Supraphysiological Doses Of Growth Hormone Research Articles

Abstract 7: Use of growth hormone therapy in short patients born small for gestational age: Data from real-life French clinical practice

Background: A national French registry was created to address the absence of data on final height and safety following long-term exposure to supraphysiological doses of growth hormone (GH) in children born small for gestational age (SGA).Methods: This observational, non-interventional study (NCT01578135) included GH-naïve and non-naïve SGA children treated with GH at 126 sites in France. The inclusion period was 2005–2010 with follow-up until 2018 or until final adult (FA) height (height velocity <2 cm/year). The primary endpoints were proportion of patients with normal (>–2) height standard deviation score (HSDS) at last visit, and with normal FA HSDS. Secondary endpoints included change from baseline in HSDS and safety. Multivariate logistic regression analysis with stepwise elimination was used to identify factors associated with achieving normal HSDS.Results: Of the 1408 registered patients, every fifth child was randomly selected (n = 291) for inclusion in this long-term follow-up study. For the full population and subpopulation, mean (SD) baseline age was 8.79 (3.53) and 8.08 (3.32) years; HSDS was –2.55 (0.95) and –3.07 (0.86); 48.4% and 46.0% were female, respectively. Normal HSDS was reached in 193/291 children (66.3%). Among the 24.7% of patients who achieved FA height at last visit, 66.7% had FA HSDS >–2. Mean change from start of treatment to last visit in HSDS was +1.35 (0.97). Factors associated with reaching normal HSDS were baseline HSDS (taller better; odds ratio [95% confidence interval]: 5.65 [3.22;9.92], P < 0.0001); age at treatment start (younger better; 0.88 [0.79;0.98], P=0.0166); treatment duration excluding discontinuation periods (longer better; 1.20 [1.04;1.38], P=0.0166); and absence of a chronic disease (0.43 [0.21;0.87], P=0.0188). The majority (70.0%) of adverse events (AEs) were non-serious; 39.0% of all AEs and 7.0% of serious AEs were considered possibly/probably related to GH treatment. The most common AEs (% of patients) were increased insulin-like growth factor-I (IGF-I; 17.2%), headache (9.3%) and arthralgia (4.5%). Sixteen patients (5.5%) discontinued treatment prematurely, most commonly because of increased IGF-I (n = 4). One malignant tumour (nephroblastoma) with a fatal outcome was reported and considered unrelated to GH treatment.Conclusions: GH therapy was effective in most short children born SGA. No new safety concerns were observed. The likelihood of achieving normal HSDS with GH therapy increased with greater baseline HSDS, longer duration of GH treatment, absence of a chronic disease and younger baseline age, reinforcing the importance of early identification and treatment of short patients born SGA.

Carotid Intima-Media Thickness in Children Treated with Growth Hormone: A Follow-Up Study over Three Years

Background: There is an ongoing discussion whether high doses of growth hormone (GH) may lead to cardiovascular diseases. Therefore, we studied the longitudinal relationships between GH treatment and carotid intima-media thickness (cIMT), which is predictive of the development of atherosclerosis. Methods: We measured blood pressure, lipids, hemoglobin HbA_1c, IGF-1, IGFBP-3, and cIMT in 28 children treated with supraphysiological doses of GH (mean age 9.8 ± 2.2 years, 39% males) and 36 children suffering from GH deficiency (GHD) and treated with physiological doses of GH (mean age 9.7 ± 2.2 years, 72% males) in a longitudinal study over 3 years. Results: The cIMT values did not change significantly in the observation period in children with GHD (Δmaximum and Δmean cIMT 0.0 ± 0.1 mm). The mean (+0.1 ± 0.1 mm) but not the maximum cIMT (0.0 ± 0.1 mm) increased significantly (p = 0.049) in the children treated with supraphysiological doses of GH. Blood pressure, lipids, and HbA_1c were not related to cIMT, while IGF-1, IGFBP-3, body mass index expressed as a standard deviation score, and treatment duration correlated significantly with cIMT. Conclusions: We did not find any robust evidence that GH treatment is associated with changes in cIMT. Further studies are necessary to analyze the impact of IGF-1 and IGFBP-3 concentrations on cIMT.

Carotid intima-media thickness in children treated with growth hormone.

There is an ongoing discussion whether high doses of growth hormone (GH) may lead to cardiovascular diseases. Therefore, we studied the relationships between GH treatment and carotid intima-media thickness (cIMT), which is predictive of the development of atherosclerosis. We measured cIMT in 38 children with supraphysiological doses of GH (mean age 10.9 ± 2.2 years; 47% male; GH indication: small for gestational age, n = 31; Turner syndrome, n = 5; SHOX deficiency, n = 2) and in 38 age- and gender-matched healthy children without GH treatment. Furthermore, we examined cIMT in 61 children with physiological doses of GH (mean age 12.0 ± 3.1 years; 64% male; GH indication: GH deficiency) and in 61 age- and gender-matched healthy children without GH treatment. Moreover, we analyzed blood pressure, lipids, HbA1c, IGF-1, and IGFBP-3 in children treated with GH. The cIMT levels did not differ significantly between children with and without GH treatment either in high-dose GH treatment or in physiological GH doses. In backwards linear regression analyses, cIMT was significantly related to HbA1c, but not to age, gender, BMI, pubertal stage, indication of GH treatment, duration or doses of GH treatment, IGF-1, IGFBP-3, or to any cardiovascular risk factor. We found no evidence that GH treatment is associated with changes in cIMT.

Reduced Pericellular Sensitivity to IGF-I in Fibroblasts From Girls With Turner Syndrome: A Mechanism to Impair Clinical Responses to GH

Girls with Turner syndrome (TS) are treated with supraphysiological doses of growth hormone (GH) to improve final height; however in some girls, the growth response can be poor. This may reflect aberrations in GH and/or IGF-I actions at the cellular level, and thus this study compared the response of skin fibroblasts from normal children (n = 5) and girls with TS (n = 8) to GH, IGF-I, or a combination, by assessing the IGF binding protein (IGFBP) profile of conditioned medium harvested over 7 d. The two cell types had a comparable IGFBP profile; IGFBP-3 and IGFBP-4 were the most abundant species. TS fibroblasts produced more IGFBP-3 (d 7, 51.4 ± 45 ng/mL versus 20 ± 22 ng/mL; p < 0.05) than control cells; levels of IGFBP-4 were similar (21 ± 12 ng/mL versus 30 ± 21 ng/mL). GH did not influence IGFBP production. IGF-I treatment did not affect IGFBP-4 levels but enhanced the production of IGFBP-3 by both cell types (p < 0.05). However, the response of TS fibroblasts to IGF-I was approximately half that observed in normal cells (p < 0.05). Altered IGF-I activity, because of reduced bioavailability and/or reduced sensitivity, could contribute to the need for high GH doses in TS and for the poor response to GH in some girls with TS.

Cardiac changes induced by excess exogenous growth hormone in juvenile miniature poodles

The transient elevated plasma growth hormone (GH) levels that occur at a young age in giant breed dogs may have consequences in adult life. The aim of this study was to investigate whether excess juvenile GH has consequences for cardiac function and morphology. To simulate the naturally occurring juvenile hypersomatotropism in giant breed dogs, elevated plasma GH and insulin-like growth factor-I (IGF-I) concentrations were induced in six miniature poodles (GH dogs) by daily administration of supraphysiological doses of GH starting at 12 weeks of age. Eight miniature poodles of the same age that received vehicle only served as controls. Cardiac anatomy and function were evaluated by echocardiography. After euthanasia at 21 weeks of age, the hearts were examined for weight, myocyte dimensions and collagen fraction. The hearts of the GH dogs had larger atria (+22%), a thicker left ventricular wall (+21%), greater weight (+84%), and their cardiomyocytes were 15% longer, 25% thicker, and 92% greater in volume than those of control dogs. The mean collagen fraction was also higher in the GH dogs (5.6%) than in the controls (3.1%). In conclusion, excess GH in juvenile miniature poodles resulted in myocardial hypertrophy and increased collagen content. These findings are consistent with observations in acromegalic human patients and in rats treated with GH.

The Neuroendocrine Effects of Traumatic Brain Injury

The Neuroendocrine Effects of Traumatic Brain Injury

The Neuroendocrine Effects of Traumatic Brain Injury

Neuroendocrine dysfunction after traumatic brain injury (TBI) is under-diagnosed, under-treated, and may adversely affect the rate of recovery. Single or multiple pituitary-target hormone disruption occurs in up to two-thirds of persons with TBI, most commonly affecting the gonadal and growth hormone axes. The time course of decline in and recovery of pituitary function in relation to cognitive dysfunction and rehabilitation progress are not well described. This article reviews the clinical spectrum of neuroendocrine deficits after TBI and their underlying mechanisms. Future studies of the effects of hormonal replacement on recovery are recommended.

Increased serum concentration of IGFBP-4 and IGFBP-5 in healthy adults during one month’s treatment with supraphysiological doses of growth hormone

Objectives To study the effects on insulin-like growth factor binding proteins (IGFBP)-4 and -5 after one month’s treatment with supraphysiological doses of growth hormone (GH) in healthy, active young adults with a normal GH–IGF-I axis. Furthermore, the possible use of IGFBP-4 and IGFBP-5 as markers of GH doping is discussed. Design Thirty healthy, physically active volunteers (15 men and 15 women), mean age 25.9 years (range 18–35), participated in this randomized, double-blind, placebo-controlled, parallel study with three groups ( n = 10; 5 men and 5 women in each group). The groups comprised the following: placebo, GH 0.1 IU/kg/day [0.033 mg/kg/day] and GH 0.2 IU/kg/day [0.067 mg/kg/day]. Results Baseline levels of IGFBP-4 were higher (+20%), while IGFBP-5 levels were lower (−37%) in women than in men. IGFBP-5 levels were positively correlated to age, but no significant correlation was found for IGFBP-4. In the pooled group with active GH treatment ( n = 20), both IGFBP-4 and IGFBP-5 levels were increased vs. the placebo group from day 14 until end of treatment [day 28, IGFBP-4 (+40%, p < 0.01) and IGFBP-5 (+61%, p < 0.001)]. After inclusion of serum IGF-I as a covariate in the linear regression analysis, the associations between GH treatment and the IGFBP-4 and IGFBP-5 levels were not significant. Conclusions This study shows that the levels of IGFBP-4 and IGFBP-5 are affected by supraphysiological GH treatment given to young, healthy, physically active adults of both genders. The present study, including relatively few subjects, does not support that IGFBP-4 and IGFBP-5 can be used as IGF-I independent markers in a forthcoming method for detecting GH doping, although, further studies are needed to investigate the potential use of IGFBP-4 and IGFBP-5 as markers of GH doping.

Longitudinal growth in children following kidney transplantation: from conservative to pharmacological strategies

Impairment of longitudinal growth in children with chronic renal failure (CRF) is multifactorial. It is mainly due to disturbances in the growth hormone (GH)/insulin-like growth factor (IGF)/IGF-binding protein axis. Growth failure can be managed by optimizing nutrition and fluid/electrolyte homeostasis, and overcoming the growth-inhibiting effects of uremia by high-dose recombinant human (rh) GH treatment. A sufficient catch-up growth is one of the determining issues for the overall success of pediatric kidney transplantation (Tx). However, despite satisfactory renal function, spontaneous catch-up growth is often insufficient as glucocorticoid treatment is the main inhibiting factor for longitudinal growth after Tx. In addition, longitudinal growth may be jeopardized by low glomerular filtration rate (GFR) and African American or Hispanic background. Supraphysiological doses of GH and/or IGF-I in vitro and in vivo can partially overcome the growth-inhibiting effects of glucocorticoid treatment. GH-associated increase of leukocyte proliferation and cytotoxicity with stimulated interferon synthesis have been demonstrated. However, it is not clear whether such stimulatory effects on leukocyte function are a transitory or a constant risk factor after organ Tx. Clinical trials of GH in children after renal Tx have suggested a rather moderate or transient effect of rhGH on the immune system, and corticosteroids induce a hyporesponsiveness to the action of GH. As long as corticosteroids are believed to be essential after renal Tx, rhGH should be considered to optimize longitudinal growth in children.

Impact of treatment with recombinant human GH and IGF-I on visceral adipose tissue and glucose homeostasis in adults

Supraphysiological doses of growth hormone (GH) therapy are generally thought to antagonize the effects of insulin, whereas the insulin-like growth factor I (IGF-I) potentiates insulin-like actions. Paradoxically, adults with GH deficiency and patients with acromegaly are both predisposed to glucose intolerance and insulin resistance; however, one cannot extrapolate from these pathological conditions to determine the true metabolic roles of GH and IGF-I in glucose homeostasis. Growth hormone also promotes lipolysis, which has been shown to be the principal determinant of its insulin-antagonistic properties; on the other hand, IGF-I, which acts as an insulin sensitizer, does not exert any direct effect on lipolysis or lipogenesis. Under physiological conditions, the insulin-sensitizing effect of IGF-I is evident only after feeding, when the bioavailability of circulating IGF-I is increased. In contrast to supraphysiological GH doses, low doses of GH treatment have been shown to increase circulating IGF-I levels and IGF-I bioavailability and, thus, may theoretically enhance insulin sensitivity without inducing lipolysis. We have recently reported that a fixed administration of a very low GH dose (1.7 μg/kg/day or 0.1 mg/day) improved insulin sensitivity in adults with GH deficiency and increased peripheral glucose uptake in subjects with impaired glucose tolerance and the metabolic syndrome. Our data raise the possibility that this very low GH dose may play a role in maintaining β-cell function and possibly delay the progression to type 2 diabetes in these high-risk patients.

Current use of growth hormone in children

Since the advent of growth hormone(GH), children with a wide variety of growth disorders have received GH treatment. In GH deficiency(GHD), Turner syndrome, chronic renal failure, children born small for gestational age, Prader-Willi syndrome, and idiopathic short stature, the therapeutic effects and safety profile of GH are reviewed. GH therapy has been clearly shown to improve height velocity and final adult height in a variety of pediatric conditions in which growth is compromised irrespective of GHD. Early initiation and individualization of GH treatment has the potential to normalize childhood growth. The supra-physiological doses of GH have been shown to increase height velocity during childhood and final height in non-GHD conditions. Adverse events during GH therapy are uncommon and often not drug related. However continued surveillance into adult life is crucial, especially in children receiving supra-physiological doses or whose underlying condition increases their risk of adverse effects

Supraphysiological growth hormone: less fat, more extracellular fluid but uncertain effects on muscles in healthy, active young adults

To study the effects on body composition after 1 month's administration of supraphysiological doses of growth hormone (GH) in healthy, active young adults with normal GH-IGF-I axis. Thirty healthy, physically active volunteers (15 men and 15 women), mean age 25.9 years (range 18-35), participated in this study, designed as a randomized, double-blind, placebo-controlled, parallel study with three groups (n = 10: five men and five women in each group). The groups comprised the following: placebo (P), GH 0.1 IU/kg/day [0.033 mg/kg/day] (GH 0.1) and GH 0.2 IU/kg/day [0.067 mg/kg/day] (GH 0.2). In the pooled group with active GH treatment (n = 20) the results showed significant increases: IGF-I increased by 134% (baseline vs. after 1 month), body weight by 2.7%, fat free mass by 5.3%, total body water by 6.5% and extracellular water (ECW) by 9.6%. Body fat decreased significantly by 6.6%. No significant change in intracellular water was detected. The observed increase in fat free mass by 5.3% was explained by the ECW increase, indicating limited anabolic effects of the supraphysiological GH doses. Changes were noticeable in both genders, although more prominent in the male subjects. Fluid retention symptoms occurred in the majority of individuals. This is, to our knowledge, the first placebo-controlled trial to show the effects of supraphysiological GH doses on body composition and IGF-I levels in physically active and healthy individuals of both genders; the results indicate limited anabolic effects of GH with these supraphysiological doses. The role of GH as an effective anabolic doping agent is questioned.

Growth hormone treatment in children: review of safety and efficacy.

Since the advent of growth hormone (GH), the pediatric applications of GH therapy have expanded. Children with a wide variety of growth disorders have received GH treatment. The therapeutic effects and safety profile of GH in a number of pediatric conditions are reviewed, including GH deficiency (GHD), Turner syndrome, chronic renal failure, children born small for gestational age, Prader-Willi syndrome, juvenile chronic arthritis, and cystic fibrosis. GH therapy has been clearly shown to improve height velocity during childhood in a variety of pediatric conditions in which growth is compromised. There is now data that confirms GH treatment also improves final height in a number of diagnostic subgroups. Early initiation and individualization of GH treatment has the potential to normalize childhood growth in children with idiopathic GHD and enable them to achieve their genetic target height in a cost-effective manner. In children in whom GHD is not the main factor compromising growth, supra-physiological doses of GH have been shown to increase height velocity during childhood and final height. The development of predictive models for these conditions may allow further improvements in height outcome while maintaining an acceptable safety profile. Survivors of childhood malignancy, particularly those who have had craniospinal irradiation, represent a particularly challenging group. They appear to be less responsive to GH than children with idiopathic GHD and have a tendency to enter puberty at an earlier age. Both of these factors have a negative impact on their final height. Strategies that combine GH treatment with suppression of puberty using a gonadotropin releasing hormone analog may result in improved height outcomes. When children with GHD are treated with standard doses of GH there is a strong safety record. Adverse events during GH therapy are uncommon and often not drug related. Continued surveillance into adult life is crucial however, particularly in children receiving supra-physiological doses of GH or whose underlying condition increases their risk of adverse effects.

Cancer risk following growth hormone use in childhood: implications for current practice.

The therapeutic use of growth hormone (GH) has caused concern, as it is anabolic and mitogenic, and its effector hormone, insulin-like growth factor (IGF)-I is anti-apoptotic. As both hormones can cause proliferation of normal and malignant cells, the possibility that GH therapy may induce cancer, increase the risk of tumour recurrence in those previously treated for a malignancy, or increase the risk of cancer in those with a predisposition, has resulted in concerns over its use. There are theoretical and epidemiological reasons that suggest GH and IGF-I may be important in tumour formation and proliferation. Malignant tumours have been induced in animals exposed to supraphysiological doses of GH, whereas hypophysectomy appears to protect animals from carcinogen-induced neoplasms. In vitro, proliferation and transformation of normal haemopoetic and leukaemic cells occurs with supraphysiological doses of GH, but not with physiological levels. IGF, IGF binding proteins (IGFBP) and IGFBP proteases influence the proliferation of cancer cells in vitro; however, GH is probably not involved in this process. Epidemiological studies have suggested an association between levels of IGF-I and cancer, and an inverse relationship between IGFBP-3 and cancer; however, these associations have been inconsistent. A number of studies have been undertaken to determine the risk of the development of cancer in children treated with GH, either de novo, or the recurrence of cancer in those previously treated for a malignancy. Despite early concerns following a report of a cluster of cases of leukaemia in recipients of GH, there appears to be no increased risk for the development of leukaemia in those treated with GH unless there is an underlying predisposition. Even in children with a primary diagnosis of cancer, subsequent GH use does not appear to increase the risk of tumour recurrence. However, a recent follow-up of pituitary GH recipients has suggested an increase in colorectal cancer. In addition, follow-up of oncology patients has suggested an increase in second neoplasms in those who also received GH therapy. These studies emphasise the importance of continued surveillance both internationally with established databases and also nationally through single-centre studies.

Growth hormone modulates cholecalciferol metabolism with moderate effects on intestinal mineral absorption and specific effects on bone formation in growing dogs raised on balanced food

The aim of the study was to investigate the influence of growth hormone (GH) on Vitamin D 3 metabolism and the subsequent effects on calcium (Ca) homeostasis and skeletal growth in growing dogs. A group of Miniature Poodles received supraphysiological doses of GH ( GH group; n=6; 0.5 IU GH per kg body per day) from 12 to 21 weeks of age and was compared with a control placebo-treated group ( n=8). Biologic activity of GH in the GH compared to the control group was indicated by (a) the 2.5- to 3.5-fold increase in the plasma concentrations of insulin-like growth factor I (IGF-I), (b) the increased production of 1,25-dihydroxycholecalciferol as indicated by the significantly increased plasma 1,25-dihydroxycholecalciferol concentrations and the 12.9-fold increase in renal 1α-hydroxylase gene expression, and (c) the inhibited production of 24,25-dihydroxycholecalciferol as indicated by the significantly lower plasma 24,25-dihydroxycholecalciferol concentrations and the similar levels of renal 24-hydroxylase gene expression. Despite the distinct effects on Vitamin D 3 metabolism in the GH group, there were only moderate effects on the intestine, i.e. at 20 weeks of age there was a significant increase of 14.4 and 5.6% in fractional absorption of Ca and phosphate (P i), respectively, compared to the control group. GH administration resulted in significantly elevated glomerular filtration rate, with no differences in P i urine excretion as a result of a concomitant increase in the tubular reabsorption of P i. GH had only limited disturbing effects on endochondral ossification as indicated by the maintenance of the regularity of the growth plates. However, GH had specific anabolic effects on bone formation without concomitant effect on bone resorption that may result in disorders of skeletal remodeling and manifestation of enostosis.

Suppression of growth plate chondrocyte proliferation by corticosteroids

Growth depression is a side effect of high-dose glucocorticoid therapy in childhood. It is partially mediated by alterations of the somatotropic hormone axis and partially by direct local effects on growth plate chondrocytes. The mechanisms of interaction of corticosteroids and somatotropic and calciotropic hormones at the cellular level were recently investigated in more detail, using experimental models of primary cultures of growth plate chondrocytes. In proliferative chondrocytes, growth hormone (GH) and the calciotropic hormones parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1alpha,25(OH)2D3] increase cell proliferation via stimulation of paracrine insulin-like growth factor-I (IGF-I) secretion. Corticosteroids decreased GH, and PTH or 1alpha,25(OH)2D3 stimulated cell growth in a dose-dependent manner. Corticosteroids in high doses reduced the expression of the GH receptor and type 1 IGF receptor. But the main antiproliferative molecular effect of corticosteroid was the reduction in basal and hormone-stimulated IGF-I secretion. The in vitro results are in accordance with the observation in animal experiments and in children treated with corticosteroids, demonstrating that the growth-depressing effect of corticosteroids can be compensated for by supraphysiological doses of GH or IGF-I.

Left ventricular volume and mass in children on growth hormone therapy compared with untreated children.

The myotropic effects of growth hormone (GH) have long been known. An excess of GH as in acromegaly, causes various problems within the circulatory system including cardiac hypertrophy. Although the latter has not been reported as a complication of GH therapy in children, we assessed this possibility in 54 children. Ninety-six echocardiographic studies were performed, in which bisectional images were analysed by Simpson's rule to determine left ventricular volume and mass. Of special interest were 47 results obtained from girls with Ullrich-Turner-syndrome (UTS) treated with supraphysiological doses of GH. Our results showed a significant increase of the myocardial mass in children on GH therapy compared with untreated children, as well as a dose related effect of GH on cardiac mass in girls and cardiac volume in boys. No cardiac hypertrophy, however, could be observed; the increase in muscular mass merely amounting to a normalization of previously low values.

Safety of growth hormone after treatment of a childhood malignancy.

The use of growth hormone therapy in children with radiation-induced growth hormone (GH) deficiency is widely accepted, but the safety of this mitogenic hormone, particularly in children previously treated for cancer, continues to cause concern. A variety of malignant tumours have been induced in animals exposed to supraphysiological doses of GH, whereas hypophysectomised animals appear protected from carcinogen-induced neoplasms. Growth hormone and insulin-like growth factor-1 have been shown to stimulate both proliferation and transformation of normal and leukaemic human lymphocytes in vitro when used in supraphysiological doses. Despite the theoretical arguments, there is no evidence of an increased risk of tumour recurrence following GH therapy in replacement dosage in children previously treated for a malignancy.

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)

Induction of insulin-like growth factor I messenger RNA in rat aorta after balloon denudation.

Insulin-like growth factor I (IGF-I) is a widely distributed mitogen that mediates the growth-promoting effects of platelet-derived growth factor in mesenchymal cells. We show that rat aortic IGF-I messenger RNA (mRNA) is induced 24 hours after deendothelialization, at a time when smooth muscle cell proliferation within the intima is still not apparent. After 7 days, IGF-I mRNA induction peaks at about ninefold control levels and then falls to about threefold 14 days after denudation when smooth muscle cell proliferation is at its peak. We also show that, of the 5' untranslated IGF-I mRNA transcripts, only the class C transcript is expressed and regulated in aortic tissue. In contrast, treatment of rats with supraphysiological doses of growth hormone, the major endocrine regulator of IGF-I gene expression, elicited only twofold induction of aortic IGF-I mRNA. Our findings suggest that IGF-I may be an important autocrine or paracrine regulator of smooth muscle cell proliferation and that it may be significant in determining the cellular response to arterial wall injury.