The impact of irradiation on growth hormone responsiveness to provocative agents is stimulus dependent: results in 161 individuals with radiation damage to the somatotropic axis.

GH provocative tests remain the mainstay for the diagnosis of GH deficiency and at present the insulin tolerance test (ITT) is the gold standard. There are, however, a variety of other stimulation tests used in clinical practice. Each necessitates the use of a specific cut-off derived from normative data, but there remains a widely held view that the implications from a "failed" test are independent of the nature of the stimulus. We sought to examine whether this is the case in individuals with evidence of radiation damage to the somatotropic axis. One hundred and sixty-one nonacromegalic patients were identified who had undergone an arginine stimulation test (AST) and an ITT within a 3-month period as part of routine testing between 1975 and 1999. They were divided into those tested before (n = 81; 48 males) and those tested after (n = 80; 36 males) completion of growth and puberty. Patients were considered for inclusion in the study if they had a history of cranial irradiation and a GH response to one provocative test of less than 8 microg/L, taken as indicating that some damage to the GH axis may have occurred. The patients were compared with 2 control groups. The first comprised 35 adults (18 males) and the second consisted of 16 prepubertal children (10 males). The median peak (range) GH response to the ITT was significantly greater (P < 0.0001) than that to the AST in the adult controls: 24.9 (4.1--76.9) vs. 12.2 (0.88--35.0) microg/L, respectively. However, in the patients the GH responses were similar (P = 0.28): 2.2 (0.2--25.7) vs. 1.4 (0.2--12.8) microg/L to the ITT and AST, respectively. In contrast to the pattern seen in the adult controls, the response to an ITT in childhood controls was of similar magnitude (P = 0.5) to that to the AST: 17.5 (8.1--40.0) vs. 19.4 (7.3--53.8) microg/L, respectively. However in the patients, the GH response to the AST was greater than that to the ITT (P < 0.0001): 4.3 (0.7--17.2) vs. 3.0 (0.4--18.1) microg/L, respectively. In summary, we have shown that the impact of irradiation on GH responsiveness to provocative agents is stimulus dependent. The GH response to an AST appears to be more resistant to the effects of irradiation than that to the ITT. When investigating the impact of irradiation on GH secretory status, the GH response to an AST may be a less sensitive guide to the functional ability of the GH axis.

Donor bone marrow from a sibling with inborn error of metabolism for treatment of acute leukaemia - clinical and biochemical consequences in the non-affected recipient.

Bone marrow transplantation (BMT) is increasingly used in an attempt to correct inborn errors of metabolism (IEM). However, little is known about effects of BMT from patients with IEM donating for non-affected recipients. We present data from a 8.5-year-old girl who underwent BMT in second remission for relapsed acute lymphoblastic leukaemia (ALL) at the age of 7 years from her HLA-identical brother who was severely affected by Hunter syndrome (Mucopolysaccharidosis type II, iduronate-2-sulphatase (IDS) deficiency). After BMT not only leukocyte but also plasma activity of IDS was absent. Mixing experiments and immunoadsorption suggest antibody-mediated enzyme inhibition. However, her urinary glycosaminoglycan excretion has not increased post BMT and clinical signs of mucopolysaccharidosis are absent 20 months after BMT. We conclude that patients with white cell enzyme deficiencies and other IEMs do not have to be excluded from bone marrow donation. Antibody production by the graft may occur and be reflected by a marked reduction in plasma enzyme levels but not tissue activity. Similar antibody responses resulting in enzyme inactivation might also affect other enzyme replacement strategies for individuals with IEM.

Survivors of childhood cancer: long-term endocrine and metabolic problems dwarf the growth disturbance.

The long-term effects of radiotherapy and chemotherapy are becoming increasingly recognized as the cure rates of certain childhood malignancies improve. The endocrine system is particularly sensitive to cancer therapies. Long-term survivors of childhood cancer who received cranial irradiation have been shown to have lower than predicted height, an increased prevalence of obesity and reductions in strength, exercise tolerance, bone mineral density, quality of life and academic achievement. Growth hormone deficiency (GHD) is the most frequent endocrine deficiency observed following cranial irradiation. Adults with GHD resulting from primary hypothalamic-pituitary disease during childhood have been shown to exhibit a clinical picture similar to that described in long-term survivors of childhood cancer: increased fat mass and reduced lean mass, strength, exercise tolerance, bone mineral density and quality of life. This review considers the possible contribution of GHD to the adverse sequelae observed in long-term survivors of childhood malignancy and includes our preliminary experience in treating 14 adults with GHD resulting from the treatment of childhood malignancies.

Sensitive measures of the nutritional status of children with cancer in hospital and in the field.

Sensitive measures of nutritional status exist. Initial assessment must include some measure that is independent of tumour mass, particularly in children with large solid tumours. Arm anthropometry, including triceps and biceps skinfold thickness (SFT), and mid-upper-arm circumference (MUAC) are ideal in this situation, but MUAC is probably the simplest measure to use. In the clinical setting, a direct measure of fat-free body mass (FFBM) does not exist, but bio-electrical impedance (BIA) measures FFBM indirectly, and has many advantages, in particular its ease of use and immediate results. The BIA analyzer is portable and hence can be used in the field as well as by the bedside. Serum proteins and insulin-like growth factors are insufficiently sensitive as nutritional indices and have only a minor role in nutritional assessment.

Growth and growth hormone status following treatment for childhood leukaemia.

The exact contribution of growth hormone (GH) deficiency to the adverse growth outcome, in those receiving cranial irradiation (18-24 Gy) or total-body irradiation for haematological malignancies in childhood, remains difficult to disentangle as nearly always the cause of the growth disturbance is multifactorial: chemotherapy, graft-versus-host disease, hypothyroidism, and skeletal dysplasia may all impact on growth. There are few published data from which one can assess the efficacy of GH replacement on final height in those children who received cranial irradiation (18-24 Gy) and/or total-body irradiation; there is no evidence, however, of an increased risk of leukaemic relapse. Endocrine reassessment in the teenagers, who received cranial irradiation (18-24 Gy) for acute lymphoblastic leukaemia many years earlier, revealed a significant incidence of GH deficiency with the additional suggestion that many had been GH deficient for several years. This raises a number of important questions: What is the best way to organize long-term endocrine follow-up? How often should GH status be reassessed? What are the specific benefits of GH replacement in adult life for such individuals? These and other questions require further study.

Growth and growth hormone status after a bone marrow transplant.

The three most common clinical situations which have given rise to diagnostic and therapeutic issues involve the child treated for: (1) a brain tumour or extracranial tumour with radiotherapy (XRT) which includes an XRT dose of > or =30 Gy to the hypothalamic-pituitary axis; (2) acute lymphoblastic leukaemia with a cranial XRT dose of 18-24 Gy, and (3) haematological malignancy or solid tumour requiring total body irradiation (dose 10-14 Gy) and BMT. The decision about the intent to treat and the timing of GH replacement needs to be taken in collaboration with the paediatric oncologist who will provide guidance about overall prognosis and the risk of relapse. After a dose of > or =30 Gy to the hypothalamic pituitary axis the risk of GH deficiency (GHD) 2 years later is very high (>50%) and therefore there is 'solid' epidemiological evidence, which predicts outcome. Therapeutically the choice is whether or not to offer GH replacement at 2 years in the presence of biochemical evidence of GHD but independent of auxology, or wait until the growth rate declines. Diagnostically the IGF-1 SDS is more useful than previously thought, particularly if XRT-induced GHD is severe; there may, however, be systematic discordancy between the GH responses to different pharmacological stimuli (ITT vs. arginine). For irradiated children in categories 2 and 3, greater emphasis is placed on auxology in determining the need for assessment of GH status. Early rather than very precocious puberty is a real issue and needs to be actively treated with a GnRH analogue if final height appears to be significantly compromised.

Growth hormone therapy and malignancy.

The possibility that human growth hormone (GH) replacement therapy might either increase the risk of cancer recurrence in a child who has previously been treated for a brain tumour or leukaemia, or induce de novo cancer, has worried paediatricians for a number of years. Concern arises from animal experiments, the association of acromegaly with malignancy, and the Japanese experience of a cluster of de novo leukaemia cases in children treated with GH. It is reassuring that so far the results from single centre studies and from the pharmaceutical industry surveillance programmes have shown no evidence of an increased risk of malignancy, recurrent or de novo. The confidence intervals, however, are wide and the scientific nature of these studies is flawed as there has never been a prospective randomized study of GH replacement in children with radiation-induced GH deficiency. For clinical reasons, such a study is unlikely to be performed and therefore surveillance must be maintained at a very high level.

How many tests are required to diagnose growth hormone (GH) deficiency in adults?

OBJECTIVE: The diagnosis of GH deficiency in adults relies on the results of GH provocative testing. Whilst in some patients the testing strategy is clear, this is not the case in all patients. The objective of this study was to further examine the concordance between the GH responses to two different provocative stimuli, to correlate this with the number of additional pituitary hormone deficits, and to produce guidelines as to which patients require two GH provocative tests and which require only one. STUDY DESIGN AND PATIENTS: The results of GH provocative tests were reviewed in 103 patients (mean age 28 years, 48 male), with documented or potential hypothalamic-pituitary disease and 35 normal volunteers (mean age 21 years, 18 male). All patients and normal volunteers underwent an insulin tolerance test (ITT) and an arginine stimulation test (AST). Severe GH deficiency was defined as a GH response to an ITT of < 5 mU/l and a GH response to an AST of < 2 mU/l, utilizing data from previous studies in this unit. Patients were divided into four groups according to the number of anterior pituitary hormone deficits present other than possible GH deficiency: no other pituitary hormone deficits (GHD0) or one, two or three other hormone deficits (GHD1, GHD2 or GHD3). RESULTS: The 103 patients were divided between the four groups as follows: 69 (67%) in GHD0, 15 (14. 6%) in GHD1, six (5.8%) in GHD2, and 13 (12.6%) in GHD3. There was a significant decline in the median GH peak to both the ITT and the AST with increasing numbers of other pituitary hormone deficits (P < 0.0001). If the magnitude of the difference between each individual's GH response to the ITT and AST is plotted against the mean GH value a clear trend is seen (Spearmans rank correlation = 0. 88, P < 0.0001) indicating that the magnitude of the difference between the GH responses to an ITT and AST increases with the underlying mean GH value. These data allow the estimation of the median ITT/AST ratio as 1.17 (CI 0.98, 1.39). None of the control subjects and 14.1% (10), 26.7% (four), 83% (five) and 92.3% (12) of groups GHD0, 1, 2 and 3, respectively, had severe GHD. The concordance between the AST and ITT (percent of patients in whom both tests confirmed or refuted the biochemical diagnosis of severe GHD) was 100%, 76.8%, 66.6%, 83.3%, and 92.3% in the controls, GHD0, 1, 2, and 3, respectively. Thus, 16/69 GHD0, 5/15 GHD1, 1/6 GHD2 and 1/13 GHD3 patients were misclassified by one or other test. CONCLUSION: We have demonstrated that a constant ratio links the GH response to an ITT and AST in an individual, rather than a constant difference, and that the difference between the GH responses to two provocative stimuli is greater in those patients with milder degrees of GH deficiency or insufficiency. These patients tend to have one or no additional pituitary hormone deficits and may be misclassified if a single GH provocative test is performed. We suggest that whilst a single GH provocative test can be used with confidence in patients with two or three additional pituitary hormone deficits, in patients with suspected isolated GH deficiency or with only one additional pituitary hormone deficit, two GH provocative tests should be performed.

Growth hormone status in adults treated for acute lymphoblastic leukaemia in childhood.

OBJECTIVE: Growth hormone status was assessed in a cohort of 32 (16 male) adults who had received cranial irradiation (XRT) in childhood as part of their treatment for acute lymphoblastic leukaemia (ALL) and compared with 35 age matched young adults (18 male). DESIGN: Height and weight were measured in all subjects and the heights of the patients at XRT were obtained from their case notes. Each patient and control underwent two provocative tests of growth hormone (GH) secretion using insulin (0.2 IU/kg body weight) and arginine (20 g/m2). Basal serum insulin like growth factor-1 (IGF-1) and IGFBP-3 (binding protein-3) concentrations were also measured. RESULTS: The patient group had a significantly lower peak GH response to both provocative tests (P < 0.01), and lower IGF-1 and IGFBP-3 levels compared with the normal controls (P < 0.01). Nine of the patient group were severely GH deficient (peak GH response < 9 mU/l to both provocative agents) and a further 12 patients were GH insufficient (peak GH response < 20 mU/l to both tests with at least one peak GH response > 9 mU/l). Overall a significant median change in height from XRT to final height of -0.5 SDS was found which was even greater in the severely GH deficient group (median change in height of -2.1 SDS). CONCLUSION: These data suggest that a significant proportion of adults treated with cranial XRT in childhood with irradiation doses between 18-25 Gy, as part of their treatment for ALL, are severely GH deficient now and should be considered for GH replacement. Changes in GH secretion evolve with time following irradiation-induced damage to the hypothalamic-pituitary axis; therefore long-term surveillance will be required in those remaining patients, in whom GH status is considered currently to be insufficient or even normal.

Reduced bone mineral density in young adults following cure of acute lymphoblastic leukaemia in childhood.

Bone mineral density (BMD), serum osteocalcin and type I collagen C-telopeptide (ICTP) were assessed in a cohort of 31 (16 males) adults who had received cranial irradiation in childhood as part of their treatment for acute lymphoblastic leukaemia (ALL). Markers of bone turnover were compared with those of 35 age and body mass index (BMI) matched young adults (18 male). Growth hormone status had previously been determined using an insulin tolerance test and arginine stimulation test. Eight patients were classified as severe growth hormone deficiency (group 1), 12 patients as growth hormone insufficient (group 2) and 11 patients as normal (group 3). Vertebral trabecular BMD, lumbar spine and femoral neck integral BMD and forearm cortical bone mineral content (BMC) was measured 17.8 (6.8-28.6) years after cranial irradiation and was expressed as Z (standard deviation) scores. There was a significant reduction in vertebral trabecular BMD (median Z score -1.25, P < 0.001), in lumbar spine integral BMD (median Z score -0.74, P = 0.001), in forearm cortical BMC (median Z score -1.35, P < 0.001), and less so in femoral neck integral BMD (median Z score -0.43, P = 0.03). There was no difference among the growth hormone status groups for the following BMD measurements: vertebral trabecular BMD, lumbar spine integral BMD or femoral neck integral BMD (P = 0.8, P = 0.96 and P = 0.4 respectively). There was only a marginal significant difference for BMD at the wrist between growth hormone status groups (P = 0.04). There was no correlation between the BMD measurements with time since or age at diagnosis and no difference in markers of bone turnover between patients and controls; median serum osteocalcin 13.3 and 12.0 ng ml (P = 0.7), respectively, and for ICTP 5.0 and 4.9 microg L (P = 0.67) respectively. In conclusion, there is a highly significant reduction in BMD in young adults following treatment for ALL in childhood. The reduction in BMD affects both trabecular and cortical bone but did not seem to be related to time since diagnosis, age at diagnosis, or current growth hormone status. Possible explanations include a direct effect of chemotherapy, steroids or both on bone during childhood and hence an effect on the accretion of bone mass. In view of the risk of fractures in patients with osteopenia, adults treated for ALL in childhood may be at an increased risk of bone fractures later in life irrespective of the underlying cause of the osteopenia and thus intervention should be considered.

Hyperleptinaemia in young adults following cranial irradiation in childhood: growth hormone deficiency or leptin insensitivity?

OBJECTIVE: In order to explore the mechanism of obesity in long-term survivors of childhood leukaemia, fat mass, lean body mass and serum leptin were assessed in a cohort of 32 (17 males) adults who had received cranial irradiation (XRT) in childhood as part of their treatment for acute lymphobiastic leukaemia (ALL), and compared with 35 age and body mass index (BMI) matched young adults (18 male). DESIGN: Thirty-one patients and 18 controls had fat mass and lean body mass assessed by dual x-ray absorptiometry (DEXA), using a lunar DPX-L scanner. Serum leptin concentrations were also measured in 27 patients and all controls. Growth hormone status had previously been determined using an insulin tolerance test and arginine stimulation test. Nine patients were classified as severe growth hormone (GH) deficient (group 1), 12 patients as GH insufficient (group 2) and 11 patients as normal (group 3). RESULTS: BMI and absolute fat mass were not significantly different between the patients and controls regardless of their gender (P = 0.1 and P = 0.14 respectively). In contrast, absolute lean mass was significantly reduced (P < 0.01) and leptin concentrations were significantly increased (P < 0.001) in patients compared with controls. BMI, fat mass and leptin concentrations but not lean mass were significantly different between the three GH status groups (P < 0.01, P < 0.01, P = 0.004, and P = 0.67 respectively). When leptin concentrations were expressed per unit of fat mass, they were increased in the patients compared with the controls (P = 0.03) with significant differences between the GH status groups (P = 0.004), being significantly higher in the severe GH deficient group. CONCLUSIONS: Young adults who receive cranial irradiation in childhood are prone to GH deficiency and hyperleptinaemia. The pathophysiological significance of the hyperleptinaemia remains to be established but it has occurred either as a consequence of radiation induced hypothalamic damage or GH deficiency.

Insulin-like growth factor I, IGF binding protein 3, and IGFBP protease activity: relation to anthropometric indices in solid tumours or leukaemia.

OBJECTIVES: To measure the serum concentrations of insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3), and the level of IGFBP-3 protease activity in 38 children presenting with malignancies, and to assess their relation with auxological parameters and nutritional status. METHODS: Height, weight, skinfold thickness, and mid-upper arm circumference (MUAC) were recorded using standard techniques. IGF-I and IGFBP-3 were measured using specific radioimmunoassays. Serum IGFBPs were also visualised on western ligand blot. IGFBP-3 protease activity was assessed by the extent of fragmentation of recombinant [125I]-IGFBP-3, compared with that induced by pregnancy serum. Anthropometric and radioimmunoassay data were expressed as standard deviation scores (SDS). RESULTS: The median (range) IGF-I SDS was significantly reduced in all patients (-1.1 (-5.1 to 1.2)) and lower in children who were malnourished (-2.5 (-3.9 to 0.1)). IGFBP-3 SDS was within the normal range for 31 of 38 patients but IGFBP-3 protease activity was raised in all patients. Neither IGFBP-3 concentration nor protease activity was affected by nutritional status. IGF-I correlated with MUAC (r = 0.41) and subscapular skinfold thickness SDS (r = 0.38), but not with weight, height, weight for height, or triceps skinfold thickness. CONCLUSIONS: IGF-I is low in children with malignancies, and even lower in those who are malnourished. IGFBP-3 concentrations were normal in most patients but interpretation is complicated by the presence of raised IGFBP-3 protease activity, which could lead to overestimating concentrations of intact peptide. IGF-I appears to relate to arm anthropometry as an index of nutritional status but not height, weight, or weight for height, as would be expected in normal children.