Deficiency of one or more anterior pituitary hormones may follow treatment with external radiation when the hypothalamic-pituitary axis falls within the fields of radiation. Hypopituitarism has been described in patients who received radiation therapy for nasopharyngeal carcinoma, tumors of the pituitary gland or nearby structures, and primary brain tumors, as well as in children who underwent prophylactic cranial irradiation for acute lymphoblastic leukemia or total body irradiation (TBI) for a variety of tumors and other diseases.
There is strong evidence that the hypothalamus is the major site of radiation-induced damage and a growing belief that the pathological basis for the damage is direct neuronal injury rather than vascular-mediated.
As radiation therapy and chemotherapy for patients with tumors of the brain and surrounding structure improve, follow-up evaluation will need to focus less on the possibility of tumor recurrence and more on the delayed effects of therapy, including the endocrine effects. Pituitary hormone deficiencies are common and may not develop for many years.

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The data base of the International Cooperative Growth Study (ICGS) in Japan includes data from 6, 298 children treated with growth hormone (GH). These children were classified into two groups, growth hormone deficiency (GHD) and non-endocrine short stature (NESS), based solely on the results of GH provocation tests. There were 3, 874 children classified as GHD (peak GH concentrations not exceeding 10 ng/mL in at least two and all provocation tests), and 2, 183 as NESS (peak GH higher than 10 ng/mL, in at least one test). Among GHD children, 3, 541 were diagnosed as having idiopathic GHD (IGHD) and 333 as organic GHD (OGHD) (congenital 22, acquired 306). Three hundred and fifty-seven children with various diseases which may cause short stature (Turner syndrome, 212; Noonan syndrome, 26; Prader-Willi syndrome, 20; Silver-Russell syndrome, 16; others, 88) were likewise classified according to the results of GH provocation tests.
Among patients with IGHD, 392 (11.1%) were born by breech delivery, and 130 of these (33.2 %) were reported to have had neonatal asphyxia. At the start of GH treatment the children showed a mean height SD score (SDS) of -3.1 for IGHD, -2.7 for OGHD and -2.9 for NESS. The mean ages at the start of treatment were 9.8, 10.3 and 9.7 years, respectively. The girls with Turner syndrome were relatively old (mean 11.7 years) at the start of treatment. Before treatment, height velocity was low in comparison to normal children of the same age, and the mean height velocity SDS were -2.5 for those with IGHD, -3.4 for OGHD, and -2.4 for NESS.

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Baseline auxology and responses to growth hormone (GH) treatment in girls with Turner syndrome (TS) from three countries, Japan, Sweden and the United Kingdom, were compared, using data from the Kabi Pharmacia International Growth Study (KEGS). Differences were observed between countries in respect to pretreatment height and height velocity, chronological and bone ages at onset of GH, parental and target heights, body proportions, weight-for-height index, birth weight, and peak GH levels in provocation tests.
Median values for height velocity in the first 3 year of GH treatment were greatest in Sweden and lowest in Japan. A previously derived model for predicting first year response in TS was applied to data from the 3 countries: there was no difference between the Studentised residuals of observed-predicted height velocities between countries.
It was concluded that although there were differences in response to GH between countries, there was no difference in “responsiveness”. The predictive model for first year response was robust but only accounted for 25% of the variability of response; other factors predicting response to GH in TS should be sought.

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Intra-uterine growth retardation (IUGR) and Silver-Russell syndrome (SRS) are born short for gestational age and many of them do not show post-natal catch-up growth Although post-natal catch-up growth frequently occurs, significant number of both IUGR and SRS newborns often fail to catch up. This may result in very short adult height (more than 2 standard deviations (SD) below the mean) in up to 20% of these patients, in association with poor school and social performance.
In order to try to induce catch-up growth and hopefully increase final height, attempts have been made in clinical trial to treat these growth hormone (GH) sufficient patients with human GH.
Using the Kabi Pharmacia International Growth Study patient data base, a group of 106 IUGR (83 males and 23 females) and 45 SRS with persistent post-natal growth failure were studied. IUGR clinical characteristics included a birth length and weight more than 2 SD below the mean for gestational age. Height deficit at start of the GH treatment was -3.0 standard deviation scores (SDS) for chronological age (CA), at a median CA of 8.7 years with a median bone age (BA) of 7.0 years. Mean parental heights were 166 cm for fathers and 153 cm for mothers. Median dose of recombinant human GH (rhGH) in 106 IUGR patients was 0.5 IU/kg/week, given at a median frequency of 5 injections per week. The median height SDS for CA at the start and at 1, 2 and 3 years of hGH treatment were -3.0, -2.5, -2.1 and -1.9 respectively.
45 patients presented with SRS. Their median CA and BA at start of treatment were 6.7 and 3.2 years respectively. Mean parental heights were 167.5 cm for fathers and 160 for mothers. Median dose of rhGH in these 45 SRS was 0.7 IU/kg/week, with a median frequency of 6 injections per week. Median height SDS of SRS patients at start, 1, 2 and 3 years of hGH treatment were -3.5, -2.9, -2.8 and -2.2 respectively. One difference between these IUGR and SRS groups is that SRS patients tended to be born of normal height parents, in contrast to IUGR with persistent post-natal growth failure. In these two groups, exogenous GH treatment tended to induce catch up growth, although long term follow up is sufficient to allow conclusions to be draw regarding these patients' final adult height.

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From a population-based postnatal growth study of 3, 650 healthy Swedish subjects born at full term a cohort of 111 (3.1%) of low birth weight (below -2 SDS) and of 141 (3.5%) of low birth length (below -2 SDS) were selected; 54 (1.5%) were both light and short at birth. Of these children born small for gestational age, 87 % showed full catch-up growth within 2 years of life. They attained puberty at a normal or early age and reached a mean final height of -0.7 SDS. The remaining subgroup of 13 % born small for gestational age remained below -2 SDS throughout childhood and also reached puberty somewhat early. Their mean final height was -1.7 SDS.

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The relationship between growth hormone (GH) secretor capacity and clinical characteristics at onset of puberty is analyzed and the prospective final height is discussed using the International Cooperative Growth Study (ICGS) database.
A total of 713 patients (464 boys and 249 girls) diagnosed as having GH deficiency of idiopathic origin by the criteria of the Foundation for Growth Science, and who entered puberty spontaneously during GH treatment, were selected from 6, 058 patients treated with Genotropin in Japan.
The age at onset of puberty was significantly later in GH-treated children than in normal Japanese children. The delayed pubertal development can be attributed to a lack of the normal action of GH on the gonads. The height at onset of puberty was significantly shorter in GH-treated children than in normal children. When the change in longitudinal height velocity is compared with the normal height velocity curve by adjusting the age at onset of puberty, the mean values are distributed below the standard mean and normal adult height is unattainable. Early diagnosis and high dose Gil treatment are thus important in order to allow sufficient catch-up growth before puberty, normal growth during puberty and the attainment of normal adult height.

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Leukemia Study Group of the Foundation for Growth Science, Japan, Epidemiology Division, National Cancer Center, Tokyo (SW SM), Hemato-oncology Division, National Children's Hospital (YT), Department of Pediatrics, Shinshu University, Nagano (AK) and Department of Pediatrics, Kyoto University, Kyoto (CY, MK), Japan The incidence of leukemia, exduding malignant histiocytosis, among growth hormone (GH) users has reached 13 cases in Japan. These consist of six with acute myeloid leukemia (AML), five with acute lymphocytic leukemia (ALL) and two with chronic myeloid leukemia (CML). In nine of these patients the leukemia was idiopathic, but the other three had underlying malignant decease and one had Fanconi's anemia. Leukemia developed during GH treatment in eight patients and after cessation of GH therapy in three. The longest interval between cessation of GH therapy and the onset of leukemia was 10 years. One patient with AML was considered to be already at the preleukemic stage when GH was started. Recently, two new leukemia cases (AML and CML) in GH deficient children who had not received GH have been reported. Analysis of these cases suggests that both high and low GH levels are risk factors for leukemia.

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A total of 1, 332 adverse events were reported in 8, 960 patients representing 26, 529 treatment years of growth hormone (GH) included in Kabi Pharmacia International Growth Study (KIGS) as of January 1993. Most were concomitant trivial illnesses. Three recurrences occurred in 174 patients (1.7%) with organic growth hormone deficiency (GHD) after leukemia, 18 in 459 patients (3.9 %) with GHD after brain tumors and 19 in 253 (7.5 %) of the original malignancy after craniopharyngioma. At the time of recurrence the patients had been on GH for 2.8-5.2, 0.1-6.1 and 0.2-8.7 years, respectively. De novo leukemia was reported in a 8-year old boy with idiopathic GHD.
The annual incidence of insulin dependent diabetes mellitus (IDDM) was 0.08/1, 000 patients and 0.90/1, 000 patients in idiopathic GHD and Turner syndrome, respectively. Five cases of NIDDM were reported in organic GHD post leukemia and CNS tumors. The annual incidence of slipped epiphysis was significantly higher in organic GHD (2.2/1, 000 patients) compared with the reference of normal healthy childhood population (0.10-0.13/1, 000) and idiopathic GHD (0.17/1, 000) and non GHD short children (0.14/1, 000).
The incidence of seizures in children with GHD post CNS tumors and incidence of headache in children with GHD after craniopharyngioma was increased compared with idiopathic GHD. The incidence of adverse events in general was lower in idiopathic GHD and short non-GHD children than in organic GHD and Turner syndrome.

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We surveyed the quality of life of adult patients with growth hormone deficiency (GHD) who ceased growth hormone (GH) therapy before the age of 20. We sent questionnaires to 1, 116 patients and their physicians, asking about their socio-economic status and medical background. Return rates were 64% and 69%, respectively. The final height was above -2 standard deviation scores in 61% of the patients. The distribution of occupation, job and income were similar to those in the general population. Patients with a final adult height below 155 cm in males and below 140 cm in females felt a disadvantage in finding jobs and marriage partners. Slight psychological problems revealed in these patients.

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Growth hormone insensitivity syndrome (GHIS) is a pathological state characterised by disturbance of the normal relationships between growth hormone (GH) secretion, insulin-like growth factor I (IGF-I) synthesis and GH action. Laron syndrome (LS) is the most severe form and is related to defects of the GH receptor gene. Twenty-seven cases of IS from 8 European countries and Australia were characterised clinically and endocrinologically. Clinical features (median) were; age 2.8-22.6 years, 12 males, 15 females, birth weight -0.72 SDS, birth length -1.59 SDS. Hypoglycaemia occurred in 33% and micropenis in 58% of males. Height was -6.0 SDS, weight -3.2 SDS, % weight for height 111.3. Bone age was delayed in 19 of the 27 patients. Endocrine values (median) were; GH 17μg/L, IGF-I<5th centile, with% increment during IGF-I generation test <20%. IG1411313-3 was <5th centile, GH-BP was low or undetectable in 20 and normal in 7 subjects.
Treatment with recombinant IGF-I offered the only form of effective therapy. Treatment of 13 patients with IGF-I, 120μg/kg bid induced a change in mean height velocity from 4.1cm/year before treatment to 10.2cm/year at 6 months and 8.8cm/year at 12 months. Adverse effects were minimal. Facial appearance showed a change in maturity associated with capital hair growth. Further studies to define the optimum dose regimen of IGF-I are in progress.

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The present study was performed to assess the potential effectiveness of IGF-I as a blood glucose lowering agent in 10 patients with the syndromes of extremeinsulin resistance including type A syndrome, congenital generalized lipodystrophy and leprechaunism. With a twice daily subcutaneous injection of recombinant human IGF-I (0.06 to 0.4 mg/kg), fasting concentrations of total IGF-I increased about two- to fourfold over the values before treatment. IGF-I was effective in improving diabetic control; both fasting and postprandial plasma glucose concentrations fell with decreases in HbA1c and fructosamine values in the majority of the patients within the follow-up period ranging from 1 to 40 months. There was, however, one patientin whom painful neuropathy and proliferative retinopathy quickly developed after a rapid improvement of her glycemic control. Severe side effects were not reported in the other 9 patients.
These results suggest that IGF-I could be used clinically as a hypoglycemic agent in diabetic patients with insulin resistance in whom insulin treatment is ineffective. However, because IGF-I stimulates cell growth in a variety of tissues, the potential unfavorable effects of IGF-I should also be monitored, particularly when IGF-I therapy is continued for a long period.

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