rhGH Administration Research Articles

Biochemical Markers of Insulin-Like Growth Factor-I Misuse in Athletes: The Response of Serum IGF-I, Procollagen Type III Amino-Terminal Propeptide, and the GH-2000 Score to the Administration of rhIGF-I/rhIGF Binding Protein-3 Complex

The GH-2000 and GH-2004 research groups developed a method for detecting GH misuse in athletes based on the measurement of serum IGF-I and procollagen type III amino-terminal propeptide (P-III-NP). There are reports that IGF-I is also misused by athletes, but currently there is no internationally recognized test designed to detect recombinant human IGF-I misuse. The objective of the study was to examine the response of serum IGF-I, P-III-NP, and the GH-2000 score to recombinant human (rh) IGF-I/rhIGF binding protein-3 (IGFBP-3) administration in recreational athletes. This was a randomized, double-blind, placebo-controlled rhIGF-I/rhIGFBP-3 administration study at Southampton General Hospital (Southampton, United Kingdom). Fifty-six recreational athletes (26 women, 30 men) participated in the study. Participants were randomized to treatment with low-dose (30 mg/d) or high-dose (60 mg/d) rhIGF-I/rhIGFBP-3 complex or placebo for 28 days. Blood was collected throughout the drug administration and washout periods. Serum IGF-I and P-III-NP were measured using commercial immunoassays and GH-2000 scores were calculated. IGF-I, P-III-NP, and the GH-2000 score rose in response to both low- and high-dose rhIGF-I/rhIGFBP-3 administration. The relative maximum response of IGF-I (approximately 4-fold increase in women and men) was greater than that of P-III-NP (40%-50% increase in women, 35%-50% increase in men). The GH-2000 formulae, which incorporate IGF-I and P-III-NP results, detected up to 61% of women and 80% of men in the rhIGF-I/rhIGFBP-3 groups but, using IGF-I concentrations alone, the sensitivity increased to 94% in both women and men during the administration period. The rise in P-III-NP after rhIGF-I/rhIGFBP-3 administration is small compared with that after rhGH administration. Although rhIGF-I/rhIGFBP-3 administration can be detected using the GH-2000 score method, a test based on serum IGF-I alone provides better sensitivity.

Administration of growth hormone and nandrolone decanoate alters mRNA expression of the GABAB receptor subunits as well as of the GH receptor, IGF-1, and IGF-2 in rat brain

ObjectiveThe illicit use of anabolic androgenic steroids (AAS), especially among young adults, is of major concern. Among AAS users it is common to combine the AAS nandrolone decanoate (ND), with intake of growth hormone (GH) and a connection between gonadal steroids and the GH system has been suggested. Both AAS and GH affect functions in the brain, for example those associated with the hypothalamus and pituitary, and several GH actions are mediated by growth factors such as insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2). The GABAergic system is implicated in actions induced by AAS and previous studies have provided evidence for a link between GH and GABAB receptors in the brain. Our aim was to examine the impact of AAS administration and a subsequent administration of GH, on the expression of GABAB receptors and important GH mediators in rat brain. DesignThe aim was to investigate the CNS effects of a high-dose ND, and to study if a low, but physiological relevant, dose of GH could reverse the ND-induced effects. In the present study, male rats were administered a high dose of ND every third day during three weeks, and subsequently the rats were given recombinant human GH (rhGH) during ten days. Quantitative PCR (qPCR) was used to analyze gene expression in hypothalamus, anterior pituitary, caudate putamen, nucleus accumbens, and amygdala. ResultsIn the pituitary gland, the expression of GABAB receptor subunits was affected differently by the steroid treatment; the GABAB1 mRNA expression was decreased whereas a distinct elevation of the GABAB2 expression was found. Administration of ND also caused a decrease of GHR, IGF-1, and IGF-2 mRNA expression in the pituitary while the corresponding expression in the hypothalamus, caudate putamen, nucleus accumbens, and amygdala was unaffected. The rhGH administration did not alter the GABAB2 expression but increased the GABAB1 gene expression in the hypothalamus as compared to the AAS treated group. ConclusionsThese results provide new insights on the impact of ND and GH on the brain and highlight the interaction of these hormones with systems influencing GABAB receptor expression. The physiological significance of the observed effects of these hormones is discussed.

Height Outcome of the Recombinant Human Growth Hormone Treatment in Subjects with Noonan Syndrome: A Meta-Analysis

Children with Noonan Syndrome (NS) present variable growth impairment associated to facial dysmorphology and cardiovascular anomalies. Mutations in several genes of RAS/MAPK signaling pathway have been identified, likely impairing Growth Hormone (GH) sensitivity. If untreated, these patients often remain short in adulthood. Although Recombinant Human GH (rhGH) treatment improves short-term linear growth, poor data on the Final Height (FHt) of rhGH-treated subjects with NS are available. After thorough search of the published literature for pertinent studies, a meta-analysis evaluation of the efficacy and safety of rhGH treatment in NS patients were performed. In total sample (n=885; 70.0% males), administration of rhGH progressively improved height pattern, but relevant catch-up growth was not shown. The rhGH-induced growth improvement appeared until FHt [n=168; –2.151 SDS (95%CI –2.792 to –1.511)]. During 1st year of rhGH treatment, height velocity gain meta-correlated with serum insulin-like growth factor 1 (IGF1) increment [n=31; r=0.685 (95%CI 0.419 to 0.843); P<0.0001] while negative meta-correlation was detected between age at rhGH start and height velocity [n=48; r=–0.608 (95%CI –0.765 to –0.383); P<0.0001]. Height gain after 1-yr rhGH treatment (dosage range 0.35-0.46 mg/kg/wk) was higher in NS patients without protein tyrosine phosphatase non-receptor type 11 (PTPN11) gene mutation [n=33; 0.903 SDS (95%CI 0.552 to 1.254)] than that observed in subjects positive for PTPN11 mutations [n=62; 0.606 SDS (95% CI 0.274 to 0.938); P<0.0001]. While few serious adverse events were reported during rhGH treatment, causal relationship to rhGH therapy was unlikely. In conclusion, this meta-analysis indicates that rhGH treatment progressively improved height outcome of short children with NS. Future studies using carefully titrated rhGH protocols are need to optimize treatment protocols and establish possible risks, if any, leading to clear indications for practice and regulatory agencies.

Effects of Recombinant Human Growth Hormone Therapy on Bone Mineral Density in Adults With Growth Hormone Deficiency: A Meta-Analysis

GH deficiency is associated with decreased bone mineral density (BMD) and increased fracture risk. Because the effects of recombinant human GH (rhGH) therapy on BMD and bone mineral content have not been systematically investigated, we conducted a meta-analysis of pertinent studies. A thorough search of the literature (MEDLINE, EMBASE, and the Cochrane Register) was performed. Relevant studies were divided and analyzed according to their design (randomized/controlled or prospective/retrospective) and duration of rhGH therapy (≤12 months and > 12 months). Administration of rhGH led to a significant increase in lumbar spine (LS) and femoral neck (FN) BMD in randomized/controlled studies of more than 1 year [weighted mean difference (95% confidence interval)] of 0.038 g/cm(2) (0.011-0.065) and 0.021 g/cm(2) (0.006-0.037) at the LS and FN, respectively, and a nonsignificant drop at the same sites in studies of shorter duration. In prospective studies, a significant increase in the LS and FN BMD was obtained. On meta-regression, a negative association was observed between the change in LS and FN BMD and subjects' age and a positive association between the BMD change and treatment duration. In a subgroup analysis, the increase in LS and FN BMD was significant in men [0.048 g/cm(2) (0.033-0.064) and 0.051 g/cm(2) (0.003-0.098), respectively] but not in women. This meta-analysis suggests a beneficial effect of rhGH replacement on BMD in adults with GH deficiency. This effect is affected by gender, age, and treatment duration. Larger studies are needed to evaluate the effect of rhGH on fracture risk.

PND27 - Cost-Effectiveness of Somatropin Administration with Increased Adherence Due to Monitoring Compared to Non-Monitored Administration in Patients with Growth Hormone Deficiency

All recombinant human growth hormones (rhGH) have the same molecular structure, therefore providing equal efficacy and safety, and are granted the same reimbursement in the Czech Republic (CR). All rhGH are currently administered subcutaneously once a day, differing only in applicators. Easypod is the only applicator that enables monitoring the dose, time and date of each injection and allows feedback control by doctors. The objective was to assess the cost-effectiveness of monitored rhGH treatment administered by Easypod with an increase in reimbursement of 10% compared to the standard non-monitored rhGH administration in CR. The interim results (n=596) of an ongoing multicenter, non-comparative, observational, longitudinal study (ECOS) were used to populate deterministic cohort model. The model simulated long-term costs and benefits development of rhGH treatment. Evaluation was developed primarily on evidence-based connection (from ECOS) between the monitoring of treatment and patient adherence to the treatment. Increased adherence of monitored patients was transferred to the increased effectiveness of the treatment, based on published study. Model further transformed the long-term treatment benefits to the increased quality of life, using QALY as the target parameter using empirical transformation. Costs were expressed from the payer’s perspective. Due to an increased adherence in monitored patients, the hypothetical cohort of 10,000 boys generated 9,517 incremental QALY and CZK1.6 billion incremental costs in a lifetime horizon. A hypothetical cohort of 10,000 girls generated 11,504 incremental QALY and CZK1.35 billion incremental costs. The average cost per 1 QALY (ICER) is approximately CZK157,000 for the patient with GHD. Monitoring of the treatment may lead to an increased adherence and more effective treatment at relatively low cost, hence being considered cost-effective. Sensitivity analysis showed that ICER did not exceed CZK500,000 upon the considered uncertainty.

EasypodTM adherence in children with growth disorders treated with r-hGH. A preliminary Italian experience

Recombinant human growth hormone (r-hGH) is indicated for pediatric patients with a variety of growth disorders. Treatment with r-hGH requires long-term daily injections (1). Non-adherence or low adherence to treatment is associated with less favorable clinical outcomes, lower quality of life and higher healthcare costs (2,3). easypodTM has been specifically designed to improve patients’ ease of daily use and to minimize discomfort and pain (4,5). Aim of this observational, national and multicentre study was to monitor the adherence to r-hGH treatment using easypodTM, which records time, date and dose of injections in patients with growth disorders during the 1st year of treatment. 98 pre-pubertal short stature patients with growth disorders (60 male and 37 female, 1 screening failure, median age 10 years) were enrolled in the study. So far data are available for 54 subjects. All subjects underwent a baseline visit, and then after 6 and 12 months. 8 patients were withdrawn from the study prematurely. Data regarding r-hGH administration was uploaded from the autoinjectors. Auxological parameters, routine blood chemistry and hematology values were collected. Adherence during the 1st year has been calculated. Adherence was defined as the proportion of injections correctly administered out of expected total number of injections during the observational period. A patient was considered as adherent if he/she correctly administered >92% of expected total number of injections during the observation period. Data on the 54 available patients show that 25 patients (46.3%) were adherent to treatment while 29 patients (53.7%) were not. The impact of low adherence on clinical and biochemical parameters is under evaluation. The study will run until January 2013. Data obtained from this study will allow to explore the potential impact of adherence to r-hGH on growth outcomes after 1st year of treatment. The long-term adherence will be evaluated in the easypodTM connect observational study, also ongoing in Italy.

The impact of nandrolone decanoate and growth hormone on biosynthesis of steroids in rats

Growth hormone (GH) and anabolic androgenic steroids (AAS) are commonly used in sports communities. Several studies have suggested an association between GH and AAS. We have investigated the impact of GH in rats treated with nandrolone decanoate (ND). Male Wistar rats received ND (15mg/kg) every third day during three weeks and were subsequently treated with recombinant human GH (1.0IU/kg) for ten consecutive days. Plasma samples were collected and peripheral organs (i.e. heart, liver, testis and thymus) were dissected and weighed. Concentration of thirteen endogenous steroids was measured in the rat plasma samples using high specificity LC–MS/MS methods. Seven steroids were detected and quantified, and concentrations of estrone, testosterone, and androstenedione were significantly different among the groups, while concentrations of pregnenolone, DHEA, 17-hydroxyprogesterone and corticosterone were not altered. Administration of rhGH alone altered the plasma steroid distribution, and the results demonstrated significantly increased concentrations of plasma estrone as well as decreased concentrations of testosterone and androstenedione in the ND-treated rats. Administration of rhGH to ND-pretreated rats did not reverse the alteration of the steroid distribution induced by ND. Administration of ND decreased the weight of the thymus, and addition of rhGH did not reverse this reduction. However, rhGH administration induced an enlargement of thymus. Taken together, the plasma steroid profile differed in the four groups, i.e. control, AAS, rhGH and the combination of AAS and rhGH treatment.

Enhanced delivery of human growth hormone across cell membrane by Tat-PTD

In this study, we utilized the HIV protein Tat protein transduction domain (Tat-PTD) to enhance the intestinal absorption of recombinant human growth hormone (rhGH) delivered by oral administration. Insulin-like growth factor 1 (IGF-1), the key factor in the GH signal transduction pathway, was differentially affected at the mRNA level by various concentrations of rhGH. At high rhGH concentrations (500 ng/ml), IGF-1 was downregulated, while low concentrations (5 ng/ml) caused IGF-1 upregulation. The addition of Tat-PTD had a significant facilitating effect on rhGH. Frozen tissue sections visualized with fluorescence microscopy, cultured cells visualized by confocal microscopy and flow cytometry all confirmed that rhGH fused to Tat-PTD demonstrated more intracellular fluorescent signal when compared to rhGH alone. ELISA showed that after 2 h of incubation, Tat-rhGH levels in the rat intestinal cavity were 1.38-fold higher than rhGH. These data indicated that Tat-PTD effectively improved the internalization of rhGH and enhance the signal transduction of rhGH, possibly laying a solid foundation for the novel oral administration of rhGH.

Low-dose growth hormone for 40 weeks induces HIV-1-specific T cell responses in patients on effective combination anti-retroviral therapy

Recombinant human growth hormone (rhGH) administered to combination anti-retroviral therapy (cART)-treated human immunodeficiency virus-1 (HIV-1)-infected individuals has been found to reverse thymic involution, increase total and naive CD4 T cell counts and reduce the expression of activation and apoptosis markers. To date, such studies have used high, pharmacological doses of rhGH. In this substudy, samples from treated HIV-1(+) subjects, randomized to receive either a physiological dose (0·7 mg) of rhGH (n = 21) or placebo (n = 15) daily for 40 weeks, were assessed. Peptide-based enzyme-linked immunospot (ELISPOT) assays were used to enumerate HIV-1-specific interferon (IFN)-γ-producing T cells at baseline and week 40. Individuals who received rhGH demonstrated increased responses to HIV-1 Gag overlapping 20mer and Gag 9mer peptide pools at week 40 compared to baseline, whereas subjects who received placebo showed no functional changes. Subjects with the most robust responses in the ELISPOT assays had improved thymic function following rhGH administration, as determined using CD4(+) T cell receptor rearrangement excision circle (TREC ) and thymic density data from the original study. T cells from these robust responders were characterized further phenotypically, and showed decreased expression of activation and apoptosis markers at week 40 compared to baseline. Furthermore, CD4 and CD8 T cell populations were found to be shifted towards an effector and central memory phenotype, respectively. Here we report that administration of low-dose rhGH over 40 weeks with effective cART resulted in greater improvement of T lymphocyte function than observed with cART alone, and provide further evidence that such an approach could also reduce levels of immune activation.

Cardiometabolic risks during anabolic hormone supplementation in older men

There is little prospective information on the cardiometabolic risks of testosterone and growth hormone (GH) replacement therapy to youthful levels during aging. We conducted a double-masked, partially placebo controlled study in 112 men 65–90 years-old. Transdermal testosterone (5g-vs-10g/day) using a Leydig Cell Clamp and subcutaneous recombinant GH (rhGH) (0-vs-3-vs-5ug/kg/day) were administered for 16-weeks. Measurements included testosterone and IGF-1 levels, body composition by DEXA, and cardiometabolic risk factors (upper body fat, blood pressure, insulin sensitivity, fasting triglycerides, HDL-cholesterol, and serum adiponectin) at baseline and after 16 weeks of treatment. Some cardiometabolic factors improved (total and trunk fat, triglycerides, HDL-cholesterol) and others worsened (systolic blood pressure, insulin sensitivity index [QUICKI], adiponectin). Cardiometabolic risk composite scores (CRCS) improved (−0.69±1.55, p<0.001). In multivariate analyses, QUICKI, triglycerides, and HDL-cholesterol contributed 33%, 16%, and 14% of the variance in CRCS, respectively. Pathway analyses indicated that changes in fat and lean mass were related to individual cardiometabolic variables and CRCS in a complex manner. Changes in BMI, reflecting composite effects of changes in fat and lean mass, were more robustly associated with cardiometabolic risks than changes in fat mass or LBM individually. In conclusion, testosterone and rhGH administration was associated with diverse changes in individual cardiometabolic risk factors, but in aggregate appeared not to worsen cardiometabolic risk in healthy older men after 4-months. The long term effects of these and similar anabolic therapies on cardiovascular events should be investigated in populations with greater funtional limitations along with important health disabilities including upper body obesity and other cardiometabolic risks.

Height Outcome of the Recombinant Human Growth Hormone Treatment in Patients with SHOX Gene Haploinsufficiency: a Meta-Analysis

Patients with mutations or deletions of the SHOX gene present variable growth impairment, with or without mesomelic skeletal dysplasia. If untreated, short patients with SHOX haplodeficiency (SHOXD) remain short into adulthood. Although recombinant human growth hormone (rhGH) treatment improves short-term linear growth, there are episodic data on the final height of treated SHOXD subjects. After a thorough search of the published literature for pertinent studies, we undertook a meta-analysis evaluation of the efficacy and safety of rhGH treatment in SHOXD patients. In SHOXD patients, administration of rhGH progressively improved the height deficit from baseline to 24 months, although the major catch-up growth was detected after 12 months. The rhGH-induced growth appeared constant until final height. Our meta-analysis suggested rhGH therapy improves height outcome of SHOXD patients, though future studies using carefully titrated rhGH protocols are needed. Original submitted 29 October 2012; Revision submitted 22 February 2013.

Circulating microRNA as a biomarker of human growth hormone administration to patients

Circulating microRNAs (miRNAs) in plasma are being studied for use as biomarkers of specific diseases and as markers of administration of pharmaceutical agents. Administration of recombinant human growth hormone (rhGH) is prohibited by sporting authorities, but it continues to be used by athletes attempting to gain an unfair advantage in athletic competition. Current methods for detection of rhGH use rely on immunoassay technology and are limited by a short time-frame in which detection of rhGH is possible. We hypothesized that administration of rhGH would alter expression of circulating miRNAs and that any changes could be detected. To identify potential miRNA targets, we utilized miRNA microarrays for screening. Confirmatory testing used real-time reverse-transcriptase (RT) quantitative PCR (qPCR) assays of selected miRNAs in 35 plasma samples obtained from (1) individuals with no known pituitary disorders, (2) patients with excess GH production, and (3) patients receiving therapeutic replacement doses of rhGH. We identified and confirmed four miRNAs that were differentially expressed in all individuals using therapeutic replacement doses of rhGH when compared to individuals with naturally high levels of GH and normal controls. This study further develops the hypothesis that circulating miRNAs may be used as biomarkers for detection of doping in sports.

The effects of two weeks of recombinant growth hormone administration on the response of IGF-I and N-terminal pro-peptide of collagen type III (P-III-NP) during a single bout of high resistance exercise in resistance trained young men

ObjectiveRecombinant human growth hormone (rhGH) is used by some athletes and body builders with the aim of enhancing performance, building muscle and improving physique. Detection of the misuse of rhGH has proved difficult for a number of reasons. One of these is the effect of preceding exercise. In this randomised, double blind placebo-controlled study, we determined the effects of rhGH administration in male amateur athletes on two candidate markers of rhGH abuse, IGF-I and N-terminal pro-peptide of collagen type III (P-III-NP), following a bout of weightlifting exercise. DesignSixteen men entered a four-week general weight training programme to homogenise their activity profile. They then undertook repeated bouts of standardised leg press weightlifting exercise (AHRET-acute heavy resistance exercise test). Blood samples were taken before and up to one hour after the AHRET. After the first laboratory visit (Test 1), the subjects were randomly assigned to receive daily injections of either rhGH (0.1IUkg−1day−1) or placebo for two weeks. The AHRET was repeated after the two-week dosing period (Test 2) and a further test was undertaken following a one-week washout (Test 3). ResultsThere was no effect of exercise on either IGF-I or P-III-NP in any test. Both markers were markedly elevated at Test 2 (p<0.001), with P-III-NP remaining elevated at Test 3 in the GH administration group (p<0.05). Application of the GH-2000 discriminant function positively identified GH administration in 17 of 40 blood samples taken at Test 2 from the rhGH group and none from the placebo group. ConclusionThe data show that rhGH results in elevated levels of IGF-I and P-III-NP in well-trained individuals and that leg press weightlifting exercise does not affect these markers. The GH-2000 discriminant function identified four of eight subjects taking rhGH with no false positive results.

The GH-releasing effect of acylated ghrelin in normal subjects is refractory to GH acute auto-feedback but is inhibited after short-term GH administration inducing IGF1 increase

GH secretion is regulated by an interplay between GH-releasing hormone (GHRH), somatostatin (SST), and other central and peripheral signals. Acylated ghrelin (AG) amplifies GH pulsatility acting, at least partially, independently from GHRH and SST. The GH response to GHRH is inhibited by recombinant human GH (rhGH), likely due to a SST-mediated negative GH auto-feedback. The effect of exogenous rhGH on the GH-releasing effect of AG has never been tested. In six healthy volunteers, we studied the GH response to acute AG administration (1.0 μg/kg i.v.) during saline or rhGH infusion (4.0 μg/kg per h i.v.) or after 4-day rhGH (10.0 μg/kg s.c.) administration. Compared with saline, rhGH infusion increased GH levels (P<0.01). During saline, acute i.v. AG induced a marked increase (P<0.01) in GH levels similar to those observed after AG administration during rhGH infusion. During s.c. rhGH, IGF1 levels rose from day 0 to day 5 (P<0.01). After 4-day s.c. rhGH, i.v. AG increased (P<0.01) GH levels, though significantly (P<0.05) less than on day 0. The marked somatotroph-releasing effect of AG is refractory to a direct GH auto-feedback whereas is markedly inhibited after 4-day rhGH administration, suggesting the possibility of a selective IGF1-mediated inhibitory feedback.

Biomarker detection of rhGH Doping: an excretion study

The purpose of this research is to validate the biomarker-based approach for the detection of doping with recombinant human growth hormone (rhGH) in sport. The GH-2000 project proposed an indirect method for the detection of exogenously administered growth hormone (GH) based on the measurement of the GH-dependent markers: insulin-like growth factor-I (IGF-I) and Type III pro-collagen (P-III-P). These markers rise in a dose-dependent manner after GH application. In this study, the concentrations of IGF-I, IGF-BP3, and P-III-P in serum were determined to provide further incentives for the implementation of this detection assay in modern anti-doping programmes. This paper reports on an administration study of rhGH involving 25 Chinese male volunteers at a dose of 0.1 IU /kg/day for a continuous 14-day period. We observed that the serum IGF-I concentration increased rapidly in the rhGH treatment group and showed significantly higher levels compared to baseline between days 4 and day 16 after administration. Although the response of P-III-P to rhGH administration was delayed compared to the IGF-I axis, the P-III-P concentration remained increased for a longer period (from day 4 to day 28). Statistical analysis was carried out to establish a discriminant formula with Statistical Product and Service Solutions (SPSS) concluding that the biomarker methodology is valid and universally applicable.

Tracking growth hormone abuse in sport: A comparison of distinct isoform-based assays

Detecting recombinant human growth hormone (rhGH) abuse in sport remains one of the major challenges in doping control. We have compared two different approaches to detect the hGH (human growth hormone) abuse. The first measures the concentrations of the 22kDa hGH isoform (rec assay) and pituitary derived isoforms (pit assay) and a ratio rec/pit is obtained. The second measures the concentrations of 22 and 20kDa hGH isoforms and also a ratio 22/20kDa is derived.Using a single set (nine healthy male subjects, 7 days, 0.026mg/kg/day of rhGH, 2 week wash out period) both approaches were compared. To quantify the agreement between the immunoassays, B.A. (Bland–Altman) analysis and P.r. (Pearson correlation) were used. To fully understand the assay readings, all relevant antibodies were characterised by surface plasmon resonance (SPR).In either approach the ratio numerator produces similar results and the denominator determines both signal-amplitude and time-frame of possible application. The rec vs pit approach displays a higher distinctive capacity to detect hGH abuse but the complex binding properties of the capture antibodies make it very difficult to evaluate the precise contributions of the individual hGH variants to the assay result. In the 22 vs 20 approach, the 20kDa hGH concentration measures determine its applicability.Both approaches are based on a different principle, should be preferably applied within 24h after rhGH administration, and are perfectly comparable given the results obtained. The reduced time frame of application indicates that their principle application should be preferably in an out-of-competition setting.

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 4mg of Freund's adjuvant. Fifteen days after adjuvant injection, 300μg/kg of rhGH or 200μg/kg of rhIGF or saline was administrated 18 and 3h 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.

The Effect of Recombinant Human Growth Hormone Therapy in Patients with Completed Stroke: A Pilot Trial

ObjectiveTo evaluate the safety and potential efficacy of "recombinant human growth hormone (rhGH)" on the functional recovery of completed stroke patients.MethodCompleted stroke patients were recruited. All participants were randomly assigned to the GH group (rhGH injection and rehabilitative therapy) or the control group (only rehabilitative therapy). Above all, they were closely monitored for safety. Further, for the efficacy measurement, Korean Modified Barthel Index (K-MBI), Manual Muscle strength Test (MMT), and Fugl-Meyer assessment (FMA) were assessed to determine the changes of functional recovery during 6-months of the study period. Along with it, diffusion tensor image was taken as the baseline, and a followed-up study to observe the changes in diffusion tensor tractography (DTT), during the period, and one patient in the GH group was also examined with functional MRI (fMRI). Index of fatigue on 5 point scale for the study period was also assessed.ResultsTwenty-two patients were enrolled, and 15 completed the study and were included in the analysis. No harmful adverse events were observed in the GH group. By comparison between the groups, the GH group showed more improvement in K-MBI than the control group (p<0.05). DTT showed less decrement of fibers in the GH group than in the control group, without statistical significance. fMRI showed an increment in the activated area. Patients in the GH group expressed no fatigue at all, during the study period (p=0.00).ConclusionThe administration of rhGH in long term resulted in the improvement in K-MBI, and subjectively less tiredness during the injection period.

Growth hormone secretagogues: out of competition

Growth hormone secretagogues (GHS) constitute a new GH deficiency treatment increasing exponentially in number and improved potency and bioavailability over the last decade. The growth hormone releasing activity makes these compounds attractive for the artificial improvement of the human sports skills, now that recombinant human growth hormone (rhGH) administration is effectively detected. The GHS family is extremely diverse both in number and chemical heterogeneity and keeps growing continuously. In this paper, a general screening test is proposed. To develop a universal method, the single common property of growth hormone secretagogues has been targeted: their capacity to bind to the GHS receptor 1a (GHS-R1a). Pretreated urine samples have been tested in a competition assay where eventually the GHS presence detached a radiolabelled ligand from the receptor in a dose-dependent manner. Blank urine samples were processed to determine potential age, gender and exercise effects, and to define a threshold beyond which a specimen is considered positive. Samples from a growth hormone releasing peptide 2 (GHRP-2) excretion study corroborated the screening assay applicability with a detection window of approximately 4.5 h, and results were confirmed by comparison with a dedicated LC-MS quantification of the intact compound.

Serum IGF-I Is Not a Reliable Pharmacodynamic Marker of Exogenous Growth Hormone Activity in Mice

Serum IGF-I is a well-established pharmacodynamic marker of GH administration in humans and has been used for this purpose in animal studies. However, its general suitability in wild-type laboratory mice has not been demonstrated. Here we show that treatment with recombinant human GH (rhGH) in four different strains of laboratory mice increases body weight, lean body mass, and liver weight but does not increase hepatic expression and release of IGF-I. In contrast and as expected, hypophysectomized rats show a rapid increase in serum IGF-I after rhGH administration. The lack of IGF-I up-regulation in mice occurs despite hepatic activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and is not explained by GH dose, route of administration, origin of GH (i.e. recombinant human, bovine, and murine GH), treatment duration, genetic background, sex, or formation of neutralizing antibodies. Effects on other components of the GH/IGF pathway were highly influenced by genetic background and sex but not consistently affected by rhGH treatment. We conclude that IGF-I is not a reliable indicator of the biological effects of exogenous GH treatment in genetically and pharmacologically unmodified mice. We speculate that IGF-I release is already maximal in these animals and cannot be further increased by exogenous GH treatment. This is also suggested by the observation of restored IGF-I up-regulation in isolated murine hepatocytes after rhGH treatment. Total body weight, lean body mass, and liver weight may be more reliable phenotypic indicators in these models.