Radiation-induced Growth Hormone Deficiency Research Articles

The Predictive Value of Insulin-Like Growth Factor 1 in Irradiation-Dependent Growth Hormone Deficiency in Childhood Cancer Survivors

Background: The literature contains conflicting reports on the value of low insulin-like growth factor 1 (IGF-1) levels in predicting radiation-induced growth hormone (GH) deficiency (GHD) in childhood cancer survivors (CCS). These reports often involve small samples of patients who have received irradiation or mixed cohorts including non-irradiated subjects. Objective: We undertook an analysis of the predictive value of low IGF-1 in CCS at risk for GHD after cranial radiotherapy involving the hypothalamic-pituitary (HP) area in a large single-centre cohort. Methods: We performed a retrospective analysis on 158 CCS diagnosed with GHD between January 1, 2003 and October 31, 2017 and identified 117 patients who received radiation for tumours not direct ly involving the HP area. Results: In this cohort, IGF-1 levels <–2 standard deviation scores (SDS) had a sensitivity of 31.9% for GHD; however, they were statistically more frequent (p = 0.0023) and had a higher sensitivity (45.6%) among patients with severe GHD. At final height reassessment, IGF-1 <–2 SDS had a sensitivity of 35.0% for GHD, but a positive predictive value of 100%. Finally, pretreatment IGF-1 values showed no correlation with the number of impaired pituitary hormonal axes in patients with multiple pituitary deficiencies. Conclusions: IGF-1 levels <–2 SDS showed a low sensitivity at predicting radiation-induced GHD both in childhood and in adulthood, but a high positive predictive value for GH status at final height reassessment.

Provincial Disparities of Growth Hormone Coverage for Young Adult Survivors of Paediatric Brain Tumours across Canada

Young adult survivors of paediatric brain tumours (PBTs) who have been treated with radiation therapy will likely be severely growth hormone-deficient when retested at the achievement of final height. Growth hormone replacement therapy (GHRT) is administered to treat growth hormone deficiency (GHD). Public drug coverage for GHRT falls under the responsibility of provincial governments across Canada. This study sought to determine the extent of public drug coverage and cost in each Canadian province for GHRT to treat GHD during adulthood for young adult survivors of PBTs. Data were collected from provincial government resources and drug formularies from 2012-2013 on the extent of coverage for GHRT based on a clinical case scenario representative of a young adult survivor of a PBT with childhood-onset radiation-induced GHD, the ingredient cost for GHRT and the applicable provincial public drug plan cost-sharing policies. A model was then created to simulate out-of-pocket costs incurred by a young adult male and a young adult female survivor of a PBT for one year of GHRT in each province with applicable cost-sharing arrangements and levels of low annual individual total income that best represent the majority of young adult survivors of PBTs. Out-of-pocket costs were expressed as a percentage of annual income. Comparisons were made between provinces descriptively, and variation among provinces was summarized statistically. Alberta, Manitoba, Ontario, Quebec, New Brunswick, and Newfoundland and Labrador provide coverage for GHD during adulthood on a case-by-case basis, while British Columbia, Saskatchewan, Nova Scotia and Prince Edward Island provide no coverage. The percentage of annual income to fund GHRT across the provinces without public coverage ranged from 14.4% to 25.5% for males and 21.5% to 38.3% for females, and with public coverage was 0.0% to 4.1% for males and 0.0% to 5.0% for females. There are considerable out-of-pocket costs and variation in coverage provided by provincial public drug plans to fund GHRT for young adult survivors of PBTs with GHD. The implementation of a national drug formulary could potentially prevent undue financial hardship and remove disparities resulting from variations in provincial drug plans.

Disorders of glucose homeostasis in young adults treated with total body irradiation during childhood: a pilot study

Impairment of glucose metabolism (in particular insulin resistance and type 2 diabetes mellitus) has been reported in patients who have undergone hematopoietic SCT (HSCT) during childhood, especially those treated with TBI. This pilot study was conducted to determine prevalence of and possible underlying mechanisms for impaired glucose homeostasis in young adults treated with HSCT and TBI and who were not previously known to have diabetes mellitus. A total of 10 subjects (6 males, 4 females) were evaluated. Mean ages were 13.0+/-1.0 years at the time of TBI and 24.0+/-1.1 years at the time of this study. Five subjects had laboratory evidence of insulin resistance using the homeostasis model assessment and the quantitative insulin sensitivity check index indices. Two of these subjects had impaired fasting glucose and four had decreased plasma insulin-like growth factor 1 levels. All 10 subjects had evidence of abdominal obesity. Insulin resistance is frequently observed in adult survivors of HSCT treated with TBI in childhood. Underlying mechanisms may include radiation-induced growth hormone deficiency and changes in body composition.

Pathophysiology of radiation-induced growth hormone deficiency: Efficacy and safety of GH replacement

Radiation-induced growth hormone deficiency (GHD) is primarily due to hypothalamic damage. GH secretion by the pituitary may be affected either secondary to some degree of quantitative deprivation of hypothalamic input or, if the radiation dose is high enough, by direct pituitary damage. As a consequence, the neurosecretory profile of GH secretion in an irradiated patient remains pulsatile and qualitatively intact. The frequency of pulse generation is unaffected, but the amplitude of the GH pulses is markedly reduced. Over the last 25 years, the final heights achieved by children receiving GH replacement for radiation-induced GHD have improved; these improvements are attributable to refinements in GH dosing schedules, increased use of GnRH analogues for radiation-induced precocious puberty, and a reduced time interval between completion of irradiation and initiation of GH therapy. When retested at the completion of growth, 80–90% of these teenagers are likely to prove severely GH deficient and, therefore, will potentially benefit from GH replacement in adult life. Such long-term GH treatment in patients treated previously for a brain tumor means that critical and continuous surveillance must be devoted to the risk of tumor recurrence and the possibility of second neoplasms.

The Impact of Short-Term Fasting on the Dynamics of 24-Hour Growth Hormone (GH) Secretion in Patients with Severe Radiation-Induced GH Deficiency

In patients with severe radiation-induced GH deficiency, we previously demonstrated that pulsatile GH secretion and diurnal rhythm are maintained in the fed state, albeit with great attenuation of the pulse amplitude. However, it remained unclear whether stressing the hypothalamic-pituitary axis could unmask neurosecretory dysregulation that is not seen under basal conditions. In addition, the impact of fasting on GH pulsatility and diurnal variation in GH-deficient patients has not been studied in detail before. STUDY SUBJECTS AND DESIGN: Twenty-four-hour GH profiles at 20-min intervals were undertaken in the fed state and in the last 24 h of a 33-h fast in eight young adult cancer survivors (two women) with severe GH deficiency after cranial irradiation for nonpituitary brain tumors in childhood and 14 matched normal controls (three women). A sensitive chemiluminescence GH assay was used with cluster analysis. Fasting induced a significant (P < 0.05) rise in all amplitude-dependent measures (absolute GH peak and nadir, profile mean GH, and mean pulse amplitude and area) in both groups. Pulse frequency was nonsignificantly increased (by 10%) in normals but significantly increased (by 20%) in the patients. The average increase in the individual fasting profile mean GH concentration was 3.7-fold (range 1.5-8.3) in normals, compared with 2.7-fold (range 1-4.7) in the patients (P > 0.05). Fasting amplified amplitude-related differences between patients and controls, and thus, unlike in the fed state, the day (0900-2040 h) mean GH completely demarcated patients from normals. An absolute GH peak level of 2 and 4 microg/liter and a profile mean GH level of 0.25 and 0.65 microg/liter completely separated patients from normals in the fed and the fasting states, respectively. Overall, fasting seems to induce a feminized pattern of GH secretion with relatively higher interpeak levels, preserved but diminished diurnal variation, and increased secretory disorderliness (increased approximate entropy scores). The overall pulsatile pattern of GH secretion during fasting in patients with radiation-induced GH deficiency and the relative augmentation in GH release are similar to that seen in normals emphasizing that GH neuroregulation is preserved in these patients even when the hypothalamic-pituitary axis is under physiological stress.

The Utility of the Growth Hormone (GH) Releasing Hormone-Arginine Test for Diagnosing GH Deficiency in Adults with Childhood Acute Lymphoblastic Leukemia Treated with Cranial Irradiation

The insulin tolerance test (ITT) is the current standard diagnostic test for the diagnosis of adult GH deficiency (GHD), but alternative tests, such as the GHRH-arginine test, have been proposed. We investigated the sensitivity and specificity of the GHRH-arginine test using ITT as the gold standard in diagnosing GHD in a group of young adults treated with cranial irradiation (CRT) for childhood acute lymphoblastic leukemia (ALL). We estimated the positive and negative predictive values of the GHRH-arginine test among patients as well as a number of individual characteristics and therapy-related factors during both the GHRH-arginine test and ITT. Forty-three young adults, treated for childhood ALL with 18-30 Gy CRT and chemotherapy, were studied, and comparison was made with matched controls. We evaluated four different cutoff levels for GHD in the GHRH-arginine test: 5, 7.5, 9, and 16.5 microg/liter. Using 7.5 microg/liter as the cutoff yielded high specificity (94%), but at the same time the sensitivity was only 66%, which leads to a low negative predictive value (27%). In contrast, a failed GH response to the GHRH-arginine test accurately reflects the presence of radiation-induced GHD, illustrated by a high positive predictive value (95% at 7.5 microg/liter). Only age at CRT and body mass index remained significant predictors of the peak GH during the GHRH-arginine test. Because a high proportion of GHD patients show a normal response to the GHRH-arginine test, it cannot be used reliably to exclude GHD in these patients. Complementary ITT is also warranted to confirm GHD in obese patients.

Reduction of adult height in childhood acute lymphoblastic leukemia survivors after prophylactic cranial irradiation

Impaired linear growth is a well-recognized complication in long-term childhood ALL survivors who received cranial irradiation. However, as many patients achieve a final height between the 5th and the 95th centile, the true incidence of linear growth impairment might be underestimated. Reduction of adult height (RAH) was estimated in adult childhood ALL survivors with and without cranial irradiation. RAH was calculated as the difference between target height (TH) and final height (FH). TH was calculated according to the formula TH = {[(height father + height mother +/- 12)/2] + 3}. RAH was assessed in 79 adult childhood ALL survivors in first complete remission who had received cranial irradiation 25 Gy (Group I, n = 53), 18 Gy (Group II, n = 10) or chemotherapy alone (controls, n = 16). RAH was 8.6 +/- 8.2 cm in Group I (P = 0.001 vs. controls), 6.2 +/- 3.2 cm in Group II (P = 0.01 vs. controls), and 1.7 +/- 4.6 in controls (chemotherapy only). There was no significant difference between Group I and Group II. In Group I females had more RAH than males (P = 0.02). RAH was related to younger age at diagnosis (P = 0.001). The deficit between target height and final height highlights the reduction of adult height in the majority of male and female childhood ALL survivors who had received prophylactic cranial irradiation, in particular in those who were diagnosed at a younger age. This reduction would have been masked if patients FH was only compared with standard methods. RAH might be a sensitive predictor for growth hormone deficiency as these results suggest that radiation-induced growth hormone deficiency in these patients is the rule rather than the exception.

The Usefulness of the Combined Growth Hormone (GH)-Releasing Hormone and Arginine Stimulation Test in the Diagnosis of Radiation-Induced GH Deficiency Is Dependent on the Post-Irradiation Time Interval

The diagnostic usefulness of the insulin tolerance test (ITT) in patients with radiation-induced GH deficiency (GHD) is well established, whereas that of the combined GHRH plus arginine stimulation test (AST) is unproven. Both tests were undertaken in 49 adult survivors (aged 16-53.7 yr), who were previously irradiated for non-pituitary brain tumors or leukemia, and 33 age-, gender-, and BMI-matched controls. The aims of the study were to examine the impact of the time interval after irradiation on the pattern of GH responsiveness to the two provocative tests and to establish the role of the GHRH + AST in the diagnosis of radiation-induced GHD. The median (range) peak GH responses to either test were significantly lower (P < 0.0001) in the patients [GHRH + AST, 19.9 (range, 2.7-103.5) microg/liter; ITT, 5 (0.2-34.8) microg/liter] than in normals [GHRH + AST, 55 (5.7-173.5) microg/liter; ITT, 23.8 (4.2-80) microg/liter]. In patients and normal controls, the median peak GH response to the GHRH + AST was significantly greater (P < 0.0001) than the response to the ITT. However, the ratio of the peak GH response to the GHRH + AST over that achieved with the ITT (discordancy ratio) was significantly higher (P = 0.007) in the patients (median, 3.45; range, 0.8-53.5) compared with normals (median, 2; range, 0.34-18.6), consistent with dominant hypothalamic damage and relatively preserved somatotroph responsiveness. The peak GH response to the ITT fell significantly within 5 yr of irradiation with little further change over the subsequent 10 yr. In contrast, the peak GH response to the GHRH + AST barely changed within 5 yr of irradiation but subsequently declined significantly over the next 10 yr. Thus, the evolution of change in GH responsiveness to the two different stimuli over time was markedly different, resulting in a significantly raised discordancy ratio of 6 within the first 5 postirradiation years, which then normalized over the next 10 yr. The peak GH responses to the GHRH + AST and the discordancy ratio were negatively correlated with the time interval after irradiation (r = -0.40, P = 0.0037; and r = -0.4, P = 0.0046, respectively). On a practical clinical level, the discordancy between the GH test results was important; 50% of those classified as severely GHD patients by the ITT were judged normal or only GH insufficient by the GHRH + AST. In conclusion, these findings suggest that hypothalamic dysfunction occurs early and somatotroph dysfunction occurs late, following radiation damage to the hypothalamic-pituitary axis. This time dependency of somatotroph dysfunction may reflect either secondary somatotroph atrophy due to hypothalamic GHRH deficiency or delayed direct radiation-induced damage to the pituitary gland. The high false negative diagnosis rate for severe GHD makes the GHRH + AST an unreliable test in clinical practice when GH status is explored in the early years after cranial irradiation with the intention to treat.

Mortality and morbidity in adult life as a consequence of radiation-induced growth hormone deficiency in childhood

Mortality and morbidity in adult life as a consequence of radiation-induced growth hormone deficiency in childhood

Serum Insulin-Like Growth Factor-I, IGF Binding Protein-3 and IGFBP-3 Protease Activity after Cranial Irradiation

The relationship between peak growth hormone (GH), insulin-like growth factor I (IGF-I), IGF-I binding protein 3 (IGFBP-3) and IGFBP-3 protease activity was studied in 28 children and adolescents undergoing investigation of pituitary function 0.4–14.2 years after cranial or craniospinal irradiation for the treatment of CNS tumours distant from the hypothalamic-pituitary axis (n = 16) or prophylaxis against CNS leukaemia (n = 12). Seven out of 15 patients with GH deficiency (GHD) (defined as a peak GH concentration <7.5 ng/ml in a stimulation test) had IGF-I <–2 standard deviation score (SDS). None of the 28 patients had serum IGFBP-3 concentrations measured by radioimmunoassay (RIA) <–1.5 SDS with no difference between those with and without GHD. IGFBP-3 concentrations measured by RIA were strongly correlated to IGFBP-3 band density on Western ligand blot (WLB) (r = 0.71; p < 0.0001). IGFBP-3 protease activity was negatively correlated to IGFBP-3 by RIA (r = –0.55; p < 0.01) and to IGFBP-3 by WLB (r = –0.51; p < 0.01). Twenty-two patients had normal IGFBP-3 protease activity (<30% of the activity in pregnancy serum) indicating that serum IGFBP-3 protease activity does not account for the normal levels of IGFBP-3 in RIA.Low serum IGF-I but normal IGFBP-3 concentrations and in the majority normal IGFBP-3 protease activity was found in patients in the years after CNS irradiation. Neither serum IGF-I nor IGFBP-3 can be used as a reliable index of the development of radiation-induced GHD.

The Monitoring of Potential Long-Term Complications in Treated Adult Cancer Patients

A wide variety of long-term complications may be noted following conventional cancer treatment. These include overwhelming postsplenectomy sepsis syndrome, central and peripheral nervous system toxicity, cardiovascular complications, chronic liver damage, and secondary malignancy. Follow-up monitoring usually incorporates both physical examination and the result of radiological and laboratory investigations. Primary care physicians will often be responsible for the majority of the follow-up monitoring involving cured cancer patients and need to be aware of possible long-term therapy-related problems, especially those that present years after successful treatment of the original malignancy.

Treatment of radiation-induced growth hormone deficiency with growth hormone-releasing hormone.

In children with hypothalamic causes for GH deficiency there are theoretical reasons why a GHRH analogue might be better than conventional GH therapy in promoting growth. We have aimed to determine the efficacy and safety of growth hormone-releasing hormone (GHRH) (1-29)-NH2 given as a twice daily subcutaneous injection in the treatment of growth failure in children with radiation-induced GH deficiency. A multicentre study comparing growth before and after 1 year of treatment with GHRH (1-29)-NH2, 15 micrograms/kg twice daily, by subcutaneous injection in children with radiation-induced GH deficiency. On completion of the study year all children were treated with GH (0.5 U/kg/week) and growth parameters were documented over the next year. Nine children (six boys) with radiation-induced GH deficiency following cranial (n = 4) or craniospinal (n = 5) irradiation for a brain tumour distant from the hypothalamic-pituitary axis (n = 8) or prophylaxis against central nervous system leukaemia (n = 1) were studied. All were prepubertal when the study commenced, which was at least 2 years from radiotherapy. Anthropometry and pubertal staging were carried out at 3-monthly intervals and bone age estimations at 6-monthly intervals (TW2 method). Pretreatment standing height velocities were compared with values during the year of GHRH treatment and then after the first year of GH therapy. In those that had received craniospinal irradiation, a change in leg-length Standard deviation score (SDS) was noted before and after GHRH therapy. Changes in skin-fold thickness and bone age during the GHRH study year were documented. Adverse events and 3-monthly measurements of clinical chemistry, haematology, lipid profile and thyroid function were recorded. There was a significant increase in height velocity from 3.3 (SD 1.1) cm/year before treatment, to 6.0 (SDS 1.5) cm/year after 1 year of GHRH treatment (P = 0.004). GHRH maintained or improved the leg length SDS in children who had received craniospinal irradiation. Bone age increased by a mean of 1.1 years/chronological year during treatment with GHRH. Subsequent height velocity during 1 year of GH therapy was 7.5 (SD 1.5)cm/year. No adverse changes in biochemical or hormonal analyses were noted or adverse events that could be attributed to GHRH therapy. One child went into puberty during the GHRH study year and three were pubertal during the first year of GH therapy. In cranially irradiated children, GHRH was effective in increasing growth velocity but this was less than that seen in response to GH therapy, although it matched that in children with isolated idiopathic GH deficiency treated with the same dose and schedule of GHRH administration.

Biochemical tests in the diagnosis of childhood growth hormone deficiency.

GH stimulation tests are widely used in the diagnosis of GH deficiency (GHD), although they are associated with a high false positive rate. We have examined, therefore, the performance of other tests of the GH axis [urinary GH excretion, serum insulin-like growth factor I(IGF-I), and IGF-binding protein-3 (IGFBP-3) levels] compared with GH stimulation tests in identifying children defined clinically as GH deficient. Group I comprised 60 children (mean age, 10.3 +/- 4.8 yr) whose diagnosis of GHD was based on a medical history indicative of pituitary dysfunction (n = 43) or on the typical phenotypic features and appropriate auxological characteristics of isolated GHD (n = 17). Group II comprised 110 short children (mean age, 9.8 +/- 4 yr) in whom GHD was not suspected, but needed exclusion. The best sensitivity for a single GH test was 85% at a peak GH cut-off level of 10 ng/mL, whereas the best specificity was 92% at 5 ng/mL. The sensitivities of IGF-I, IGFBP-3, and urinary GH, using a cut-off of -2 SD score were poor at 34%, 22%, and 25%, respectively, with specificities of 72%, 92%, and 76% respectively. Only 2 of 21 pubertal children in group I and none of the 27 subjects with radiation-induced GHD had an IGFBP-3 SD score less than -1.5. We devised a scoring system based on the positive predictive value of each test, incorporating data from the GH test and the IGF-I and IGFBP-3 levels. A specificity of 94% could be achieved with a score of 10 or more (maximum 17) (sensitivity 34%). The latter could not be improved above 81% with a score of 5 points or more (specificity, 69%). A high score was, therefore, highly indicative of GHD, but was achieved by few patients. A normal IGFBP-3 level, however, did not exclude GHD, particularly in patients with radiation-induced GHD and those in puberty. A GH test with a peak level more than 10 ng/mL was the most useful single investigation to exclude a diagnosis of GHD.

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.

Growth and puberty after growth hormone treatment after irradiation for brain tumours.

The impact of treatment with either cranial or craniospinal irradiation with or without cytotoxic chemotherapy for a brain tumour distant from the hypothalamic-pituitary axis was assessed in 29 children who had reached final height. All had received growth hormone treatment for radiation induced growth hormone deficiency. Final height, segmental growth during puberty, and duration of puberty were studied. Both craniospinal irradiation and the use of chemotherapy resulted in a significant and equal reduction in final height; this effect in those children who received both craniospinal irradiation and chemotherapy was additive. The degree of height loss was related to the age at irradiation, the most profound effect on final height occurring in the youngest at irradiation. The mean duration of puberty from G2-G4/B2-B4 (1.97 years) was not significantly different from the duration of puberty in normal children. Growth hormone increases growth velocity in children with radiation induced growth hormone deficiency but their final height is significantly less than their mid-parental height. The use of spinal irradiation and chemotherapy in the original treatment of brain tumours has a marked effect on growth which is not overcome with the use of growth hormone treatment in current doses. Early puberty of normal duration contributes to poor growth.

Cranial irradiation and early puberty.

Low doses of cranial irradiation (18-24 gray) employed in the management of acute lymphoblastic leukemia may cause early or precocious puberty, predominantly in girls. To determine whether this sexual dichotomy exists at higher irradiation doses (25-47 gray), the onset of puberty was identified in 46 GH-deficient children (30 males) previously irradiated for a brain tumor not involving the hypothalamic-pituitary axis and compared with the normal pubertal standards of Marshall and Tanner. Age at irradiation was at least 2 SD below the mean age of pubertal onset in normal children. There was a significant linear association between age at irradiation and age at onset of puberty. The onset of puberty occurred at an early age in both sexes (mean, 8.51 yr in girls and 9.21 yr in boys plus 0.29 yr for every year of age at irradiation). For example, the estimated age at onset of puberty in a boy irradiated at 2 yr of age would be 9.79 yr, and that for a boy irradiated at 9 yr of age would be 11.82 yr. In the context of GH deficiency, which is usually associated with a delay in the onset of puberty, this is abnormal. At each age of irradiation, the estimated age at the onset of puberty was approximately 0.7 yr earlier in girls than boys. A similar trend was seen for bone age, which was abnormally early at the time of pubertal onset (mean, 7.39 yr in girls and 8.66 yr in boys plus 0.25 yr for every year of age at the time of irradiation). At the doses of irradiation employed in the treatment of brain tumors, radiation-induced early puberty is not restricted to girls. The clinical consequence of early puberty in the management of poor growth associated with radiation-induced GH deficiency is to foreshorten the time available for treatment with GH.

CRANIAL IRRADIATION AND EARLY PUBERTY

Low doses of cranial irradiation (1800-2400 cGy) employed in the management of acute lymphoblastic leukaemia may cause early or precocious puberty in girls but not boys. To determine if this sexual dichotomy exists at higher irradiation doses (2500-4700 cGy) the onset of puberty was identified in 46 children (30 male), previously irradiated for a brain tumour not involving the hypothalamic-pituitary axis, and compared with the normal pubertal standards of Tanner. Regression analysis was employed to assess whether tumour diagnosis, sex, age at irradiation, chemotherapy, use of GH before puberty and radiotherapy protocol influenced age at pubertal onset. The onset of puberty occurred at an early age in both sexes (mean 8.5l years in girls and 9.21 years in boys plus 0.29 years for every year of age at irradiation). In the context of GH deficiency which is usually associated with a delay in the onset of puberty this is abnormal. There was a significant linear association between age at irradiation and age at onset of puberty in both sexes. At each age of irradiation the estimated age at the onset of puberty was approximately 0.7 years earlier in girls than boys. A similar trend was seen for bone age, which was abnormally early at the time of pubertal onset (mean 7.39 years in girls and 8.66 years in boys plus 0.25 years for every year of age at the time of irradiation). Radiation induced early puberty is not restricted to females at the doses of irradiation employed in the treatment of brain tumours. The clinical consequence of early puberty in the management of poor growth associated with radiation induced GH deficiency is to foreshorten the time available for treatment with GH.

Tumour occurrence and recurrence.

There is growing concern about the oncogenic potential of growth hormone (GH) used therapeutically. In rat experiments, a variety of malignant tumours have been induced following administration of supraphysiological doses of GH, whilst in other studies in hypophysectomized animals a lower than normal incidence of carcinogen-induced neoplasms was reported. In acromegaly, in which there is a pathologically sustained high GH level, there is a significantly increased incidence of cancer in general and specifically of colonic neoplasia. To determine whether the use of GH in the treatment of radiation-induced GH deficiency causes tumour recurrence, a comparison was made of tumour recurrence rates between 47 children treated with GH for radiation-induced GH deficiency after treatment for a brain tumour and a control population from the North West Children's Cancer Registry who did not receive GH (n = 160). All cases of acute lymphoblastic leukaemia (ALL), including those that were (n = 15) and were not (n = 146) treated with GH were reviewed. The computerized tomography (CT) scans in the children with brain tumours were reviewed at the time of GH commencement and subsequently. There were 5 brain tumour recurrences after GH therapy: 1 astrocytoma, 2 ependymomas and 2 medulloblastomas. Adjusting for variables other than GH which might affect tumour recurrence, the estimated relative risk of tumour recurrence was 0.82 (95% confidence interval: 0.28-2.37). In each tumour category there was no association between the use of GH and subsequent tumour recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose dependency of time of onset of radiation-induced growth hormone deficiency

Growth hormone (GH) secretion during insulin-induced hypoglycemia was assessed on 133 occasions in 82 survivors of childhood malignant disease. All had received cranial irradiation with a dose range to the hypothalamic-pituitary axis of 27 to 47.5 Gy (estimated by a schedule of 16 fractions over 3 weeks) and had been tested on one or more occasions between 0.2 and 18.9 years after treatment. Results of one third of the GH tests were defined as normal (GH peak response, greater than 15 mU/L) within the first 5 years, in comparison with 16% after 5 years. Stepwise multiple linear regression analysis showed that dose (p = 0.007) and time from irradiation (p = 0.03), but not age at therapy, had a significant influence on peak GH responses. The late incidence of GH deficiency was similar over the whole dose range (4 of 26 GH test results normal for less than 30 Gy and 4 of 25 normal for greater than or equal to 30 Gy after 5 years), but the speed of onset over the first years was dependent on dose. We conclude that the requirement for GH replacement therapy and the timing of its introduction will be influenced by the dose of irradiation received by the hypothalamic-pituitary axis.

7 Irradiation-induced growth failure

Short stature may complicate the treatment during childhood of brain tumours and, to a lesser extent, ALL. A number of factors may be responsible, including spinal irradiation, malnutrition, recurrent tumour, chemotherapy, precocious puberty and radiation-induced GH deficiency. GH is always the first pituitary hormone to be affected by radiation damage to the hypothalamic-pituitary axis but larger radiation doses may result in panhypopituitarism. Some children retain normal GH responses to certain provocative stimuli, although physiological GH secretion is reduced. Nonetheless, in children suspected of radiation-induced GH deficiency, pharmacological tests of GH secretion remain useful, the ITT being the test of choice because of the marked radiation sensitivity of the GH response to hypoglycaemia. The hypothalamus is more radiosensitive than the pituitary. In many patients with radiation-induced GH deficiency, the damage appears to be at the hypothalamic level resulting in a deficiency of endogenous GRF. Treatment with synthetic GRF may provide an alternative to GH therapy in such children. Finally, there is no evidence to suggest that GH therapy given to a child with radiation-induced GH deficiency might induce a brain tumour recurrence or a relapse of ALL.