Exogenous Growth Hormone Treatment Research Articles

The growth hormone-insulin like growth factor axis in pregnancy.

The growth hormone (GH)-insulin-like growth factor (IGF) axis is one of the main drivers of mammalian growth and development. Pituitary secretion of GH is pulsatile and under positive and negative hypothalamic control, as well as stimulation from gastric-secreted acyl-ghrelin. GH has anabolic and metabolic effects both directly via the GH-receptor (GHR) and indirectly via stimulation of IGF1 production at multiple target tissues. In this review, we describe the major changes to this axis during pregnancy, with increasing GH abundance in the maternal circulation across multiple species. This stimulates secretion of IGFs, whose bioavailability is also increased by proteolytic cleavage of their circulating binding proteins during pregnancy. These changes in turn induce maternal metabolic adaptations to pregnancy and promote placental function and fetal growth, as does exogenous GH or IGF treatment in animal models of normal and compromised pregnancy. Finally, we explore alternative approaches to enhance maternal GH abundance during pregnancy to promote maternal adaptations, placental function and hence fetal growth.

Treatment of growth hormone attenuates hepatic steatosis in hyperlipidemic mice via downregulation of hepatic CD36 expression

ABSTRACT The recombinant human growth hormone (GH) has been used for the treatment of growth hormone deficiency (GHD) and diverse short stature state, and its physiological and therapeutic effects are well documented. However, since the effect of GH treatment on metabolic disorders has not been well characterized, we injected GH to Western diet-fed low-density lipoprotein receptor-deficient (Ldlr −/−) mice to understand the exact effect of GH on metabolic diseases including atherosclerosis, hepatic steatosis, and obesity. Exogenous GH treatment increased plasma IGF-1 concentration and decreased body weight without affecting serum lipid profiles. GH treatment changed neither atherosclerotic lesion size nor collagen and smooth muscle cells accumulation in the lesion. GH treatment reduced macrophage accumulation in adipose tissue. Importantly, GH treatment attenuated hepatic steatosis and inflammation. The hepatic expression IL-1β mRNA were decreased by GH treatment. The mRNA and protein levels of CD36 were markedly decreased in GH treated mice without significant changes in other molecules related to lipid metabolism. Therefore, the treatment of GH treatment could attenuate hepatic steatosis and inflammation with downregulation of CD36 expression in hyperlipidemic condition.

Suppression in growth hormone during overeating ameliorates the increase in insulin resistance and cardiovascular disease risk

Previously, we reported that overeating for only a few days markedly suppressed the secretion of growth hormone (GH). The purpose of the present study was to determine the role of this reduction in GH concentration on key metabolic adaptations that occur during 2 wk of overeating. Nine nonobese, healthy adults were admitted to the hospital for 2 wk, during which time they ate ∼4,000 kcal/day (70 kcal·kg fat-free mass(-1)·day(-1); 50% carbohydrate, 35% fat, and 15% protein), and their plasma GH concentration was allowed to decline naturally (control). An additional eight subjects underwent the same overeating intervention and received exogenous GH treatment (GHT) administered in four daily injections to mimic physiological GH secretion throughout the 2-wk overeating period. We measured plasma insulin and glucose concentrations in the fasting and postprandial state as well as fasting lipolytic rate, proteolytic rate, and fractional synthetic rate (FSR) using stable-isotope tracer methods. GHT prevented the fall in plasma GH concentration, maintaining plasma GH concentration at baseline levels (1.2 ± 0.2 ng/ml), which increased fasting and postprandial assessments of insulin resistance (P < 0.05) and increased fasting lipidemia (all P < 0.05 vs. control). In addition, preventing the suppression in GH with overeating also blunted the increase in systemic proteolysis (P < 0.05 GHT vs. control). However, GHT did not alter lipolysis or FSR in response to overeating. In conclusion, our main findings suggest that the suppression in GH secretion that naturally occurs during the early stages of overeating may help attenuate the insulin resistance and hyperlipidemia that typically accompany overeating.

Growth hormone reduces growth in free‐living Atlantic salmon fry

Summary1. Although life‐history theory predicts that juvenile growth rates should be high, there is substantial evidence that most juveniles grow below their physiological maximum. The endocrine system plays an important role in the determination of fundamental life‐history traits, and hormones often serve as a link between an organism’s environment and the expression of a trait. Particularly, growth is a life‐history trait, which is strongly associated with growth hormone (GH) in fish, as well as most vertebrates.2. To elucidate trade‐offs related to elevated GH in fish in a natural environment, we experimentally administrated GH exogenously to juvenile Atlantic salmon using sustained‐release GH implants, at an earlier ontogenetic stage than previously achieved (1·5 months). We assessed the effects on growth, dispersal and survival in contrasting environments.3. Exogenous GH treatment increased the growth rate when fish were fed ad libitum in captivity. However, in a natural stream, GH treatment had a significant negative effect on growth and no apparent effect on survival or dispersal. This contrasts with previous studies conducted at later developmental stages, which show either a positive growth effect or no effect of elevated GH levels.4. This study shows that environmental conditions strongly affect the response to GH and that under some natural conditions, it may also reduce growth. We suggest that the endogenous plasma GH levels may be maximizing growth during early, but not later, juvenile stages in nature.

Noonan‐like syndrome with loose anagen hair associated with growth hormone insensitivity and atypical neurological manifestations

Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM 607721), recently related to the invariant c.4A>G missense change in SHOC2, is characterized by features reminiscent of Noonan syndrome. Ectodermal involvement, short stature associated with growth hormone (GH) deficiency (GHD), and cognitive deficits are common features. We report on a patient with molecularly confirmed NS/LAH exhibiting severe short stature associated with GH insensitivity (GHI), and chronic complex tics, a neurological feature never described before in this syndrome. IGF1 generation test revealed only a blunted increase in IGF1 after exogenous GH treatment, revealing mild GH insensitivity associated with proper STAT5 activation. Most common causes of secondary tics in childhood were excluded.

Suppression of Insulin-Like Growth Factor Acid-Labile Subunit Expression—A Novel Mechanism for Deoxynivalenol-Induced Growth Retardation

Consumption of deoxynivalenol (DON), a trichothecene mycotoxin commonly detected in cereal-based foods, causes impaired growth in many animal species. While growth retardation is used as a basis for regulating DON levels in human food, the underlying mechanisms remain poorly understood. Oral exposure of mice to DON rapidly induces multiorgan expression of proinflammatory cytokines, and this is followed by upregulation of several suppressors of cytokine signaling (SOCS), some of which are capable of impairing growth hormone (GH) signaling. The purpose of this study was to test the hypothesis that impairment of the GH axis precedes DON-induced growth retardation in the mouse. Subchronic dietary exposure of young (4-week old) mice to DON (20 ppm) over a period of 2-8 weeks was found to (1) impair weight gain, (2) result in a steady-state plasma DON concentration (40-60 ng/ml), (3) downregulate hepatic insulin-like growth factor acid-labile subunit (IGFALS) mRNA expression, and (4) reduce circulating insulin-like growth factor 1 (IGF1) and IGFALS levels. Acute oral exposure to DON at 0.5-12.5 mg/kg body weight (bw) markedly suppressed hepatic IGFALS mRNA levels within 2 h in a dose-dependent fashion, whereas 0.1 mg/kg bw was without effect. DON-induced IGFALS mRNA upregulation occurred both with and without exogenous GH treatment. These latter effects co-occurred with robust hepatic suppressors of cytokine signaling 3 upregulation. Taken together, these data suggest that oral DON exposure perturbs GH axis by suppressing two clinically relevant growth-related proteins, IGFALS and IGF1. Both have potential to serve as biomarkers of effect in populations exposed to this common foodborne mycotoxin.

Lack of growth enhancement by exogenous growth hormone treatment in yellow perch ( Perca flavescens) in four separate experiments

The effect of exogenous growth hormone (GH) treatment on the growth of juvenile yellow perch ( Perca flavescens) was investigated in four experiments. In the first two experiments, juvenile yellow perch were reared at either 13 °C or 21 °C, and injected weekly with bovine GH (bGH) at 0.1, 1.0 or 10.0 μg/g body weight for 84 days. No significant growth enhancement in GH-treated fish was measured in fish in either of the experiments. In the third experiment, juvenile yellow perch were treated with estradiol-17β (E 2, 15 μg/g of diet), bGH (1.0 μg/g body weight) injected weekly or both hormones for 70 days at 21 °C. E 2 alone stimulated growth, but no further growth stimulation occurred in the E 2 + bGH-treated fish. In addition, no growth enhancement was found in fish treated with bGH alone. We measured no difference in serum insulin-like growth factor-I (IGF-I) levels between the treatment groups at 12 and 24 h after the final injection of GH; however, a drop in IGF-I levels after 24 h was observed. In a fourth study, the effect of recombinant yellow perch GH (rypGH, 0.2 or 1.0 μg/g body weight) injected weekly was evaluated in yellow perch juveniles. The fish were reared for 42 days at 18 °C. Neither GH dosages improved growth compared to control-injected and non-injected fish. Taken together, the lack of effect of mammalian GH or rypGH in our experiments suggests (1) low binding affinity between these hormones and the GH receptor in yellow perch, (2) that the endogenous GH levels were already at biologically maximal levels or (3) that other endocrine factors are needed in order for GH to promote yellow perch growth. The reduction in IGF-I levels 24 h after handling suggests a negative effect of handling stress on the GH-IGF-I axis in yellow perch.

Growth Hormone Releaser Attenuates β-Amyloid (1 – 42)-Induced Memory Impairment in Mice

Accumulating evidence indicates that growth hormone (GH) might be effective at preventing the development of Alzheimer’s disease. However, exogenous GH treatment has exhibited side effects for clinical application; thus supplementation with amino acids to promote the release of GH could be a possible alternative treatment. In this study, mice that were fed with a diet of GH-releasing supplements had significantly attenuated memory impairments and hippocampal changes in the acetylcholinesterase activity and acetylcholine level induced by amyloid beta protein (Aβ) (1 – 42). Our results suggest that the use of GH-releasing supplement exerts beneficial effects on the memory impairment induced by Aβ (1 – 42).

Recombinant human growth hormone enhances tibial growth in peripubertal female rats but not in males.

A novel non-invasive technique termed microknemometry, which allows daily leg length measurement, was used to investigate the growth promoting effect of growth hormone (GH) on peripubertal rats. We compared the effect of different patterns of recombinant human (rh) GH administration to peripubertal male rats with the effect produced by two daily administrations of the same amount of rhGH to peripubertal female rats or adult male rats. Another group of peripubertal male rats was also submitted to a 3-day period of starvation, in order to study catch-up growth during refeeding and to determine whether this process could be stimulated by exogenous GH administration. GH treatment was unable to stimulate tibial growth or weight gain in peripubertal males, whereas a clear growth promoting effect was observed in female rats and also in adult male rats. Starvation caused a dramatic body weight loss, and a reduction in tibial growth rate. Peripubertal male rats gained body weight faster than unstarved animals during refeeding, although recovery was not complete after nine days. Tibial growth, however, was resumed at the same speed as in normally fed males. This means that no catch-up effect was observed after refeeding in animals either with or without GH treatment. During peripuberty, normal male rats grow at a maximal speed that cannot be further increased by exogenous GH treatment, whereas age-matched female rats or older males grow at a slower rate than peripubertal males. Thus, exogenous rhGH administration is capable of enhancing growth velocity.

Growth hormone improves body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome: A controlled study

Background: Obesity and hypotonia in children with Prader-Willi syndrome (PWS) are accompanied by abnormal body composition and diminished energy expenditure resembling a growth hormone–deficient state. Hypothalamic dysfunction in PWS often includes decreased growth hormone (GH) secretion, suggesting a possible therapeutic role for exogenous GH treatment. Objectives and methods: After 6 months of observation to determine baseline growth rate, and with the use of a 12-month randomized controlled study design, the effects of GH treatment (1 mg/m 2/d) on growth, body composition, strength and agility, pulmonary function, resting energy expenditure (REE), and fat utilization were assessed in 54 children with PWS (n = 35 treatment and n = 19 control). Percent body fat and bone mineral density were measured by dual x-ray absorptiometry. Indirect calorimetry was used to determine REE and to calculate respiratory quotients. Results: Stimulated levels of GH in response to clonidine testing were low in all patients (peak, 2.0 ng/mL). After 12 months, GH-treated subjects showed significantly increased height velocity Z scores (mean, –1.0 ± 1.7 to 4.6 ± 2.9; P < .001), decreased percent body fat (mean, 46.3% ± 8.4% to 38.3% ± 10.7%; P < .001), and improved respiratory muscle function, physical strength, and agility (sit-ups, weight-lifts, running speed, and coordination). A significant decline in respiratory quotients occurred during GH therapy (0.81 to 0.77, P < .001), but total REE did not change. Conclusions: GH treatment of children with PWS accelerated growth, decreased percent body fat, and increased fat oxidation but did not significantly increase total REE. Improvements in respiratory muscle strength, physical strength, and agility also occurred, suggesting that GH treatment may have value in reducing some physical disabilities experienced by children with PWS. (J Pediatr 1999;134:215-21)

Growth hormone-binding protein in the goat: characterization, evolution under exogenous growth hormone treatment, and correlation with liver growth hormone receptor levels

This report describes the identification and characterization of a specific, high-affinity growth hormone-binding protein (GHBP) in lactating goat serum. Serum samples were incubated with [ 125I]human GH as ligand and in the absence or in the presence of bovine GH as competitor. GH-GHBP complex formation was performed by high-performance liquid chromatography, and the radioactivity was recorded on-line with a Berthold LB detector connected to a computer. The results showed that a serum protein was able to bind specifically to human GH and bovine GH but not to ovine prolactin. Scatchard plots indicated an affinity constant of 4.5 × 10 8 M −1 and a maximum binding capacity of 4.8 × 10 −10 mol/l. In addition, we conducted a 4-wk study to determine the effects of recombinant bovine GH administration on milk production in lactating goats. The effects of recombinant bovine GH treatment on milk production and on the regulation of GHBP and hepatic GH receptor levels were studied. As expected, recombinant bovine GH injected daily increased yields of milk, fat, protein (40, 61, and 40%, respectively), and circulating insulin-like growth factor 1 concentrations compared with controls. During the pretreatment and treatment periods, the control goats exhibited a constant amount of GHBP in serum. No consistent effect of GH treatment on GHBP level was observed. The binding of [ 125I]bovine GH to hepatic microsomal membranes of GH-treated goats was significantly decreased compared with that of control goats. After MgCl 2 desaturation of membranes, the results demonstrated that the down-regulation of GH hepatic receptors, observed for the treated goat group, was induced by receptor occupancy without modification of binding affinity. The GH receptor gene expression, analyzed by slot blot and hybridization with an [α- 32P]GH receptor cDNA probe, was not modified by the GH treatment. In lactating goats, the galactopoietic effect of exogenous GH involved a hepatic receptor occupancy. The individual concentration of GHBP in serum cannot explain the individual variations of responses to GH treatment in goats.

Intra-Uterine Growth Retardation (IUGR) and Silver-Russell Syndrome (SRS): Etiological Aspects and Some Auxological Characteristics of Their Post-Natal Short Stature

Intra-uterine growth retardation (IUGR) and Silver-Russell syndrome (SRS) are born short for gestational age and many of them do not show post-natal catch-up growth Although post-natal catch-up growth frequently occurs, significant number of both IUGR and SRS newborns often fail to catch up. This may result in very short adult height (more than 2 standard deviations (SD) below the mean) in up to 20% of these patients, in association with poor school and social performance.In order to try to induce catch-up growth and hopefully increase final height, attempts have been made in clinical trial to treat these growth hormone (GH) sufficient patients with human GH.Using the Kabi Pharmacia International Growth Study patient data base, a group of 106 IUGR (83 males and 23 females) and 45 SRS with persistent post-natal growth failure were studied. IUGR clinical characteristics included a birth length and weight more than 2 SD below the mean for gestational age. Height deficit at start of the GH treatment was -3.0 standard deviation scores (SDS) for chronological age (CA), at a median CA of 8.7 years with a median bone age (BA) of 7.0 years. Mean parental heights were 166 cm for fathers and 153 cm for mothers. Median dose of recombinant human GH (rhGH) in 106 IUGR patients was 0.5 IU/kg/week, given at a median frequency of 5 injections per week. The median height SDS for CA at the start and at 1, 2 and 3 years of hGH treatment were -3.0, -2.5, -2.1 and -1.9 respectively.45 patients presented with SRS. Their median CA and BA at start of treatment were 6.7 and 3.2 years respectively. Mean parental heights were 167.5 cm for fathers and 160 for mothers. Median dose of rhGH in these 45 SRS was 0.7 IU/kg/week, with a median frequency of 6 injections per week. Median height SDS of SRS patients at start, 1, 2 and 3 years of hGH treatment were -3.5, -2.9, -2.8 and -2.2 respectively. One difference between these IUGR and SRS groups is that SRS patients tended to be born of normal height parents, in contrast to IUGR with persistent post-natal growth failure. In these two groups, exogenous GH treatment tended to induce catch up growth, although long term follow up is sufficient to allow conclusions to be draw regarding these patients' final adult height.

Growth, Metabolic and Endocrine Responses of Broiler Cockerels Given a Daily Subcutaneous Injection of Natural or Biosynthetic Chicken Growth Hormone

The effects of daily injection of natural chicken growth hormone (ncGH) or recombinant-derived chicken growth hormone (rcGH) on growth, heat production rate, plasma hormone levels and body composition were determined in rapidly growing broiler chickens. Beginning at 3 wk of age, eight broiler chickens were given a daily injection of either bicarbonate buffer (control), 100 or 200 micrograms ncGH/kg body wt, or 200 micrograms rcGH/kg body wt for 14 d. Blood samples were taken preinjection and 4 h postinjection on d 7 and 14 of chicken growth hormone (GH) treatment. Compared to preinjection levels, plasma GH levels at 4 h postinjection were significantly (P less than 0.05) elevated by daily injection (per kg body wt) of 100 micrograms ncGH (2.3-fold), 200 micrograms ncGH (5.5-fold) or 200 micrograms rcGH (6.4-fold). Although exogenous chicken GH treatment failed to increase body weight gain, ncGH injections did increase (P less than 0.05) body fat content to 117% that of the control group. Daily injection of chicken GH did not alter plasma levels of immunoreactive insulin-like growth factor-I (IGF-I), thyroid hormones, insulin, glucagon or glucose. Feed efficiency, heat production rate and respiratory quotient were also not affected by chicken GH treatment. Plasma levels of nonesterified fatty acids were elevated (P less than 0.05) by treatment with 200 micrograms ncGH/kg body wt. In contrast to domestic mammals, it is apparent that exogenous chicken GH can not be used to increase lean body mass or improve productive efficiency in chickens. Our results indicate that exogenous chicken GH exerts a strong lipogenic, rather than lipolytic, action in rapidly growing broiler cockerels.

Exogenous growth hormone treatment alters body composition and increases natural killer cell activity in women with impaired endogenous growth hormone secretion

In order to assess the potential relationship between human growth hormone (GH) and body composition (BC) and natural immunity (NI), we measured the effects of exogenous GH on fat weight (FW), fat-free weight (FFW), and the cytotoxic activity of natural killer (NK) cells in women with impaired GH secretion. Mean peak serum concentrations of GH in response to l-dopa/arginine stimulation were 6.2 ± 1.1 (SEM) ng/mL in 6 untreated subjects (US) and 5.4 ± 1.5 ng/mL in 6 GH-treated subjects (TS). Moreover, the pretreatment circulating levels of IGF-I were low in both groups (US 684 ± 121 mU/mL and TS 583 ± 83 mU/mL), and they correlated with pretest levels of NK cell activity ( r = .59, P < .05) when both groups were combined. The TS were given 700 μg of human GH IM for an average of 14 days while the US were studied in parallel without GH treatment. As measured by hydrodensitometry or skinfold anthropometry, FW decreased (26.1 ± 6.8 kg to 23.8 ± 6.3 kg, P < .05) and FFW increased (44.9 ± 3.3 kg to 46.2 ± 3.8 kg, P < .05) in the TS. In the US, there were no significant ( P > .05) changes in either FW or FFW. Using a standard 51Cr release assay to measure the specific lytic (SL) activity of NK cells, mean SL activity increased from 24.4 ± 7.0% to 44.1 ± 8.9% ( P < .05) in the TS, whereas levels in the US were not altered significantly ( P > .05). We conclude that daily exogenous GH treatment favorably influences BC and increases NK cell activity in women with an impaired secretion of the hormone.

Exogenous growth hormone inhibits growth hormone-releasing factor-induced growth hormone secretion in normal men.

Previous studies from this laboratory and by others in rats, monkeys, and humans support the concept that growth hormone (GH) can regulate its own secretion through an autofeedback mechanism. With the availability of human growth hormone-releasing factor (GRF), the possible existence of such a mechanism was reexplored by examining the effect of exogenous GH on the GH response induced by GRF-44-NH2 in six normal men (mean age, 32.4 yr). In all subjects the plasma GH response evoked by GRF-44-NH2 (1 microgram/kg i.v. bolus) was studied before and after 5 d of placebo (1 ml normal saline i.m. every 12 h), and then before and 12 h after 5 d of biosynthetic methionyl human GH (5 U i.m. every 12 h). The GH response to GRF (maximal increment over time 0 value) was significantly inhibited after GH treatment (0-1.3 vs. 2.3-11.2 ng/ml before treatment, P = 0.05), but was not significantly affected by placebo. This impaired pituitary response to GRF persisted for at least 24 h following exogenous GH treatment in two subjects who underwent further study. Serum somatomedin-C concentrations were significantly increased after 5 d of GH treatment (2.66-5.00 vs. 0.92-1.91 U/ml before treatment, P = less than 0.01). The impaired pituitary response to GRF may be mediated indirectly through somatomedin, somatostatin, by a direct effect of GH on the pituitary somatotropes, or by all of these mechanisms. These data suggest that after GH treatment, the blunted GH response to synthetic GRF is not solely a consequence of the inhibition of hypothalamic GRF secretion.