High-dose Growth Hormone Treatment Research Articles

Efficacy and safety of long-acting growth hormone in children with short stature: a systematic review and meta-analysis.

Long-acting growth hormone (GH) has been developed to address the noncompliance and decreased efficacy associated with daily GH injections. We aimed to evaluate the efficacy and safety of long-acting GH replacement therapy in children with short stature. Randomized controlled trials (RCTs) that investigated the efficacy and safety of long-acting GH therapy in children with short stature in comparison with daily GH injections were searched in Medline, Embase, and the Cochrane Central Register of Controlled Trials. A random-effect model was used to pool data using mean difference and odds ratios (OR). (PROSPERO registration number: CRD42018111105). Seven relevant studies were finally included. Meta-analysis found there was no significant difference between high-dose long-acting GH and daily GH in terms of height velocity (HV) (mean difference (MD) = -0.10, 95% CI, -0.79 to 0.60, P = 0.79). Moreover, no significant difference was observed in height standard deviation scores (Ht SDS) between high-dose long-acting GH and daily GH (MD = -0.07, 95% CI, -0.18 to 0.03, P = 0.17). Treatment with high-dose long-acting GH significantly increased IGF-1 SDS when compared with daily GH (MD = 0.31, 95% CI, 0.06-0.56, P = 0.02). In safety assessment, no significant difference was observed in the incidence of adverse events between high-dose long-acting GH and daily GH (OR 1.42, 95% CI, 0.65-3.11, P = 0.38). There is no evidence to support differences in the effects of long-acting GH compared with those of daily GH. More RCTs that focus on the safety of high-dose long-acting GH treatment, especially the detection of adverse events caused by elevated levels of serum IGF-1, are needed in the future.

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.

Insulin Sensitivity Modulates the Growth Response during the First Year of High-Dose Growth Hormone Treatment in Short Prepubertal Children Born Small for Gestational Age

Aim: To study the relationship between insulin sensitivity and growth response in short children born small for gestational age (SGA) treated with growth hormone (GH). Methods: Randomized, open-label, 24-month intervention study in 40 short prepubertal SGA children [age (mean ± SD) 5.3 ± 1.5 years], who either remained untreated (n = 20) or were treated with GH (66 µg/kg/day; n = 20). Changes in fasting glucose, insulin, quantitative insulin sensitivity check index (QUICKI), IGF-1 and leptin after 1 and 2 years were studied. Results: Mean height SDS increased from –3.3 ± 0.7 to –2.3 ± 0.7 after 1 year, and to –1.9 ± 0.7 after 2 years of treatment. QUICKI decreased significantly (p = 0.008) in the first year of GH treatment and stabilized in the second year. Baseline QUICKI was positively associated (r = 0.40; p < 0.05) with the change in height SDS in the first year. Conclusion: Higher insulin sensitivity at the start of GH therapy is associated with greater first-year growth response to GH, and could be a promising parameter in selecting prepubertal short SGA children for GH treatment. However, this finding needs to be confirmed in larger studies.

Improved insulin sensitivity, preserved beta cell function and improved whole-body glucose metabolism after low-dose growth hormone replacement therapy in adults with severe growth hormone deficiency: a pilot study

Growth hormone-deficient patients show deterioration of insulin sensitivity and beta cell function. High-dose growth hormone treatment often induces further impairment of insulin sensitivity, leading to an increase in insulin and glucose levels or even, in cases of preexisting beta cell defect, to overt diabetes. However, low-dose treatment may improve insulin sensitivity, although data in humans with detailed metabolic phenotyping are as yet not available. We postulated that long-term low-dose growth hormone replacement, restoring IGF-1 to the low-normal range, might beneficially affect glucose metabolism. We studied prospectively the metabolic responses to 24 and 48 weeks of growth hormone treatment in a small group of six adults with severe growth hormone deficiency (four men, two women; age 40-59 years; BMI 30.2 +/- 1 kg/m(2); mean growth hormone dose 0.3 +/- 0.04 mg/day). All participants underwent an oral glucose tolerance test, euglycaemic-hyperinsulinaemic clamp and hyperglycaemic-hyperinsulinaemic clamp plus i.v. L: -arginine on three occasions. Insulin sensitivity was measured by calculating the M value during the steady state of the euglycaemic-hyperinsulinaemic clamp. Insulin secretion and clearance were estimated from AUC(C-peptide), AUC(insulin) and their ratio at each phase of the hyperglycaemic-hyperinsulinaemic clamp. Growth hormone significantly improved insulin sensitivity (M value 13.8 +/- 2.6 [baseline] vs 19.6 +/- 2.6 [24 weeks] and 23.7 +/- 1.9 [48 weeks] micromol kg(-1) min(-1); p < 0.01). Although the insulin response to glucose and arginine decreased slightly, the disposition index, integrating insulin sensitivity and secretion, significantly increased (p < 0.01), indicating an improvement in whole-body glucose metabolism. Insulin clearance was not affected during treatment (p > 0.05). Our data indicate that long-term low-dose growth hormone treatment may improve insulin sensitivity and whole-body glucose metabolism in adults with severe growth hormone-deficiency.

Concerns, Expectations and Perception Regarding Stature, Physical Appearance and Psychosocial Functioning before and during High-Dose Growth Hormone Treatment of Short Pre-pubertal Children Born Small for Gestational Age

Background/Aims: Few data are available about parental concerns and psychosocial functioning of young children born small for gestational age (SGA) treated with growth hormone (GH). The present study focused on the perception of short stature and the concerns and expectations of the parents regarding GH treatment. Methods: Forty prepubertal short SGA children, randomized into a GH-treated and a GH-untreated group, and their parents were evaluated by a questionnaire and a semi-structured interview at start and after 2 years of follow-up. Results: Before start, 85% of the parents were concerned about short stature, 76% expected an increase in adult height of ≧10 cm and 81% expected a positive impact on well-being. Half of the parents expressed fears regarding GH treatment. After 2 years, more parents of treated children reported obvious growth and physical changes, and fewer parents reported teasing because of short stature. An improvement of well-being was reported by half of the parents of treated and untreated children. Fears about GH treatment disappeared almost completely. Conclusion: The perspective of GH treatment induced major adult height expectations. In treated children, the physical effects of GH treatment became obvious, teasing because of short stature decreased and initial concerns about short stature and GH therapy decreased.

High Serum Levels of Growth Hormone (GH) and Insulin-Like Growth Factor-I (IGF-I) during High-Dose GH Treatment in Short Children Born Small for Gestational Age

Epidemiological studies have indicated that high serum levels of GH and IGF-I are associated with long-term risks. The objective of the study was to evaluate the changes in serum levels of GH during overnight profiles, IGF-I, and IGF binding protein 3 (IGFBP-3) in short small for gestational age (SGA) children during GH treatment with two doses. Thirty-six prepubertal short SGA children were the subjects of this study. Subjects received 1 (group A) or 2 (group B) mg GH/m(2).d. At baseline and after 6 months of GH treatment, overnight GH profiles were performed, and serum IGF-I and IGFBP-3 levels were measured. After 6 months, group B had significantly higher GH levels during the profile (mean, maximum, and area under the curve above zero line) than group A (P < 0.009). In group B, maximum GH levels increased from 43.9-161 mU/liter (P < 0.0002), and in group A, from 57.2-104 mU/liter (P = 0.002). During the profile (i.e. 12 h per day), children of group B had mean GH levels of 64.4 vs. 34.8 mU/liter in group A (P = 0.001). The IGF-I and IGF-I to IGFBP-3 ratio sd scores increased significantly in both groups, but were higher in group B than A [1.5 vs. 0.2 (P = 0.002) and 1.4 vs. 0.3 (P = 0.007), respectively]. In group B, 74% of the children had IGF-I levels in the highest quintile during GH treatment compared with 19% in group A. Our study shows that high-dose GH treatment in short SGA children results in high serum GH and IGF-I levels in most children. We recommend monitoring IGF-I levels during GH therapy to ensure that these remain within the normal range.

High dose growth hormone treatment induces acceleration of skeletal maturation and an earlier onset of puberty in children with idiopathic short stature

Background: Long term growth hormone (GH) treatment in children with idiopathic short stature (ISS) results in a relatively small mean gain in final height of 3–9 cm, which may not...

Effects of Growth Hormone Treatment on Left Ventricular Dimensions in Children with Noonan’s Syndrome

Objective: To study the effects of long-term growth hormone (GH) treatment on left ventricular (LV) dimensions in children with Noonan’s syndrome (NS). Methods: Echocardiographic measurements of LV dimensions were performed before and during GH treatment in 27 participants (21 boys, 6 girls) in a partly controlled 3-year trial of high-dose GH treatment (0.15 IU/kg/day). Nineteen children had a congenital heart defect, 1 of them had hypertrophic obstructive cardiomyopathy. In the first 3 years, the children were assigned to 1 of 2 groups: group A with discontinuation of GH treatment in the 3rd year, or group B without GH treatment in the 1st year. After the 3rd year, 12 of the 27 children were followed up for 2 additional years to evaluate the long-term effects of GH treatment on the heart. Results: At baseline, LV internal diameters were smaller, while posterior wall thickness were thicker than normal. Over the 1st year, changes in LV dimensions were comparable between the 2 groups. No significant differences were found in LV dimensions between the situation at baseline and after 4 years of GH treatment. Conclusion: Long-term high-dose GH treatment does not have clinically significant adverse effects on LV dimensions in children with NS.

Potential atherogenic effects of short-term high dose growth hormone treatment in the rat model

Potential atherogenic effects of short-term high dose growth hormone treatment in the rat model

Growth-Promoting and Psychological Effects of High-Dose Growth Hormone Treatment in Children with Intrauterine Growth Retardation.

Growth-Promoting and Psychological Effects of High-Dose Growth Hormone Treatment in Children with Intrauterine Growth Retardation.

Serum Leptin in Short Children Born Small for Gestational Age: Dose-Dependent Effect of Growth Hormone Treatment

Objective: To study the effects of different regimens of growth hormone (GH) treatment on serum leptin levels in 78 short prepubertal children born small for gestational age (SGA). Methods: The children were originally included in two independent multicenter trials, one in Belgium and one in the Nordic countries. SGA children were randomized either to remain untreated or to be treated with GH at a daily dose of 0.1, 0.2 or 0.3 IU/kg for 2 years. Thereafter, treatment was continued for another 2 years in the Nordic children, whereas it was discontinued in the Belgian children. Results: In the GH treatment groups, a significant dose-dependent decrease in leptin levels was found during the first year of therapy, with a mean decrease of 13, 23 and 32% in the groups receiving GH at 0.1, 0.2 and 0.3 IU/kg, respectively. When high-dose treatment was interrupted, serum leptin increased within 1 year to pretreatment levels. Conclusion: Serum leptin levels in short children born SGA are transiently reduced by GH treatment in a dose-dependent fashion. The most pronounced changes in serum leptin were documented within the first year after initiation and withdrawal of high-dose GH treatment.

Early, Discontinuous, High Dose Growth Hormone Treatment to Normalize Height and Weight of Short Children Born Small for Gestational Age: Results Over 6 Years

Early, Discontinuous, High Dose Growth Hormone Treatment to Normalize Height and Weight of Short Children Born Small for Gestational Age: Results Over 6 Years

Early, Discontinuous, High Dose Growth Hormone Treatment to Normalize Height and Weight of Short Children Born Small for Gestational Age: Results Over 6 Years

Most children born small for gestational age (SGA) normalize their size through spontaneous catch-up growth within the first 2 yr after birth. Some SGA children fail to do so and maintain an abnormally short stature throughout childhood. We have previously reported that high dose GH treatment (66 or 100 microg/kg x day s.c. over 2 yr; age at start, 2-8 yr; n = 38) induces pronounced catch-up growth in short children born SGA, thereby normalizing their height and weight in childhood. Here, we report on the further prepubertal growth course of these children over the first 4 yr after withdrawal of early, high dose GH treatment. Of the 38 treated children, none developed precocious puberty, and 22 remained prepubertal. Mean age of the latter at start of GH was 4.4 yr, height was -3.7 SD score, and height after adjustment for midparental height was -2.9 SD score. Height increased by an average of 2.5 SD during the 2 yr of GH treatment and decreased by 0.4 and 0.3 SD, respectively, during the first and second year after GH withdrawal. Subsequently, when stature was not extremely short at the start (mean adjusted height SD score, -2.7; n = 13), no further GH treatment was given, and the adjusted height was stabilized around -1.0 SD score; when stature was very short at the start (mean adjusted height, -3.3 SD score; n = 9), a second course of GH treatment (66 microg/kg x day s.c.) was initiated either 2 yr (n = 5) or 3 yr (n = 4) after initial GH withdrawal. This second course was associated with renewed catch-up growth and also resulted in a mean adjusted height of -1.0 SD score. In each subgroup, the pattern of the weight course paralleled that of the height course; GH treatment was well tolerated. In conclusion, early, discontinuous, high dose GH treatment appears to be a safe and efficient option to normalize prepubertal height and weight in the majority of short SGA children. It remains to be examined whether the normalized stature will be maintained during pubertal development, either with or without further GH treatment.

Pharmacokinetics and metabolic effects of high-dose growth hormone administration in healthy adult men.

To evaluate pharmacokinetics of growth hormone (GH) and its effects on IGF-I, glucose, insulin, nonesterified fatty acid (NEFA) and triglyceride (TG), fifteen Japanese healthy adult male volunteers (20-27 years old) were studied. The subjects were divided into three groups, and received with a single s.c. injection of 0.075, 0.15 and 0.30 IU/kg of GH, respectively. The subjects assigned to receive 0.30 IU/kg were administered for additional 6 days. After a single administration of GH, Cmax and AUC of GH were increased in a dose-dependent manner. There was a significant positive correlation between the AUC and the T1/2 (r=0.516, P<0.05). Total body clearance was significantly greater in 0.075 IU/kg group than the other groups and showed a significant negative correlation with Cmax (r=-0.694, P<0.005) and AUC (r=-0.723, P<0.005). After a single administration of each dose, serum IGF-I concentrations were increased gradually. In the repeated administered group (0.30 IU/kg), IGF-I concentrations almost reached a plateau at a significantly high level four days after the start of administration and remained at a high level (786-405.4 ng/ml) until day 8. There was no significant difference in diurnal change of blood glucose and serum insulin after a single administration of GH among three groups. In the 0.3 U/kg group, there was no significant difference in diurnal change of blood glucose between day 1 and day 7, but serum insulin level was significantly higher in day 7 than in day 1 (P<0.01). Serum concentrations of NEFA were increased over time after administration in all subjects administered once or repeatedly. TG concentrations showed no changes after single administration of each dose level, but were significantly increased on day 7 in the subjects repeatedly treated with 0.30 IU/kg/day. This effect is speculated to be caused by high dose GH treatment. The above findings demonstrated that higher GH dose significantly influences on carbohydrate and lipid metabolism. It remains necessary to elucidate what kinds of effects of the long-lasting increased levels of insulin and triglyceride, even if reversible, would have on glucose and lipid metabolism.

Growth hormone treatment of short children born small for gestational age: reappraisal of the rate of bone maturation over 2 years and metanalysis of height gain over 4 years

A minority of children born small for gestational age (SGA) fail to achieve sufficient catch-up growth during infancy and remain short throughout childhood, apparently without being growth hormone (GH) deficient. A previous metanalysis of four trials revealed that GH treatment over a period of 2 years induced a dose-dependent acceleration of linear growth and, to a lesser extent, of the rate of bone maturation in short, prepubertal children born SGA. The rate of bone maturation and the change in height SDS for bone age from the previous 2-year metanalysis have been re-analysed according to chronological age (two prepubertal age groups: group A, 3.0-5.9 years old; group B, 6.0-8.9 years old). The rate of bone maturation was slower in younger than in older prepubertal children; this difference was more marked in children receiving high-dose (0.2 or 0.3 IU/kg/day) GH treatment (p < or = 0.01). Accordingly, the change in height SDS for bone age was increased by high-dose GH treatment in both age groups (p < or = 0.01), and was more pronounced in younger than in older children (1.45 +/- 0.28 versus 0.63 +/- 0.20; p < or = 0.01). Height SDS data from 100 short, prepubertal children born SGA have been analysed over 4 years. The change in height SDS appeared to be related to the average dose of GH. A mean GH dose of 0.1 IU/kg/day over 4 years was administered either as 0.1 IU/kg/day for 4 years (continuous) or as 0.2 IU/kg/day for 2 years, followed by 2 years without GH treatment (discontinuous). After 4 years of treatment, the increase in height SDS for the continuous and discontinuous treatment schedules was similar, being 1.42 +/- 0.10 SDS and 1.58 +/- 0.17 SDS, respectively. In a second regimen, a mean GH dose of 0.2 IU/kg/day over 3 years was administered either as 0.2 IU/kg/day for 3 years (continuous) or as 0.3 IU/kg/day for 2 years, followed by 1 year without GH treatment (discontinuous). After 3 years, the increase in height SDS with the continuous and discontinuous treatment schedules was similar, being 2.01 +/- 0.18 SDS and 2.22 +/- 0.16 SDS, respectively. GH administration was well tolerated in all treatment groups. In conclusion, the rate of bone maturation in short, prepubertal children born SGA treated with GH appeared to depend not only on the dose of GH, but also on the age of the child. GH treatment resulted in a prolonged increase in height SDS, the magnitude of the rise being dependent on the average GH dose rather than on the continuous or discontinuous mode of GH administration.

Growth performance and respiratory burst activity in rainbow trout treated with growth hormone and vaccine

Size-selected (167±11mm) female rainbow trout were: given a high (1·8μgg−1body weight per week) or low (0·35μgg−1) dose of recombinant bovine growth hormone (GH), delivered by cholesterol pellet implant; injected with a commercial bivalent (vibriosis–furunculosis) vaccine; provided with each dose of GH plus vaccine; implanted with a pellet alone; or left untreated (N=20 per group). Growth in each treatment group was monitored over a 7 week period. Four weeks into the trial, and at trial termination, head kidney neutrophils were quantified using a histochemical method, and their respiratory burst (CL) response evaluated (N=10 per group). By week 4 of the trial, high dose GH treatment was observed to enhance the CL response of vaccinated fish (P<0·05) above that of control and other groups. High dose GH treated animals also returned greater, although relative to week 4 data significantly lower, CL response at trial termination. Vaccination had an overall negative effect (P<0·05) upon trout growth performance during the trial, although this consequence was annulled when vaccine was co-administered with high dose GH. When considered conjointly with the findings of others, the results of the present investigation provide evidence in support of the existence of a hypothalamo-pituitary-immune axis in teleosts.

High-dose growth hormone treatment of short children born small for gestational age

High-dose growth hormone treatment of short children born small for gestational age

Cardiovascular effects of high-dose growth hormone treatment in growth hormone-deficient children.

Growth hormone (GH) hypersecretion is associated with an increased incidence of cardiac hypertrophy and subclinical abnormalities of left ventricular (LV) function. The unlimited availability of biosynthetic GH has led to progressively increased dosage when treating GH-deficient children, raising the question of its cardiovascular effects during long-term therapy. We compared 22 children (8 girls, 14 boys), mean age 12.1 years (range 3-17 years) with GH deficiency who were receiving chronic GH treatment (GH group) with 22 normal controls matched for sex and body size in order to evaluate: (1) LV volume, mass, and systolic function by two-dimensional guided M-mode echocardiography; (2) LV diastolic function by pulsed-wave Doppler sampling of the transmitral flow; and (3) cardiac output and systemic vascular resistance by Doppler echocardiography. All patients had been on chronic GH therapy for 13.8 +/- 7.6 months (range 5-30 months) with an average dose of 0.95 +/- 0.12 IU/kg per week (range 0.69-1.17 IU/kg per week). Blood pressure did not differ between the two groups. LV volume, mass, ejection fraction, and mean velocity of circumferential shortening did not differ significantly between the GH group and controls; nor did the peak- and end-systolic meridional stress. All patients had a normal contractile state as estimated by the relation between mean velocity of circumferential shortening and end-systolic meridional stress. The LV filling parameters did not differ between the two groups, and there was no difference in cardiac index and systemic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Growth Hormone on Glucose Metabolism

Growth hormone (GH) counteracts in general the effects of insulin on glucose and lipid metabolism, but shares protein anabolic properties with insulin. Under physiological circumstances GH does not affect total glucose turnover directly. There is however evidence that GH acutely decreases glucose oxidation (secondary to an increase in lipid oxidation) and suppresses muscle uptake of glucose, suggesting that GH redistributes glucose fluxes into a non-oxidative pathway, which could be a build up of glycogen depots through gluconeogenesis. Since GH secretion is inhibited in the fed state these actions are mainly important in the postprandial or fasting state. Under pathological conditions of GH excess (e.g. acromegaly, poorly controlled tp. 1 diabetes or high dose GH treatment) the diabetogenic actions of GH become apparent. In these patients increased endogenous glucose production, decreased muscle glucose uptake and rising blood glucose levels are observed. In patients with intact beta-cell function these changes are counterbalanced by hyperinsulinemia--such hyperinsulinemia may in the long term induce increased cardiovascular morbidity and mortality ('Reavens syndrome X'). When stimulated with insulin these patients exhibit insulin resistance at the liver, in adipose tissue and in muscle. Few elaborate studies on the effects of GH on glucose metabolism in GH deficient patients have been conducted. These patients are hypersensitive to the actions of insulin on glucose metabolism and there is some evidence that when GH initially is given to such patients in the GH deprived state, paradox insulin-like effects of GH may be observed. Whether this may relate to increased activity of insulin-like growth factors is unsettled.

Possible Metabolic Side Effects of High Dose Growth Hormone Treatment

Possible Metabolic Side Effects of High Dose Growth Hormone Treatment