary brain tumours or leukaemia. Stimulated and physiological hormonal secretions were studied simultaneously. It was shown that, in patients with severe radiation-induced GH deficiency diagnosed by failure to pass both the ITT and the GHRH + AST, pulsatile GH secretion and diurnal rhythm are preserved, yet with severe amplitude attenuation and an overall feminised pattern of GH secretion characterized by relatively higher inter-peak levels (tonic secretion) and increased secretory disorderliness, as measured by ApEn. Patients with normal individual peak GH responses to the ITT and the GHRH+AST still showed evidence of damage to the h-p axis, as the overall mean GH responses were reduced by 50%. However, spontaneous fed and fasting GH secretion in this group was fully maintained both individually and at a group level compared with a matched control group. This finding argues against the previously held belief that somatotroph dysfunction is primarily due to radiation-induced GHRH deficiency, as the combined effect of reduced GHRH and secondary somatotroph atrophy would be expected to result in reduced spontaneous GH secretion. It was, therefore, concluded that radiation causes direct pituitary damage and that endogenous hyperstimulation of the h-p axis mediated by a compensatory increase in GHRH release restores normality of GH secretion in these patients with partially damaged somatotrophic axis (compensated GHD). Based on the findings in some patients, it was also suggested that 'near maximal' endogenous hyper-stimulation and GHRH release may limit further stimulation with the ITT, so much so, that a failed ITT response can occur in the presence of normal GHRH+AST response and normal spontaneous GH secretion. . These findings in adults has lead to the suggestion that failure of the hyperstimulated partially damaged h-p axis to increase GH secretion during periods of increased demand, such as growth and puberty may explain what has previously been described as radiation-induced GH neurosecretory dysfunction. It was reasonable to conclude that unlike the ITT, a failed response to the GHRH+AST almost always indicated GHD in the irradiated adult. On the contrary, failure to pass the ITT reflects 'a potential failure of the h-p axis to respond to increased demands and therefore it should remain the gold standard guide for the need for GH replacement therapy in children. Adult cancer survivors with normal ACTH reserve indicated by normal cortisol responses to the ITT have showed parallel and significant increases in fed and fasting 24-hour integrated cortisol concentrations and secretion rates with no change in half-life. This has been attributed to a pro-active h-p-adrenal axis with increased CRH-ACTH release mediated by the direct effects of radiation on the axis or perhaps the higher level of chronic stress in cancer survivors. In addition, euthyroid adult cancer survivors have significantly increased stimulated and integrated 24-hour TSH levels, especially in spinally irradiated patients with severe GHD. There was no change in the TSH bioactivity and the increase in TSH levels could be attributed to subclinical thyroidal damage, GHD-induced reduction in somatostatin tone and/or radiation-induced reduction in somatostatin and dopamine tone. The maximum TSH surge in the. 24-hour profile was slightly but significantly reduced. The subnormal nocturnal TSH surge seen in some patients reflected a shift in the timing of the peak and/or nadir TSH levels rather than a genuine loss of the TSH diurnal rhythm, as similarly seen in some normal individuals. This finding argues against the existence of so-called hidden central hypothyroidism. In summary, this thesis has provided novel insights into the pathophysilogy and site of radiation damage and its relevance to the clinical application ofthe diagnostic tests currently in use.