Growth cartilage expression of growth hormone/insulin-like growth factor I axis in spontaneous and growth hormone induced catch-up growth

IntroductionCatch-up growth following the cessation of a growth inhibiting cause occurs in humans and animals. Although its underlying regulatory mechanisms are not well understood, current hypothesis confer an increasing importance to local factors intrinsic to the long bones' growth plate (GP).AimThe present study was designed to analyze the growth-hormone (GH)-insulin-like growth factor I (IGF-I) axis in the epiphyseal cartilage of young rats exhibiting catch-up growth as well as to evaluate the effect of GH treatment on this process.Material and methodsFemale Sprague–Dawley rats were randomly grouped: controls (group C), 50% diet restriction for 3 days + refeeding (group CR); 50% diet restriction for 3 days + refeeding &; GH treatment (group CRGH). Analysis of GH receptor (GHR), IGF-I, IGF-I receptor (IGF-IR) and IGF binding protein 5 (IGFBP5) expressions by real-time PCR was performed in tibial growth plates extracted at the time of catch-up growth, identified by osseous front advance greater than that of C animals.ResultsIn the absence of GH treatment, catch-up growth was associated with increased IGF-I and IGFBP5 mRNA levels, without changes in GHR or IGF-IR. GH treatment maintained the overexpression of IGF-I mRNA and induced an important increase in IGF-IR expression.ConclusionsCatch-up growth that happens after diet restriction might be related with a dual stimulating local effect of IGF-I in growth plate resulting from overexpression and increased bioavailability of IGF-I. GH treatment further enhanced expression of IGF-IR which likely resulted in a potentiation of local IGF-I actions. These findings point out to an important role of growth cartilage GH/IGF-I axis regulation in a rat model of catch-up growth.     

Comparison between weight-based and IGF-I-based growth hormone (GH) dosing in the treatment of children with GH deficiency and influence of exon 3 deleted GH receptor variant

ObjectiveCompare the most frequently used weight-based GH dosing with an IGF-I level-based strategy in the treatment of children with severe GH deficiency. Additionally, analyse the influence of the GH receptor exon 3 polymorphism on IGF-I levels during GH therapy.DesignThirty children with GH deficiency on treatment with GH for 4.3 ± 3.2 yr in a single University Hospital were divided in group W (weight-based GH dosing) and group I (IGF-I-based dosing). In group I, GH doses were changed by 8.3 μg/kg d to maintain IGF-I levels between 0 and +2 SDS, whereas in group W the dose was fixed at 30 μg/kg d in prepubertal and 50 μg/kg d in pubertal patients. Growth velocity was measured after 1 yr, IGF-I and IGFBP3 levels quarterly. GH receptor exon 3 was genotyped by PCR.ResultsMost patients in Group I reached target IGF-I levels after 6 months with a GH dose ranging between 25 and 66 μg/kg d (mean ± SD, 38 ± 8). Each change of 8.3 μg/kg d of GH dose, resulted in change of 1.17 ± 0.6 SDS of IGF-I levels. Mean IGF-I levels were higher in Group I 0.8 ± 0.5 SDS than in Group W ?0.3 ± 1.9 SDS (p < 0.05), but growth velocities were similar, 6.8 ± 2.6 cm/yr and 6.9 ± 2.6 cm/yr (p = NS), respectively. Serum IGFBP3 levels were similar in both groups and were less useful to individualize GH therapy. Even treated with a similar mean GH dose, patients carrying at least one GH receptor d3-allele reached higher IGF-I levels (0.7 ± 1.2 SDS) than those homozygous for the full-length allele (?0.3 ± 1.2 SDS; p < 0.05), however, growth velocities were not different.ConclusionsBy adjusting the GH dose, it was feasible to maintain IGF-I in the desired range (0–+2 SDS). Patients carrying at least one GH receptor d3-allele reached higher circulating IGF-I levels than those homozygous for the full-length allele. A multiple regression analysis failed to demonstrate an independent influence of IGF-I levels on GV during the 12 months of observation.     

Amino acid profiles in adults with growth hormone (GH) deficiency before and during GH replacement therapy

ObjectiveGH replacement to growth hormone deficient (GHD) adults improves body composition. In a subset however, lean body mass (LBM) fails to increase despite normalization of IGF-I and amino acid availability could be of importance. We analyzed amino acid (AA) profiles in plasma and erythrocytes (RBC) and associations with LBM, serum IGF-I and IGFBP-1 before and during GH replacement.Design and methodsExaminations were performed in 15 GHD patients (six women), aged 34–61 yrs before and after 12 months of GH therapy and in a control group of 20 healthy males aged 31–68 yrs. LBM was measured by dual energy X-ray absorptiometry (DXA), free AAs in plasma and RBC by high performance liquid chromatography and serum IGF-I and IGFBP-1 by in-house RIAs.SettingTertiary care referral centre.ResultsAt baseline, female GHD patients tended to have lower concentrations of the essential branched – chain AAs isoleucine and leucine, total essential AAs, and of the non-essential AA glutamine than the male patients. Male GHD patients tended to have higher plasma and RBC glutamate than controls. At 12 months, IGF-I had normalized in all but one patient and mean LBM gain was 1.9 ± 0.4 kg. AA levels were unchanged. The change in LBM at 12 months was positively correlated to the ratio between the sum of isoleucine, leucine and valine and baseline LBM kg/m² (r = 0.76, p = 0.001, n = 15).ConclusionOur results suggest that the essential branched-chain amino acids in plasma are important for the LBM response to GH substitution. Our finding has to be confirmed in larger groups of GHD adults before making a proper selection of AAs to be measured in plasma and added as dietary supplement during GH therapy. GH administration did not change AA levels and measurements are not useful for monitoring of GH therapy at the time being.     

Growth and endocrine effects of recombinant bovine growth hormone treatment in non-transgenic and growth hormone transgenic coho salmon

To examine the relative growth, endocrine, and gene expression effects of growth hormone (GH) transgenesis vs. GH protein treatment, wild-type non-transgenic and GH transgenic coho salmon were treated with a sustained-release formulation of recombinant bovine GH (bGH; Posilac). Fish size, specific growth rate (SGR), and condition factor (CF) were monitored for 14 weeks, after which endocrine parameters were measured. Transgenic fish had much higher growth, SGR and CF than non-transgenic fish, and bGH injection significantly increased weight and SGR in non-transgenic but not transgenic fish. Plasma salmon GH concentrations decreased with bGH treatment in non-transgenic but not in transgenic fish where levels were similar to controls. Higher GH mRNA levels were detected in transgenic muscle and liver but no differences were observed in GH receptor (GHR) mRNA levels. In non-transgenic pituitary, GH and GHR mRNA levels per mg pituitary decreased with bGH dose to levels seen in transgenic salmon. Plasma IGF-I was elevated with bGH dose only in non-transgenic fish, while transgenic fish maintained an elevated level of IGF-I with or without bGH treatment. A similar trend was seen for liver IGF-I mRNA levels. Thus, bGH treatment increased fish growth and influenced feedback on endocrine parameters in non-transgenic but not in transgenic fish. A lack of further growth stimulation of GH transgenic fish suggests that these fish are experiencing maximal growth stimulation via GH pathways.     

Impact of the growth hormone replacement on bone status in growth hormone deficient adults

IntroductionGrowth hormone deficiency (GHD) is associated with reduced bone mineral density (BMD). GH replacement has positive effect on BMD but the magnitude of this effect and its mechanism are debated.ObjectivesThe objectives of this study was first, to assess the effect of GH replacement on BMD, and second, to evaluate the effect of GH treatment on bone turnover and microarchitecture and to assess the factors influencing the effect of the therapy on BMD.Patients and MethodsAdult GHD (AO-GHD) and childhood onset GHD (CO-GHD) patients treated with GH using IGF-I normalization GH replacement regimen were prospectively followed during 2 years. Lumbar spine (L1–L4) and total femur BMD by Hologic discovery, in the subset of patients also bone turnover markers; osteocalcin and carboxy-terminal collagen crosslinks (CTx) were assessed at baseline and at months 3, 6, 12 and 24, respectively. The trabecular bone score (TBS) derived from lumbar spine DXA by the iNsight® software was assessed in a subset of study population at baseline and months 12 and 24.ResultsIn total, 147 GHD patients (age 35.1 years, 84 males/63 females, 43 of childhood onset GHD/104 AO-GHD) were included. BMD of lumbar spine and femur increased significantly during the treatment (14% and 7% increase at 2 years, respectively; p < 0.0001).Bone markers increased during the first 12 months of treatment with subsequent decrease of CTx. At month 24, significant increase in TBS was observed (4%, p = 0.02).BMD increase was significantly higher in males (15% increase in males vs. 10% in females, p = 0.037) and childhood onset GHD (CO-GHD) patients (13% increase in CO-GHD, p = 0.004).ConclusionGH supplementation leads to an increase of BMD with corresponding changes in bone turnover markers and changes in microarchitecture as assessed by trabecular bone score. Positive effect of GH on bone status is more pronounced in males and CO-GHD adults.     

Short-term growth hormone or IGF-I administration improves the IGF-IGFBP system in arthritic rats

ObjectiveAdjuvant-induced arthritis is an experimental model of rheumatoid arthritis that inhibits the GH-IGF-I axis and decreases body weight gain and muscle mass. Although chronic GH or IGF-I treatment increases body weight gain in arthritic rats, muscle resistance to GH and IGF-I is a very common complication in inflammatory diseases. In this study we examine the effect of short-term administration of rhGH and rhIGF-I on liver and muscle IGF-I, IGFBP-3 and ? 5 as well as on the ubiquitin-ligases MuRF1 and atrogin-1 in the muscle of arthritic rats.DesignArthritis was induced in adult male Wistar rats by an intradermal injection of 4 mg of Freund's adjuvant. Fifteen days after adjuvant injection, 300 μg/kg of rhGH or 200 μg/kg of rhIGF or saline was administrated 18 and 3 h before decapitation. A pair-fed group injected with saline was included in order to discard a possible effect of decreased food intake. Gene expression of IGF-I, GHR, IGFBP-3, IGFBP-5, atrogin-1 and MuRF1 were quantified using RT-PCR. In serum, IGF-I was measured by radioimmunoassay (RIA) and IGFBP-3 by ligand blot.ResultsArthritis decreased serum IGF-I and IGF mRNA in liver (P < 0.05), but not in skeletal muscle. In arthritic rats, rhGH increased serum IGF-I and liver IGF-I mRNA similar to the levels of pair-fed rats. Arthritis increased atrogin-1, MuRF1, IGFBP-3 and IGFBP-5 mRNA in muscle (P < 0.01). IGFBP-3 mRNA was downregulated by rhIGF-I, but not by rhGH, administration in control and arthritic rats (P < 0.05). Administration of rhGH and rhIGF-I increased IGFBP-5 in the gastrocnemius of arthritic rats.ConclusionsShort-term rhGH and rhIGF-I administration was found to increase muscle IGFBP-5 mRNA, whereas only rhIGF-I administration decreased muscle IGFBP-3 mRNA in control and arthritic rats. These data suggest that arthritis does not induce GH or IGF-I resistance in skeletal muscle.     

Effects of levothyroxine on growth hormone (gh) sensitivity in children with idiopathic short stature

BackgroundThe possible relationship between the circulating concentrations of T4 and GH sensitivity has not been elucidated.ObjectiveThe aim of this study is to evaluate the effect of levothyroxine supplementation on GH sensitivity in prepubertal boys with idiopathic short stature (ISS).MethodsWe selected 28 prepubertal boys with ISS (mean age 8.2 ± 0.5 years) and free T4 (Ft4) concentrations between the 3rd and the 25th percentiles (Ft4: 0.8–1.5 ng/dl). They were randomly divided into two groups: Group A received thyroid supplementation (1–3 μg/kg/day) for 120 days, and Group B received placebo for the same period. To evaluate GH sensitivity, an IGF-I generation test (GH: 33 μg/kg/day sc for 3 days) was performed in both groups: under basal conditions, and after 120 days of levothyroxine supplementation (or placebo).ResultsAfter thyroid supplementation, Group A had higher Ft4 concentrations compared with Group B (2.14 ± 0.06 vs 1.48 ± 0.06 ng/dl, p = 0.01), their growth velocity was significantly higher (2.3 ± 0.1 vs 1.5 ± 0.2 cm/4 months), and they exhibited a greater increase in IGF-I after GH administration (Group A: 32.5 ± 3.8% vs Group B 17.3 ± 2.6%).ConclusionSupplementation with levothyroxine for 120 days promotes an increase in growth velocity, and a greater IGF-I response to short-term GH administration in prepubertal boys with ISS and low-normal thyroid hormone concentrations.     

Autosomal recessive form of isolated growth hormone deficiency is more frequent than the autosomal dominant form in a Brazilian cohort

BackgroundIn most studies, the autosomal dominant (type II) form of isolated growth hormone deficiency (IGHD) has been more frequent than the autosomal recessive (type I) form.Our aim was to assess defects in the GH1 in short Brazilian children with different GH secretion status.Subjects and methodsWe selected 135 children with postnatal short stature and classified according to the highest GH peak at stimulation tests in: severe IGHD (peak GH ≤ 3.3 μg/L, n = 38, all with normal pituitary magnetic resonance imaging); GH peak between 3.3 and 10 μg/L (n = 76); and GH peak > 10 μg/L (n = 21). The entire coding region of GH1 was sequenced and complete GH1 deletions were assessed by Multiplex Ligation Dependent Probe Amplification and restriction enzyme digestion.ResultsPatients with severe IGHD had a higher frequency of consanguinity, were shorter, had lower levels of IGF-1 and IGFBP-3, and despite treatment with lower GH doses had a greater growth response than patients with GH peak ≥ 3.3 μg/L. Mutations were found only in patients with severe IGHD (GH peak < 3.3 μg/L). Eight patients had autosomal recessive IGHD: Seven patients were homozygous for GH1 deletions and one patient was compound heterozygous for a GH1 deletion and the novel c.171 + 5G > C point mutation in intron 2, predicted to abolish the donor splice site. Only one patient, who was heterozygous for the c.291 + 1G > T mutation located at the universal donor splice site of intron 3 and predicts exon 3 skipping, had an autosomal dominant form.ConclusionAnalysis of GH1 in a cohort of Brazilian patients revealed that the autosomal recessive form of IGHD was more common than the dominant one, and both were found only in severe IGHD.     

Vitamin D and growth hormone regulate growth hormone/insulin-like growth factor (GH–IGF) axis gene expression in human fetal epiphyseal chondrocytes

ObjectiveCell proliferation and gene expression regulation were studied in human fetal epiphyseal chondrocytes to ascertain the involvement of GH–IGF axis components in human fetal growth regulation by 1,25-dihydroxyvitamin D₃ (VitD) and growth hormone (GH).DesignChondrocytes from primary cultures were plated in serum-free medium for 48 h and incubated for a further 48 h with VitD (10^?11 to 10^?6 M) and/or IGF-I (100 ng/ml) and/or GH (500 ng/ml). We analyzed ³H-thymidine incorporation into DNA and IGF-I, IGFBP-3, GHR, SOX9, COL2A1, aggrecan and COMP gene expression by real-time quantitative PCR.ResultsVitD dose-dependently and significantly inhibited ³H-thymidine incorporation whereas GH had no effect on proliferation and, when combined with VitD, the same inhibition was observed as with VitD alone. IGF-I (100 ng/ml) significantly stimulated proliferation and opposed inhibition by VitD. VitD dose-dependently stimulated IGF-I (11.1 ± 19.8 at VitD 10^?6 M), IGFBP-3 (2.6 ± 0.9), GHR (3.8 ± 2.8) and COMP (1.5 ± 0.6) expression whereas it inhibited SOX9 (0.7 ± 0.2), COL2A1 (0.6 ± 0.3) and aggrecan (0.6 ± 0.2) expression and had no significant effect on IGF-II. IGF-I stimulated IGF-I, IGFBP-3, SOX9, COL2A1 and aggrecan expression and opposed COL2A1 and aggrecan gene expression inhibition by VitD. GH alone had no effect on gene expression whereas, in the presence of VitD, significantly-increased IGF-I expression stimulation was observed above values obtained with VitD alone (17.5 ± 7.4).ConclusionsOur results suggest that VitD regulation of fetal growth cartilage could have consisted of parallel enhancing of cell differentiation and conditioning to a phenotype more sensitive to regulation by other hormones such as GH as shown by increased GHR and IGF-I expression, but not by IGF-II expression which was not regulated.     

Growth hormone responses to acute resistance exercise with vascular restriction in young and old men

ObjectiveResistance exercise (RE) stimulates growth hormone (GH) secretion in a load-dependent manner, with heavier loads producing larger GH responses. However, new research demonstrates that low-load RE performed with blood flow restriction (BFR) produces potent GH responses that are similar to or exceed those produced following high-load RE. We hypothesized that low-load RE with vascular restriction would attenuate the known age-related reduction in GH response to RE.DesignIn a randomized crossover design, ten young (28 ± 7.8 years) and ten older (67.4 ± 4.6 years) men performed bilateral knee extension RE with low-load [20% of one-repetition maximum (1RM)] with BFR and high-load (80% 1RM) without BFR. GH and lactate were measured every 10 minutes throughout a 150-minute testing session (30 minutes prior to and 120 minutes following completion of the exercise); IGF-I was measured at baseline and 60 minutes post-exercise.ResultsArea under the GH curve indicated that both age groups responded similarly to each exercise condition. However, young men had a significantly greater maximal GH response to low-load RE with BFR than the high-load condition without BFR. Additionally, younger men had greater maximal GH concentrations to low-load RE with BFR than older men (p = 0.02). The GH responses were marginally correlated to lactate concentration (r = 0.13, p = 0.002) and IGF-I levels were unchanged with RE.ConclusionsGH responses to low-load RE with vascular restriction are slightly higher than high-load RE without vascular restriction in young men. However, low-load RE with vascular restriction did not attenuate the known age-related reduction in GH response with exercise. These data suggest that while low-load RE with vascular restriction is as effective for inducing a GH response than traditionally-based high-load RE, there is a more potent response in young men.     

Early programming of the IGF-I axis: Negative association between IGF-I in infancy and late adolescence in a 17-year longitudinal follow-up study of healthy subjects

Background: IGF-I is a major regulator of growth, influenced primarily by diet in infancy and primarily by GH in childhood. Breastfed infants have lower IGF-I levels compared to formula fed and tend to be shorter. The higher protein content of infant formula has a stimulatory effect on IGF-I production. Conversely, studies suggest that later in childhood, those breastfed are taller and have higher IGF-I levels. Therefore, it has been suggested that the IGF-I axis may be programmed by diet during infancy. The association between IGF-I in infancy and later life is not known.Objective: To examine the association between IGF-I in infancy and adolescence.Design: Infants (109) from the observational Copenhagen cohort study.Methods: Serum-IGF-I was measured during infancy (2, 6, and 9 months) and at follow-up at 17 years. Associations were examined by correlation tests and linear regression controlling for gender, breastfeeding, and other covariates. Likelihood ratio test based on residual log likelihood was applied for analysis including all measurements during infancy.Results: There was an inverse association between IGF-I at 9 months and 17 years (r = ?0.39, P = 0.014, and n = 40). A 1 ng/ml higher IGF-I concentration at 9 months corresponded to 0.95 ng/ml lower IGF-I concentration at 17 years. IGF-I levels at 2 and 6 months were not significantly associated with IGF-I at 17 years, but the estimated directions were negative. These associations were not changed when adjusted for breastfeeding and other covariates except IGF-I at 2 months which was significantly negatively associated with IGF-I at 17 years (P = 0.030) corresponding to a 0.96 ng/ml lower IGF-I concentration at 17 years per ng/ml IGF-I at 2 months. Inclusion of all measurements during infancy showed a negative association with 17-year values (r = ?0.26, P = 0.043, and n = 109).Conclusion: The results support the hypothesis that the IGF-I axis can be programmed early in life.     

Behavioural phenotyping of male growth hormone-releasing hormone (GHRH) knockout mice

ObjectiveGH-releasing hormone (GHRH) is a key regulator of GH secretion. The role of GH in anxiety is somewhat contradictory. The aim of this study is to elucidate the consequences of lack of GHRH on emotional behaviour in a mouse model of GH deficiency due to removal of the GHRH gene (GHRH knock out, GHRHKO).DesignHomozygous GHRHKO and wild type male mice were utilized for this study. The emotional behaviour was measured through a battery of behavioural tests (locomotor activity/open field, light–dark exploration, elevated plus maze, forced swim test, tail suspension test). To correlate the emotional behaviour with brain neurochemistry, we evaluated thyrotropin-releasing hormone (TRH) gene expression in hypothalamic tissue by real-time PCR, and the levels of norepinephrine (NE), dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) in prefrontal cortex by HPLC analysis.ResultsGHRHKO mice showed increased exploratory activity. In the open field test (P < 0.005), light–dark box (P < 0.005) and elevated plus maze (P < 0.05), GHRHKO mice demonstrated a decrease in anxiety-related behaviour. In addition, GHRHKO mice showed reduced immobility time with respect to control in forced swim test and tail suspension test (P < 0.0001). The gene expression of hypothalamic TRH (P < 0.05) was increased, while NE levels in prefrontal cortex were decreased compared to control (P < 0.05).ConclusionThese results suggest that in male mice GHRH deficiency brings about an increased physical activity and decreased anxiety- and depression-related behaviour, possibly related to increased TRH and decreased NE levels in the brain.     

Insulin-like Growth Factor I and its binding protein 3 in sepsis

ObjectiveTo investigate the Growth Hormone (GH)/Insulin-like Growth Factor-I (IGF-I) axis and identify the factors that determine IGF-I levels in adult septic patients of variable severity, i.e., with sepsis, severe sepsis or septic shock, in the acute phase of disease.DesignIn 107 consecutive septic patients (44 with sepsis, 13 with severe sepsis, and 50 with septic shock), GH, IGF-I, Insulin-like Growth Factor Binding Protein-3 (IGFBP-3), insulin, cortisol, albumin, thyroid hormones, C-reactive protein and interleukin-6 serum levels were measured once within 48 h after onset of a septic episode. Twenty-nine healthy volunteers served as controls.ResultsIGF-I and IGFBP-3 levels were decreased in patients with sepsis and severe sepsis (versus controls), decreasing further in patients with septic shock (versus sepsis). IGF-I levels were positively related to IGFBP-3, albumin, triiodothyronine and thyroxine, and inversely related to cortisol, sepsis severity, C-reactive protein, interleukin-6 and age. In multiple regression analysis, IGF-I levels were independently related to IGFBP-3 and albumin (lower in patients with decreased IGFBP-3 and albumin levels) (p < 0.001 and p = 0.01, respectively), and cortisol (lower in patients with increased cortisol levels) (p = 0.04). IGFBP-3 accounted for most of the variance explained by the model (R² = 0.519). GH levels were not related to IGF-I levels or mortality. IGF-I and IGFBP-3 levels were not associated with mortality.ConclusionsThe GH/IGF-I axis is severely disrupted in septic patients. IGFBP-3 is the major determinant of IGF-I levels.     

Evaluation of cognitive performance by using P300 auditory event related potentials (ERPs) in patients with growth hormone (GH) deficiency and acromegaly

ContextImpaired cognitive performance has been demonstrated in adults with GH deficiency and acromegaly by using different neuropsychological tests. P300 event related potential (ERP) application is a well established neurophysiological approach in the assessment of cognitive performance.ObjectivesEvaluation of cognitive performance by using P300 ERPs has not been reported in acromegaly, and the comparisons of the P300 ERPs between the patients with GH deficiency and GH excess have not been done yet. Therefore present study was designed to investigate the effects of GH deficiency and GH excess on cognitive performance by using P300 ERPs.Design and MethodsThe study comprised 19 patients with severe GH deficiency, 18 acromegalic patients and 16 age, education and sex matched healthy controls. Baseline auditory ERPs were obtained at Fz (frontal), Cz (central), Pz (parietal) and Oz (occipital) electrode sites in GH deficient group, GH excess group and control group.ResultsThere was a significant difference between mean serum IGF-I levels in the GH deficient and acromegalic patients (48 ± 38 ng/ml and 742 ± 272 ng/ml, respectively) (P = 0.01). The mean P300 latency of the patients with GH deficiency was significantly (P = 0.0001) prolonged when compared with that of normal controls and acromegalic patients at all electrode sites. The mean P300 amplitude of the patients with acromegaly was significantly (P = 0.005) lower when compared with that of normal controls and GH deficient patients at all electrode sites.ConclusionsUsing ERPs recordings, the present study indicates the prolongation of P300 latencies in patients with severe GH deficiency and reduction of P300 amplitudes in patients with acromegaly. This study provides the electrophysiological evidence for the presence of cognitive dysfunction in both GH deficiency and GH excess, and different components of the cognitive performance are impaired in these conditions.     

Heat acclimation decreases the growth hormone response to acute constant-load exercise in the heat

ObjectiveThe major objective of this study was to elucidate the effect of heat acclimation on blood growth hormone (GH) response to moderate intensity exhausting exercise in the heat. In addition, the potential relationship between inter-individual differences in GH response to exercise and variability in exercise-induced sweat loss was investigated.DesignTwenty young men completed three exercise tests on a treadmill: H1 (walk at 60% VO₂peak until exhaustion at 42 °C), N (walk at 22 °C; duration equal to H1) and H2 (walk until exhaustion at 42 °C after a 10-day heat acclimation program). Core temperature (T_c) was recorded continuously and venous blood samples were taken before, during and after each exercise test. Exercise-induced sweat production was calculated on the basis of body mass change taking into account water intake and the volume of blood samples drawn.ResultsLower pre-exercise T_c, lower rate of rise in T_c during exercise, and prolonged time to exhaustion in H2 compared with H1 revealed that the subjects successfully achieved an acclimated state. Overall, serum GH level was higher in H1 compared with both N and H2 (p < 0.001) but did not differ between the two latter trials (p > 0.05). T_c correlated with serum GH concentration (r = 0.615, p < 0.01). Analysis of the individual data revealed a group (n = 9) possessing a threshold-like pattern of the relationship between T_c and blood GH response, whereas a plateau-like pattern was evident in the rest of the subjects (n = 11). Both sweat production (r = 0.596; p < 0.001) and the rate of sweat production (r = 0.457; p < 0.001) correlated with the growth hormone area under the curve.ConclusionHeat acclimation decreases the GH response to moderate intensity exhausting exercise in the heat. GH may have a modest stimulating effect on whole-body sweat production during exercise.     

Impact of moderate interval exercise versus supine rest on the pharmacokinetics and pharmacodynamic profiles of subcutaneously administered growth hormone in adult growth hormone deficient patients

BackgroundDiurnal variation in serum growth hormone (s-GH) levels after exogenous GH delivery has previously been reported in patients with no endogenous GH secretion. Changes in postural position or physical activity, leading to changes in blood flow and/or lymphatic drainage may be underlying explanations.Primary objectivesThe primary aim of this study is to study a possible impact of exercise and supine rest on pharmacokinetics (PK) and day-to-day variation of subcutaneously (sc) administered GH in adult GH deficient (AGHD) patients.Secondary objectiveThe secondary aim of this study is to compare s-IGF-I, s-insulin, and plasma (p)-glucose profiles after a carbohydrate rich breakfast following sc GH injection vs. continuous infusion.Design and methodsDuring supine rest eight AGHD males (59.8 ± 8 years, BMI 29.7 ± 4.9 kg/m²) were treated with one daily sc GH injections of 3 mg/24 h for 48 h (treatment sessions A, B) or a continuous sc GH infusion of 3 mg/24 h for 60 h (treatment sessions C, D). Exercise comprised 1 h bicycling with 50 W load on two consecutive days during treatment sessions B and D.ResultsAdministration of GH as a bolus injection, but not as a continuous GH infusion, resulted in about 32% higher s-GH levels during exercise (60 min) as well as 30 min after (s-GH logAUC_(B-A) difference was 0.28; 95% CI: 0.14–0.4; p < 0.001). However, the total s-GH_{AUC 0–24 h} (p = 0.75) and s-IGF-I_{AUC 0–48 h} levels (p = 0.51) remained unchanged between the two occasions. P-glucose and insulin profiles were significantly higher after carbohydrate rich breakfast before first and second dosing both following sc GH injection and continuous infusion (p < 0.05).ConclusionsModerate exercise intermittently increased s-GH levels. These changes seem to have no clinical short-term relevance, since total s-GH_24 h and s-IGF-I_48 h levels were unaffected.     

The growth hormone receptor exon 3 polymorphism is not associated with height or metabolic traits in healthy young adults

ContextThe GHR polymorphisms contribution to the interindividual variability in prenatal and postnatal growth as well as to metabolic traits is controversial.ObjectiveThe aim of this study is to analyze the association of the GHRfl/d3 polymorphism with prenatal and postnatal growth and metabolic outcomes in adult life and to compare the genotype distribution in different populations.Design385 community healthy subjects followed from birth to adult life (23–25 years old) were grouped according to birth size: small—SGA (n = 130, 62 males), appropriate—AGA (n = 162, 75 males) and large for gestational age—LGA (n = 93, 48 males). GHRfl/d3 genotype distribution and its potential association with anthropometric (at birth, childhood and adult life) and metabolic features (in adult life) were analyzed and compared with data obtained from a systematic review of GHRfl/d3 association studies (31 articles).ResultsThe frequency of the GHR d3/d3 genotype was lower in the LGA (χ2 p = 0.01); SGA and AGA subjects exhibited an increased chance of the d3/d3 genotype (OR = 3.58; 95%CI: 1.55; 8.24) and (OR = 2.39; 95%CI: 1.02; 5.62), respectively. Despite the different prevalence among different birth size groups, in adults, GHRfl/d3 genotype was not associated with height, plasma IGF1 levels or metabolic phenotype and cardiovascular risk. GHRfl/d3 genotype distributions in AGA, SGA and LGA groups were comparable with those found in subjects of European origin but not with those of Asian ancestry.ConclusionsThe GHRd3 genotype was negatively associated with birth size but it was not associated with adult height or weight, plasma IGF1, metabolic phenotype or any marker of increased cardiovascular risk in young adults.     

Pharmacodynamic hormonal effects of anamorelin,a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers

ObjectiveActivation of ghrelin receptors stimulates GH secretion and appetite, increasing lean body mass and body weight. However, clinical use of ghrelin is limited because it has a short half-life and must be administered parenterally. Anamorelin is a novel, orally active, non-peptidic ghrelin mimetic and growth hormone secretagogue. Our objective was to evaluate its hormonal effects in healthy subjects.DesignA double-blind, randomized, placebo-controlled study evaluated the short-term effects of anamorelin on GH, insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), prolactin, ACTH, LH, FSH, TSH, cortisol, insulin and glucose. Normal healthy volunteers (n = 32) recruited from the general population were administered escalating doses of anamorelin (25, 50, and 75 mg daily) vs. placebo.ResultsAnamorelin significantly increased GH levels at all doses (p ? 0.01). Effects on the somatotropic axis were maintained, as evidenced by sustained increases in IGF-1 and IGFBP-3 compared to placebo following 5–6 days of treatment. Negligible effects on other anterior pituitary hormone profiles and on fasting glucose were noted and all mean hormone levels remained within normal range. Some degree of insulin resistance as assessed by HOMA-IR was evident after treatment with 75 mg dose but not with the 25 or the 50 mg doses. Significant dose-related increases in body weight were recorded. Changes in body weight directly correlated with changes in IGF-1 levels. Anamorelin was well tolerated.ConclusionsAnamorelin increases GH, IGF-1, IGFBP-3 and body weight with good tolerability and selectivity, without affecting other anterior pituitary axes or fasting glucose levels.