Insulin sensitivity in adults with growth hormone deficiency and effect of growth hormone treatment

Adult growth hormone deficiency (GHD) is a multifactorial disorder in which pituitary dysfunction associated with pituitary adenomas or their treatment plays a major role. The introduction of recombinant growth hormone (GH) for the treatment of GHD has opened up new treatment avenues but has also raised concerns about possible untoward long-term metabolic effects of GH, such as the potential effect of GH on insulin sensitivity and a deterioration in glucose tolerance. Research has shown that GH induces insulin resistance by the stimulation of lipolysis and a concomitant switch from oxidation of glucose to oxidation of lipids, during both acute and chronic treatment. However, although this is a consistent effect of GH therapy, it does not mean per se that it leads to abnormal glucose tolerance and diabetes mellitus. This article discusses this and other potential long-term metabolic effects of GH, and raises a number of questions to be addressed by future research.     

Non-compliance with growth hormone treatment in children is common and impairs linear growth

Background

GH therapy requires daily injections over many years and compliance can be difficult to sustain. As growth hormone (GH) is expensive, non-compliance is likely to lead to suboptimal growth, at considerable cost. Thus, we aimed to assess the compliance rate of children and adolescents with GH treatment in New Zealand.

Methods

This was a national survey of GH compliance, in which all children receiving government-funded GH for a four-month interval were included. Compliance was defined as ≥85% adherence (no more than one missed dose a week on average) to prescribed treatment. Compliance was determined based on two parameters: either the number of GH vials requested (GHreq) by the family or the number of empty GH vials returned (GHret). Data are presented as mean ± SEM.

Findings

177 patients were receiving GH in the study period, aged 12.1±0.6 years. The rate of returned vials, but not number of vials requested, was positively associated with HVSDS (p<0.05), such that patients with good compliance had significantly greater linear growth over the study period (p<0.05). GHret was therefore used for subsequent analyses. 66% of patients were non-compliant, and this outcome was not affected by sex, age or clinical diagnosis. However, Maori ethnicity was associated with a lower rate of compliance.

Interpretation

An objective assessment of compliance such as returned vials is much more reliable than compliance based on parental or patient based information. Non-compliance with GH treatment is common, and associated with reduced linear growth. Non-compliance should be considered in all patients with apparently suboptimal response to GH treatment.     

Comparative effect of galanin and pyridostigmine on the growth hormone response to growth hormone-releasing hormone in normal aged subjects.

The aim of our study was to investigate the effects of aging on the growth hormone (GH) response to growth hormone-releasing hormone (GHRH) alone and in combination with either the neuropeptide galanin or the acetylcholinesterase inhibitor pyridostigmine (PD) in normal subjects. In protocol 1 (GHRH/galanin), 9 old healthy volunteers, ranging in age from 68 to 97 years, and 6 young subjects, ranging in age from 25 to 31 years, received: (a) human GHRH (1-29)NH2, 100 micrograms in 1 ml saline, as an intravenous bolus, and (b) porcine galanin, 500 micrograms in 100 ml saline, as an intravenous infusion from -10 to 30 min combined with GHRH, 100 micrograms i.v. at time 0. In protocol 2 (GHRH/PD), 14 old healthy volunteers, ranging in age from 65 to 91 years, and 11 young subjects, ranging in age from 19 to 34 years, received: (a) GHRH (1-29)NH2, 100 micrograms in 1 ml saline, as an intravenous bolus, and (b) PD, 120 mg administered per os 60 min before GHRH, 100 micrograms as an intravenous bolus. Blood samples for GH were drawn at -75, -60 (time of PD administration), -45, -30, -15, -10 (time of beginning of galanin infusion), 0 (time of GHRH injection), 15, 30, 45, 60, 90, and 120 min. The GH response to GHRH was significantly (< 0.05) enhanced either by galanin or PD pretreatment both in young and old subjects. However, the GH response to GHRH alone or combined with either galanin or PD was significantly greater in the young subjects as compared to the old subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of chronic clonidine treatment on urinary growth hormone excretion and linear growth in children with short stature

Eleven prepubertal children with short stature were treated with clonidine (0.15 mg/m2 daily) for a period of 1 year. The effect of this drug was evaluated on both clinical (growth velocity, height standard deviation scores for chronological age and bone age) and hormonal (urinary growth hormone excretion and insulin-like growth factor I) parameters. Our study shows that long-term clonidine administration in children with short stature did not result in significant differences in growth velocity, height standard deviation scores for chronological age and bone age, insulin-like growth factor I or in urinary growth hormone excretion.     

Low-dose growth hormone treatment with diet restriction accelerates body fat loss, exerts anabolic effect and improves growth hormone secretory dysfunction in obese adults.

Growth hormone (GH) can induce an accelerated lipolysis. Impaired secretion of GH in obesity results in the consequent loss of the lipolytic effect of GH. Dietary restriction as a basic treatment for obesity is complicated by poor compliance, protein catabolism, and slow rates or weight loss. GH has an anabolic effect by increasing insulin-like growth factor (IGF)-I. We investigated the effects of GH treatment and dietary restriction on lipolytic and anabolic actions, as well as the consequent changes in insulin and GH secretion in obesity. 24 obese subjects (22 women and 2 men; 22-46 years old) were fed a diet of 25 kcal/kg ideal body weight (IBW) with 1.2 g protein/kg IBW daily and were treated with recombinant human GH (n = 12, 0.18 U/kg IBW/week) or placebo (n = 12, vehicle injection) in a 12-week randomized, double-blind and placebo-controlled trial. GH treatment caused a 1.6-fold increase in the fraction of body weight lost as fat and a greater loss of visceral fat area than placebo treatment (35.3 vs. 28.5%, p < 0.05). In the placebo group, there was a loss in lean body mass (-2.62 +/- 1.51 kg) and a negative nitrogen balance (-4.52 +/- 3.51 g/day). By contrast, the GH group increased in lean body mass (1.13 +/- 1.04 kg) and had a positive nitrogen balance (1.81 +/- 2.06 g/day). GH injections caused a 1.6-fold increase in IGF-I, despite caloric restriction. GH response to L-dopa stimulation was blunted in all subjects and it was increased after treatment in both groups. GH treatment did not induce a further increase in insulin levels during an oral glucose tolerance test (OGTT) but significantly decreased free fatty acid (FFA) levels during OGTT. The decrease in FFA area under the curve during OGTT was positively correlated with visceral fat loss. This study demonstrates that in obese subjects given a hypocaloric diet, GH accelerates body fat loss, exerts anabolic effects and improves GH secretion. These findings suggest a possible therapeutic role of low-dose GH with caloric restriction for obesity.     

Effects of discontinuation of growth hormone treatment on body composition and metabolism

This study was directed to the investigation of two different aspects of growth hormone: What are the metabolic consequences following the discontinuation of treatment and are these metabolic effects correlated with the growth-promoting effects seen in the first year of treatment? The study was performed on 12 growth hormone-deficient (GHD) patients who reached their final height. Each patient was matched with a non-GHD person of the same sex and about the same age. Immediately after the discontinuation of treatment, and 6 weeks and 6 months later, the following anthropometric variables were assessed: height, weight, skinfold thicknesses (biceps, triceps, subscapular and suprailiacal), body volume (underwater weighing) and total body water (deuterium dilution). To describe energy metabolism, basal metabolic rate assessed by ventilated hood, and sleep metabolic rate assessed by respiration chamber, were studied. Body composition was calculated from weight, volume and total body water. Clear metabolic effects were found after the discontinuation of treatment in GHD children: there was a decrease in fat free mass and sleep metabolic rate. Also, a strong correlation between the above-mentioned effects and the growth-promoting effects of human growth hormone at the beginning of the treatment was observed. The fact that this correlation exists poses the interesting question of whether the results from a test treatment lasting some weeks could be used to predict the long-term effects of hGH.     

The effect of growth hormone therapy on craniofacial growth and dental maturity in children with Down syndrome.

Craniofacial growth was evaluated 3 years after termination of growth hormone (GH) therapy in ten Down syndrome (DS) children. The control group consisted of 16 age-matched children with DS. The treatment started at 6-9 months of age, and the duration was 36 months. There were no statistically significant differences in craniofacial development between DS children treated with GH or DS children not treated. In conclusion, the results of this study indicate that GH therapy for 36 months in children with DS did not change the craniofacial morphology compared to a group of DS children not given GH.     

Leu-enkephalin-stimulated growth hormone and prolactin release in the rat: comparison with the effect of morphine

The effect of Leu⁵-enkephalin on growth hormone (GH) and prolactin (PRL) release was studied $\text{in vivo}$ in the infant rat and compared to that of morphine. In 10 day-old pups, intracerebroventricular injection of Leu⁵-enkephalin (50, 75 and 100 μg) resulted in a dose-related increase in plasma GH; morphine was active as GH releaser at the dose of 5 and 10 μg, but not at 2.5 μg. Pretreatment with naloxone (2 mg/kg ip) suppressed the GH-releasing effect of either Leu⁵-enkephalin (100 μg) or morphine (10 μg). Leu⁵-enkephalin (75 and 100 μg) induced a rise in plasma PRL which was neither dose-related nor antagonized by naloxone; morphine (5 and 10 μg) was active as PRL releaser and its effect was antagonized by naloxone. These results indicate that: 1) Leu⁵-enkephalin stimulates both GH and PRL release; 2) the release of GH by Leu⁵-enkephalin but likely not that of PRL involves specific opiate receptors; 3) morphine releases GH and PRL through specific opiate receptors.     

Combination of angiopoietin-1 and vascular endothelial growth factor gene therapy enhances arteriogenesis in the ischemic myocardium

We hypothesised that angiopoietin-1 (Ang-1), in conjunction with vascular endothelial growth factor (VEGF) gene therapy, can enhance arteriogenesis and angiogenesis during myocardial ischemia. Mice were given a single intramyocardial injection of saline, phVEGF-A(165) and phAng-1 or a combination thereof into the non-ischemic normal heart or into the ischemic border zone of the infarcted heart. In the normal and the ischemic myocardium, gene transfer of phVEGF-A(165) alone increased the myocardial capillary density by 16% and 36%, respectively, and phAng-1 had a similar effect. In the normal heart, the ratio of arteriolar to capillary densities increased with phVEGF-A(165) and more so in the ischemic myocardium where phAng-1 also had an effect. Furthermore, the combination of plasmids induced an up to 7.5-fold increase. Transient overexpression of VEGF-A(165) boosts endogenous arteriogenesis in addition to capillary angiogenesis. Ang-1 further boosts this effect at the arteriolar level.     

Modification of bone formation rate by growth hormone, melanocyte-stimulating hormone, and cortisone in the normal rat

Bone growth and remodelling was studied in rats after injection of growth hormone, melanocyte-stimulating hormone (alpha-MSH), and cortisone daily for 20 days with tetracycline as intravital marker. An increase of both longitudinal and periosteal growth with growth hormone was found. A decrease of both was found after a high cortisone dose. Lower cortisone doses seem to have stimulated periosteal growth. No effect of alpha-MSH was found.     

Exercise-induced stress enhances mammary tumor growth in rats: beneficial effect of the hormone melatonin

We hypothesized that intense exercise training (forced swimming for 30 min, 5 days/week) may enhance the progression of mammary carcinogenesis through the involvement of stress hormones, such as catecholamines and prolactin, which can promote breast cancer. After the appearance of the DMBA-induced tumors in Sprague-Dawley rats, the effect was evaluated of exercise-induced stress (with or without administration of the hormone melatonin) on the survival time, tumor multiplicity, and tumor growth until the death of the animals. In a second set of experiments, after one month of exercise, the NK cells count in blood, and the plasma concentrations of catecholamines and prolactin were determined. Although no significant change was found in either the survival time of the rats or the tumor multiplicity, exercise significantly increased the tumor growth rate. Stress was confirmed by the enhanced adrenaline and prolactin concentrations in the blood of the exercised rats. Exercise-induced stress did not change the percentage of NK cells in the tumor-bearing rats. Melatonin counteracted the increased tumor growth, returning the prolactin and adrenaline concentrations to their optimal physiological levels in the exercised tumor-bearing rats, thus confirming an “anti-stress” role of this hormone. In conclusion, intense exercise-induced stress enhances mammary carcinogenesis through the involvement of adrenaline and prolactin. The results also confirmed a role of melatonin as a therapeutic aid against breast cancer in general, and in particular during situations of stress.     

Transforming growth factor-beta enhances the extent of intercellular communication between normal rat kidney cells

Normal rat kidney (NRK) cells cultured in the presence of epidermal growth factor are contact-inhibited at confluent densities. In the additional presence of transforming growth factor (TGF)-beta, however, cells undergo phenotypic transformation which is accompanied by a loss of contact inhibition. In this study, we show by means of the fluorescence photobleaching recovery technique and a scrape-loading dye transfer technique that quiescent confluent cultures of NRK cells do not show extensive gap junction-mediated intercellular communication. Cells contact-inhibited in the presence of epidermal growth factor also show only limited intercellular communication, although with an enhanced permeability coefficient. Cells phenotypically transformed upon addition of TGF beta, however, show extensive intercellular communication, with a similarly enhanced permeability coefficient. This enhanced intercellular communication induced by TGF beta is paralleled by an increase in intracellular pH. It is concluded that in contrast to what has been observed during tumorigenic transformation, phenotypic transformation of NRK cells induced by TGF beta results in an enhancement of the extent of gap junction-mediated intercellular communication.     

The effect of hypophysectomy and growth hormone replacement on albumin synthesis and catabolism in the rat

Albumin synthesis and catabolism were respectively measured by McFarlane's (1963) sodium [(14)C]carbonate method and I-labelled albumin in hypophysectomized rats, both untreated and treated with growth hormone. Hypophysectomy resulted in a decrease in both albumin synthesis and catabolic rates. These changes as shown by pair-feeding experiments could not be ascribed to decreased food intake alone. Growth hormone was shown to partially restore both albumin synthesis and catabolic rates. It is proposed that growth hormone stimulates albumin synthesis and that its effect on albumin catabolism is secondary to changes in the mass of the intravascular albumin pool.     

Effect of neonatal hypoxia on leptin, insulin, growth hormone and body composition in the rat.

The purpose of the present study was to evaluate the effect of exposure to hypoxia from birth to 7 days of age on leptin, insulin, growth hormone (GH), insulin-like growth factor-1 (IGF-1), glucose, corticosterone, body weight, and body composition in rats studied at 7 days of age and then after return to normoxia. Hypoxia for the first 7 days of life resulted in a significant decrease in plasma leptin, body weight, and an increase in corticosterone and insulin with no change in plasma glucose, GH or IGF-1. There was no significant effect of hypoxia on % lean body mass, but a small but significant increase in % body fat. Bone mineral density (BMD) was lower in 7-day-old hypoxic rats as compared to normoxic controls. All hormonal variables and BMD had normalized by 7 days after return to normoxia. However, body weight remained lower even 5 weeks after return to normoxia. We conclude that leptin is decreased during neonatal hypoxia despite no change in adiposity. Furthermore, insulin is increased probably to overcome the effects of increased counterregulatory hormones (such as corticosterone).