GH-Deficient Survivors of Childhood Cancer: GH Replacement during Adult Life

Childhood survivors of cancer are prone to a number of adverse sequelae related to the therapeutic interventions undertaken to achieve remission. The endocrine system is frequently affected; hypothalamo-pituitary dysfunction, in particular GH deficiency, is common after cranial irradiation. It is unclear to what extent GH deficiency contributes to the abnormalities observed in adult survivors of childhood cancer, and whether GH replacement reverses these anomalies. We compared 27 GH-deficient survivors of childhood cancer with 27 adult age-and sex-matched controls and went on to replace GH in the patient group to determine whether GH resulted in improvements of the baseline abnormalities. The GH-deficient survivors of childhood cancer had an adverse lipid profile (total cholesterol, 5.4 vs. 4.6 mM, P ‫؍‬ 0.004; high-density lipoprotein cholesterol, 1.05 vs. 1.6 mM, P < 0.001; and triglycerides, 1.3 vs. 1.0 mM, P < 0.001) and were osteopenic (lumbar spine z-score, ؊1.53 vs. ؊0.31 SD score, P < 0.001; femoral neck z-score, ؊1.23 vs. ؊0.27 SD score, P ‫؍‬ 0.02); additionally, the female subgroup had an increased percentage body fat (43.6 vs. 32.8%, P ‫؍‬ 0.016). In keeping with the selection criterion, quality of life in the patient cohort, relative to the healthy controls, was severely impaired [adult GHdeficiency assessment (AGHDA), 15.5 (range, 8 -25) vs. 1 (range, 0 -19), P < 0.0001; psychological general well-being schedule, 67.5 (range, 18 -86) vs. 89.0 (range, 51-104), P < 0.0001]. After 12 months of GH replacement, small (but significant) improvements were observed in body composition in the male subgroup (waist-hip ratio, 0.871 vs. 0.863, P < 0.05); and in the female cohort, total cholesterol (6.0 vs. 5.2 mM, P ‫؍‬ 0.01) and triglyceride (2.1 vs. 1.4 mM, P ‫؍‬ 0.01) levels fell. Bone mineral density improved in only one of the four sites studied (ultradistal radius, ؊1.21 vs. ؊1.09, P ‫؍‬ 0.048) after a median duration of GH therapy of 18 months. Quality of life improved dramatically by 3 months (AGHDA, 15.5 vs. 10.0, P < 0.001), and the improvement was maintained at 12 months (AGHDA, 15.5 vs. 9.0, P < 0.001). Importantly, there was no clinical suggestion of tumor recurrence during the 12 months of GH replacement. The minor improvements observed in body composition, the lipid profile, and bone mineral density in GH-deficient adult survivors of childhood cancer after 12-18 months of physiological GH replacement suggest that GH deficiency may not be the major etiological factor in their pathogenesis; the converse seems to be true for the quality of life status of these individuals. We propose that, as in patients with hypopituitarism caused by pituitary disease, the main indication for GH replacement in GH-deficient survivors of childhood cancer should be severe impairment of quality of life. (J Clin Endocrinol Metab 87: 129 -135, 2002

Pituitary insufficiency after operation of supratentorial intra- and extraaxial tumors outside of the sellar–parasellar region?

Recent studies investigating pituitary function after non-sellar brain tumor surgery showed that up to 38.2% of patients have pituitary insufficiency (PI). It has been assumed that the operation causes the PI, but preoperative hormone testing, which would have been necessary to prove this assumption, was not performed. The objective of this study is to answer the question if indeed microsurgery is the culprit of PI in patients with operatively treated non-sellar brain tumors. In this prospective trial, 54 patients with supratentorial non-sellar tumors were included. The basal levels of cortisol, prolactin, testosterone, estrogen, IGF-1, fT3, fT4, STH, TSH, ACTH, FSH, and LH were recorded preoperatively on days 1 and 7 after surgery. If basal hormone screening revealed an abnormality, a releasing hormone assay was performed. Before surgery, 24 of the 54 patients (44.4%) already had PI. Additional 25 patients showed either hypocortisolism or hypothyreoidism. As those patients had been pre-treated with dexamethasone and l-thyroxine, these findings were considered not to represent PI but drug effects. Hormone testing on days 1 and 7 after surgery revealed no changes. With 44.4% PI is a frequent finding in brain tumor patients already before surgery. The factors causing preoperative PI remain yet to be identified. The endocrine results after surgery are unchanged which rules out that surgery is the cause of PI

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Copeptin reflects physiological strain during thermal stress.

PURPOSE: To prevent heat-related illnesses, guidelines recommend limiting core body temperature (T c) ≤ 38 °C during thermal stress. Copeptin, a surrogate for arginine vasopressin secretion, could provide useful information about fluid balance, thermal strain and health risks. It was hypothesised that plasma copeptin would rise with dehydration from occupational heat stress, concurrent with sympathoadrenal activation and reduced glomerular filtration, and that these changes would reflect T c responses. METHODS: Volunteers (n = 15) were recruited from a British Army unit deployed to East Africa. During a simulated combat assault (3.5 h, final ambient temperature 27 °C), T c was recorded by radiotelemetry to differentiate volunteers with maximum T c > 38 °C versus ≤ 38 °C. Blood was sampled beforehand and afterwards, for measurement of copeptin, cortisol, free normetanephrine, osmolality and creatinine. RESULTS: There was a significant (P  38 °C (n = 8) vs ≤ 38 °C (n = 7) there were significantly greater elevations in copeptin (10.4 vs. 2.4 pmol L(-1)) and creatinine (10 vs. 2 μmol L(-1)), but no differences in cortisol, free normetanephrine or osmolality. CONCLUSIONS: Changes in copeptin reflected T c response more closely than sympathoadrenal markers or osmolality. Dynamic relationships with tonicity and kidney function may help to explain this finding. As a surrogate for integrated physiological strain during work in a field environment, copeptin assay could inform future measures to prevent heat-related illnesses

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

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.EThOS - Electronic Theses Online ServiceGBUnited Kingdo