Growth hormone hypersecretion in a girl with neurofibromatosis type 1 and an optic nerve glioma: resolution following chemotherapy

Growth hormone hypersecretion is extremely rare in childhood. We report a girl with neurofibromatosis type 1, an extensive optic nerve glioma and growth hormone hypersecretion. She was treated with chemotherapy to prevent further extension of her sight-threatening tumour. Three years after chemotherapy her growth hormone hypersecretion has resolved although she has gone on to develop precocious puberty.     

Growth hormone and aging

In elderly people, vascular alterations and degenerative alterations of the Central Nervous System (CNS) are two of the most common reasons for illness and death. Lipid pattern modifications and menopause in women are some of the causes for the appearance of these alterations. Vascular endothelium is in part responsible for vascular homeostasis, through the production of several vasoactive factors. Growth hormone (GH) exerts effects on the CNS and on the vascular endothelium, since GH deficient subjects exhibit endothelium-dependent alterations, which recover under substitutive GH treatment. Growth hormone has important actions on lipid metabolism that also play a role on vascular and endothelial function. Moreover, cardiac function improves when GH is associated to angiotensin II receptor blockers. Elderly people exhibit a physiological GH deficiency that could affect their vascular and cerebral functions. A study was carried out using old Wistar rats to clarify the effects of GH on the vessels under chronic «in vivo» conditions. The response to various vasoactive substances in aortic rings has been evaluated. An increase in the aortic media thickness was seen in old rats, which showed also a reduction in the vasodilator response to isoprenaline as compared to young animals. GH treatment partially restored the vasodilator response and reduced media thickness. Neuronal population was reduced in the hypocampus of old rats as compared to young ones and GH treatment was able to significantly enhance the number. Neurotransmitters were measured in several cerebral areas to establish differences between young and old GH-treated or untreated animals. Glutamine, Arginine and Aspartate were reduced in old animals whereas Citruline was increased. GH treatment restored in all cases the levels corresponding to young rats.     

Growth hormone and fluid retention

A major side effect of growth hormone (GH) administration is fluid retention. Most data indicate that adult GH-deficient patients are dehydrated, i.e. they have low total body water, low extracellular water and low plasma volume. When GH substitution is initiated in these patients their body fluid compartments are restored to normal. The fluid retaining capacity of GH should therefore be regarded as a desirable physiological normalization of fluid homeostasis rather than an unpleasant side effect.     

Growth hormone and glucose homeostasis

Patients with active acromegaly are insulin-resistant and glucose-intolerant, whereas children with growth hormone (GH) deficiency (GHD) are insulin-sensitive and may develop fasting hypoglycaemia. Surprisingly, however, hypopituitary adults with unsubstituted GHD tend to be insulin-resistant, which may worsen during GH substitution. During fasting, which may be considered the natural domain for the metabolic effects of GH, the induction of insulin resistance by GH is associated with enhanced lipid oxidation and protein conservation. In this particular context, insulin resistance appears to constitute a favourable metabolic adaptation. The problem is that GH substitution results in elevated circadian GH levels in non-fasting patients. The best way to address this challenge is to employ evening administration of GH and to tailor the dose. Insulin therapy may cause hypoglycaemia and GH substitution may cause hyperglycaemia. Such untoward effects should be minimized by carefully monitoring the individual patient.     

Growth hormone and bone health

Growth hormone (GH) and insulin-like growth factor-I have major effects on growth plate chondrocytes and all bone cells. Untreated childhood-onset GH deficiency (GHD) markedly impairs linear growth as well as three-dimensional bone size. Adult peak bone mass is therefore about 50% that of adults with normal height. This is mainly an effect on bone volume, whereas true bone mineral density (BMD; g/cm(3)) is virtually normal, as demonstrated in a large cohort of untreated Russian adults with childhood-onset GHD. The prevalence of fractures in these untreated childhood-onset GHD adults was, however, markedly and significantly increased in comparison with normal Russian adults. This clearly indicates that bone mass and bone size matter more than true bone density. Adequate treatment with GH can largely correct bone size and in several studies also bone mass, but it usually requires more than 5 years of continuous treatment. Adult-onset GHD decreases bone turnover and results in a mild deficit, generally between -0.5 and -1.0 z-score, in bone mineral content and BMD of the lumbar spine, radius and femoral neck. Cross-sectional surveys and the KIMS data suggest an increased incidence of fractures. GH replacement therapy increases bone turnover. The three controlled studies with follow-up periods of 18 and 24 months demonstrated a modest increase in BMD of the lumbar spine and femoral neck in male adults with adult-onset GHD, whereas no significant changes in BMD were observed in women. GHD, whether childhood- or adult-onset, impairs bone mass and strength. Appropriate substitution therapy can largely correct these deficiencies if given over a prolonged period. GH therapy for other bone disorders not associated with primary GHD needs further study but may well be beneficial because of its positive effects on the bone remodelling cycle.     

Growth hormone and tumour recurrence.

OBJECTIVE--To determine whether using growth hormone to treat radiation induced growth hormone deficiency causes tumour recurrence. DESIGN--Comparison of tumour recurrence rates in children treated with growth hormone for radiation induced deficiency and an untreated population. Computed tomograms from children with brain tumours were reviewed when starting growth hormone and subsequently. SETTING--North West region. PATIENTS--207 children treated for brain tumour, 47 of whom received growth hormone and 161 children with acute lymphoblastic leukaemia 15 of whom received growth hormone. MAIN OUTCOME MEASURES--Tumour recurrence and changes in appearances on computed tomography. RESULTS--Among children with brain tumour, five (11%) who received growth hormone had recurrences compared with 42 (26%) who did not receive growth hormone. Also adjusting for other variables that might affect tumour recurrence the estimated relative risk of recurrence was 0.82 (95% confidence interval 0.28 to 2.37). The only child with acute lymphoblastic leukaemia who relapsed while taking growth hormone had relapsed previously before starting treatment. Two of the five children with brain tumours who relapsed had abnormal appearances on computed tomography when growth hormone was started. 14 other children who remained relapse free and had follow up computed tomography showed no deterioration in radiological appearance during treatment. CONCLUSIONS--In this population growth hormone did not increase the risk of tumour recurrence but continued surveillance is essential. Abnormal results on computed tomography are not a contraindication to treatment with growth hormone.     

Growth hormone therapy in achondroplasia

Achondroplasia is one of the most common causes of severe rhizomelic dwarfism. We have previously reported the growth-promoting effect of growth hormone (GH) in this disorder. In this expanded clinical study, dose dependency and the long-term effect of GH were also investigated. Prepubertal children with achondroplasia (82 males and 63 females) were randomly divided into 2 groups. Patients were treated with 0.5 IU/kg per week or 1.0 IU/kg per week subcutaneous recombinant human GH. Of 75 patients, the mutational analysis of fibroblast growth factor receptor-3 revealed that G1138A was detected in 70 and G1138C was found in 2. GH increased growth rate and height z score in a dose-dependent manner. GH also increased serum insulin-like growth factor (IGF)-I, IGF-binding protein-3 and osteocalcin. No adverse effects were observed in either group. We conclude that GH therapy is a useful method for improvement of severe growth retardation of achondroplasia.     

Growth hormone regulation of growth hormone-releasing hormone gene expression

Slot-blot hybridization technique was used to evaluate growth hormone-releasing hormone (GHRH) mRNA levels in the hypothalamus of long-term (14 days) hypophysectomized (HPX) rats treated or not with 125 micrograms hGH/rat, twice daily IP, since the first day postsurgery. In addition, mRNA levels were determined in the hypothalamus of short-term (4 days) GH-treated (250 micrograms hGH/rat, twice daily IP) intact rats. GHRH mRNA levels were increased in HPX rats, and GH treatment partially counteracted this rise. Short-term administration of GH decreased GHRH mRNA levels in intact rats. These results, evaluated together with previous findings showing decreased hypothalamic GHRH-like immunoreactivity in both HPX rats and intact rats given GH (6, 7, 9), indicate that GH exerts a negative feedback action on the synthesis and release of GHRH.     

Growth hormone and carbohydrate intolerance in cirrhosis

Patients with cirrhosis of the liver often have insulin resistance and elevated circulating growth hormone levels. This study was undertaken (a) to evaluate glucose intolerance, insulin resistance and abnormal growth hormone secretion and (b) to determine if GH suppression improves insulin resistance. Glucose tolerance tests (GTT), intravenous insulin tolerance tests (IVITT), arginine stimulation tests (AST) and glucose clamp studies before and during GH suppression with somatostatin were performed in a group of patients with alcohol-induced liver cirrhosis. During GTT cirrhotic subjects had a 2-hour plasma glucose of 200 +/- 9.8 ng/dl (N = 14) compared to 128 +/- 8.0 ng/dl in normal controls (N = 15), P less than 0.001. Basal GH was elevated in cirrhotic patients and in response to arginine stimulation reached a peak of 17.0 +/- 5.4 ng/ml (N = 7), compared to a peak of 11.3 +/- 1.8 ng/ml in 5 normal controls (P = NS). During IVITT patients with cirrhosis had a glucose nadir of 60.0 +/- 4.0 mg/dl (N = 9), compared to 29.0 +/- 7.0 mg/dl in controls (N = 5), P less than 0.001. Peak GH levels during IVITT were not significantly different in cirrhotics and controls. Glucose utilization rates in 4 patients with cirrhosis of the liver before somatostatin mediated GH suppression was 3.1 +/- 0.5 mg/kg/min and 6.5 +/- 1.5 mg/kg/min during somatostatin infusion, P less than 0.025. We conclude that patients with alcohol induced cirrhosis have sustained GH elevations resulting in insulin resistance which improves after GH suppression.