High-dose Growth Hormone Therapy Research Articles

Chiari type 1 malformation associated with central sleep apnea after high dose growth hormone (GH) therapy in a 12-year-old boy: A case report.

.We describe the case of a short-statured 12-yr-old boy who developed a Chiari type 1 malformation associated with central sleep apnea after administration of high-dose GH therapy, which he had been receiving since the age of 10 yr and 4 mo. He responded well to GH therapy, and his height increased by 18.8 cm in 2 yr. At 12 yr and 4 mo of age, his mother reported that he had developed sleep apnea during the previous year and it had worsened over a month prior to presentation at our hospital. Otolaryngological examination did not reveal tonsillar or adenoidal hypertrophy. Polysomnography demonstrated severe central sleep apnea with an apnea-hypopnea index of 46.5/h. Sagittal T1-weighted magnetic resonance imaging (MRI) demonstrated herniation of the cerebellar tonsils 15 mm below the foramen magnum into the cervical spinal cord. Continuous positive airway pressure therapy initiated prior to performing neurosurgery was ineffective. Following uncomplicated foramen magnum decompression, his breathing pattern during sleep returned to normal. Sagittal MRI examination should be considered in patients who develop sleep apnea during/following administration of GH therapy.

Metabolic Impact of Growth Hormone Treatment in Short Children Born Small for Gestational Age

Background: Growth hormone (GH) treatment in short children born small for gestational age (SGA) may result in metabolic changes with potential long-term effects. Methods: 149 short SGA children (mean birth weight 2.0 ± 0.6 kg, age 5.5 ± 1.5 years, height standard deviation score (SDS) –3.1 ± 0.6) were randomised to: low-dose GH therapy (0.033 mg/kg/day) for 2 years; high-dose GH therapy (0.100 mg/kg/day) for 1 year, or mid-dose GH therapy (0.067 mg/kg/day) for 1 year. Leptin, ghrelin, insulin-like growth factor-I (IGF-I), IGF binding protein-1 (IGFBP-1), lipids, fasting blood glucose and fasting insulin were assessed at baseline, 12 and 24 months. Results: After 1 year of active treatment, GH significantly reduced serum ghrelin and increased IGF-I SDS and insulin levels. Regression analysis showed an inverse correlation between ghrelin and IGF-I SDS (p < 0.001). Leptin and IGFBP-1 also declined (both p < 0.05). Changes in insulin levels reversed upon discontinuation. Improvements in lipid profile were nonsignificant and fasting blood glucose levels remained within the normal range. Conclusion: In short SGA children, ghrelin and leptin reductions associated with GH treatment may occur through a negative feedback loop of the GH–IGF-I axis. Consequently, via ghrelin and leptin suppression, GH treatment may modify food intake and body composition and potentially improve long-term metabolic outcomes.

Moderate Deterioration in Glucose Tolerance during High-Dose Growth Hormone Therapy in Glucocorticoid-Treated Patients with Juvenile Idiopathic Arthritis

Objectives: To describe glucose metabolism changes during growth hormone (GH) treatment in juvenile idiopathic arthritis (JIA). Study Design: Observational study in 58 children on glucocorticoid therapy (GC) for JIA, of whom 28 received late GH therapy (7.3 ± 3.4 years into GC), 15 early GH therapy (1.2 ± 0.1 years into GC), and 15 no GH therapy. The GH dose was 0.46 mg/kg/week. Oral glucose tolerance testing with insulin and glycosylated hemoglobin assays were performed yearly. Nonparametric tests were used to compare groups after 3 years and regression analyses to estimate factors predicting glucose AUC and HOMA-IR at baseline and after 3 years. Results: GH combined with GC was associated with an increase in mean fasting insulinemia. Late GH therapy patients exhibited significant increases over time in mean fasting glycemia (p = 0.01), mean 2-hour postglucose load glycemia (p < 0.05), mean AUC for glucose (p < 0.05), and mean HOMA-IR (p < 0.05). Impaired glucose tolerance was found in 16/43 GH-treated patients (37%) and transient diabetes in 2 (5%) patients. Conclusions: GH treatment in JIA children decreased insulin sensitivity but had only modest effects on glucose tolerance. Close monitoring by oral glucose tolerance testing is crucial before and during GH treatment, particularly during puberty and relapses.

Effect of 2 years of high-dose growth hormone therapy on cognitive and psychosocial development in short children born small for gestational age

Children born small for gestational age (SGA) are not only at risk for short stature, but also for neurodevelopmental and behavioral problems. In this study, we analyzed the effects of high-dose GH therapy on cognitive development and psychosocial functioning in 34 prepubertal (3-8 years) short SGA children, equally randomized into a GH-treated group (TRG) and an untreated group (UTRG). At start and after 2 years, children underwent standardized tests measuring the intellectual abilities (Wechsler Preschool and Primary Scale of Intelligence-Revised, or Wechsler Intelligence Scale for Children-Revised); their parents completed a standardized questionnaire evaluating psychosocial functioning (Child Behavior Checklist; CBCL). At start, total IQ scores were significantly (P < 0.05) lower in the SGA group than in the general population: 32% of the SGA patients had scores below 85. After 2 years, IQ scores remained unchanged in the TRG, but increased significantly (P < 0.05) in the UTRG. After exclusion of children with developmental problems, however, no significant changes in IQ scores occurred in the UTRG as well as the TRG. At baseline, 24% (8/34) children had problematic CBCL total problems scores, equally distributed among the two groups; no significant changes in the different subscale scores occurred after 2 years. No beneficial effect of 2 years of GH therapy on cognitive and behavioral profile could be observed in a cohort of rather young short SGA children presenting a variable degree of developmental delay and behavioral problems. Subsequent follow-up could reveal potential long-term effects of GH therapy on development and behavior.

Growth hormone therapy in adults.

Growth hormone (GH) is classically linked with linear growth in childhood but continues to have important metabolic actions throughout life. GH deficiency in adulthood causes a distinct syndrome with significant morbidities. These include increased total and visceral fat, decreased muscle mass and aerobic capacity, affective disturbances, abnormal lipids, and increased vascular mortality, all of which are ameliorated with GH replacement. The possibility of adult GH deficiency (AGHD) should always be considered in individuals with a history of childhood GH deficiency or significant hypothalamic-pituitary damage, and the diagnosis should then be confirmed by biochemical testing. Adult GH dosing is much lower than that in pediatric practice, as appropriate for physiologic reconstitution. Hormonal side effects are minimized by stepwise dose titration. Lingering concerns remain regarding the possibility of increased cancer risk with long-term treatment, but this hazard has not been unequivocally demonstrated. Compared with AGHD, there is much less information about GH replacement in other diseases or in normal aging, or about the use of supraphysiologic GH doses to treat catabolic states. In critical illness, high-dose GH therapy has proven clearly harmful, and the balance of risks and benefits of GH administration in most adult contexts other than AGHD has not been defined.

Response to growth hormone therapy in experimental ischemic acute renal failure

In acute renal failure (ARF), the gene and peptide expression of insulin-like growth factor-I (IGF-I) falls. Because IGF-I is regulated by growth hormone (GH) and because kidney GH receptor expression is also attenuated in ARF, the impaired IGF-I expression may partly reflect local GH resistance. Because IGF-I treatment accelerates recovery from ARF, we determined whether high-dose GH therapy could overcome this putative GH resistance, stimulate IGF-I production, and enhance recovery. Rats with ARF were given 2.5 mg GH or vehicle (V) over 2 days, beginning 24 hours before the onset of ARF. GH prevented weight loss but did not modify the course of ARF. Next we determined whether the failure of GH to modify kidney recovery could reflect a failure to stimulate renal IGF-I gene expression. Rats were treated with GH or V over an 18-hour period beginning 1 day after the induction of ARF. Hepatic IGF-I mRNA and serum IGF-I peptide levels rose significantly with GH treatment, but the low kidney IGF-I mRNA levels did not respond. We conclude that the failure of GH to enhance recovery from ARF is caused by impaired GH-stimulated renal IGF-I production, while the maintenance of body weight likely reflects the systemic effects of the increase in hepatic IGF-I production.

Expectation bias with respect to growth hormone therapy in Turner syndrome.

More than 10 years ago, preliminary reports indicated that high-dose growth hormone therapy was beneficial in treating short stature in girls with Turner syndrome (1, 2). In previous reports, with lower doses of growth hormone and suboptimal therapeutic regimens i.e. three times weekly vs daily, and intramuscular vs subcutaneous injection, no growth promoting effect was demonstrated (3, 4). Until recently, the positive effects of growth hormone therapy were documented by increased growth velocities, improved height predictions and/or a gain in actual height, when height during therapy was compared with ‘projected height’ using Turner syndrome specific growth charts (5, 6). The positive results were viewed with cautious optimism. It was generally stated that further studies were needed to document the effects of different therapeutic regimens on bone maturation, long-term growth and final height. In several studies bone age advanced significantly more than chronological age during high-dose growth hormone therapy alone or in combination with oxandrolone or estrogens (7–9). Bone age accelerates especially at younger ages, so it is suggested that the optimal age of starting growth promoting therapies is 9 years (7). This recommendation contradicts the general observation in patients with ‘classical’ growth hormone deficiency, that an earlier start of therapy significantly improves adult height. Today, results on long-term growth and adult height are available. The results vary from study to study indicating major improvements in adult height and overt psychosocial benefit in some (9–11) or minor, insignificant height gains and little changes in the psychosocial status in other clinical trials (12, 13). It is a major disadvantage of all published studies that changes in growth velocity and adult height have been compared with historical controls only, thus not accounting for a possible normal acceleration of growth in untreated Turner syndrome patients. The presently available data are encouraging, though still controversial. Optimism still prevails and will hopefully be substantiated after all ongoing clinical trials, including the data from the two randomized clinical trials initiated in Canada (14) and the US (15), have published their final results. In addition, it is necessary to establish whether a psychosocial benefit is obtained during, at the end of, and years after therapy with or without a documented effect of growth hormone therapy on adult height. A bias in favor of the publication of positive and statistically significant results is well documented in clinical medicine (16). It should be avoided by reporting the results of all ongoing trials with growth promoting therapies in Turner syndrome. This is especially important, since concerns have been raised about bias in industry-supported clinical research, about data presented in the absence of peer review (14) and the pressure in favor of treatment exerted by parental groups. Many questions still remain, so that additional prospective and randomized clinical trials with psychosocial guidance are required to evaluate, for example, bone age development in patients and controls, to document a possible normal acceleration of growth in untreated patients, and to determine final height in treatment and control groups (17). The major determinant of randomized clinical trials is the assessment of the psychosocial well-being in treated and untreated girls with Turner syndrome. The effects should be assessed during therapy and at the time when adult height is reached. Furthermore, long-term evaluations should be performed several years after therapy, when the enthusiasm and positive reinforcement of the therapeutic intervention by physicians and parents have waned. It will be necessary to assess the importance of a ‘minor’ or ‘major’ increase in adult height during the routine of everyday adult life and with the knowledge that adult stature for many patients is still far from being ‘normal’. In the coming years we, hopefully, will be able to justify the long and expensive treatments whose potential long-term risks still remain uncertain. More than 10 years ago, large clinical trials of growth hormone therapy were started in girls with Turner syndrome. Hopefully it will not take another 10 years until randomized, prospective and controlled clinical trials are initiated to find the necessary answers to the many remaining questions.

Carbohydrate metabolism on high dose growth hormone therapy in children treated for leukaemia.

The effect on carbohydrate metabolism of a high dose growth hormone (GH) regimen (1.2 U/kg per week) was assessed on 24 children who had previously been treated for leukaemia. Sixteen patients received high dose GH and eight patients received a conventional dose of GH (0.6 U/kg per week). Oral glucose tolerance tests (OGTT) were performed at baseline and after 3 months of treatment with GH. For the entire group between 0 and 3 months, there was a significant increase in mean (and standard deviation) fasting plasma glucose (0.3 +/- 0.6 mmol/L), fasting insulin level (11 +/- 26 mU/L), and 2 h insulin level (20 +/- 40 mU/L). One patient, who received a conventional dose of GH, developed substantial carbohydrate intolerance. For the entire group, there was no change in response to a carbohydrate load at 3 months as measured by the area under the plasma glucose or insulin curve. There was no significant difference between conventional and high dose groups at 3 months as assessed by these parameters. This study demonstrates that a higher dose of GH may be used in these children in an attempt to improve their final height, without increased risk of carbohydrate intolerance in the short term.

Acquired refractoriness to growth hormone in a patient with isolated growth hormone deficiency: Growth and plasma somatomedin-C response to high-dose growth hormone therapy

Acquired refractoriness to growth hormone in a patient with isolated growth hormone deficiency: Growth and plasma somatomedin-C response to high-dose growth hormone therapy