rhGH Administration Research Articles

A new pen device for injection of recombinant human growth hormone: a convenience, functionality and usability evaluation study.

PurposeAdherence to recombinant human growth hormone (r-hGH) is critical to growth and other outcomes in patients with growth disorders, but the requirement for daily injections means that ease of use is an important factor. This study assessed the perceived ease of use and functionality of the prototype of a reusable pen injector (pen device) for r-hGH that incorporates several advanced features.Participants and methodsSemi-structured 60-minute qualitative interviews were conducted in 5 countries with 57 health care professionals (HCPs) and 30 patients with GH deficiency/caregivers administering r-hGH to patients, including children. HCPs had to be responsible for training in the use of r-hGH pen devices and to see ≥4 r-hGH patients/caregivers per month. Patients/caregivers had to have experience with r-hGH administration for at least 6 months.ResultsThirty-seven (65%) of HCPs described the pen device as “simple” or “easy” to use. The aluminum body was generally perceived as attractive, high quality and comfortable to hold and operate. The ease of preparation and use made it suitable for both children and adults. The ability to dial back the r-hGH dose, if entered incorrectly, was mentioned as a major benefit, because other devices need several user steps to reset. Patients/caregivers felt the pen device was easy to use and the injection-feedback features reassured them that the full dose had been given. Overall, 40 (70%) HCPs and 16 (52%) patients/caregivers were likely to recommend or request the pen device. Moreover, patients/caregivers rated the pen device higher than their current reusable pens and almost equal to the leading disposable device for ease of learning, preparation, administration and ease of use.ConclusionThe prototype pen device successfully met its design objectives and was very well accepted by HCPs and patients/caregivers for its ease of use, appearance and functionality.

Short-term, supra-physiological rhGH administration induces transient DNA damage in peripheral lymphocytes of healthy women.

While a good safety for recombinant human growth hormone (rhGH) therapy at replacement doses is recognized, a possible link between high concentration of the GH-IGF-I axis hormones and side negative effect has been reported. The aim of this pilot study was to assess whether a short-term exposure to supra-physiological doses of rhGH may affect DNA integrity in human lymphocytes (PBL). Eighteen healthy Caucasian female (24.2 ± 3.5 years) were randomly included in a Control (n = 9) and rhGH administration group (n = 9, 3-week treatment). DNA damage (comet assay), chromosomal breaks, and mitotic index in phytohemagglutinin-stimulated PBL were evaluated before (PRE), immediately (POST), and 30 days (POST30) after the last rhGH administration (0.029 mgkg- 1 BW; 6 days/week), together with serum IGF-1 and IGFBP-3 concentrations. rhGH administration increased IGF-I, without evidence of persisting IGF-I and IGFBP-3 changes 30 days after withdrawal. Total DNA breakage (% DNA in tails) was not significantly different in subjects treated with rhGH in comparison with controls, although the rhGH-treated subjects showed an higher percentage of heavily damaged nuclei immediately after the treatment (POST30 vs. PRE: p = 0.003), with a lower mitogenic potential of lymphocytes, detectable up to the POST30 (PRE vs. POST: p = 0.02; PRE vs. POST30: p = 0.007). This pilot study showed that 3 weeks of short-term supra-physiological rhGH administration in healthy women induce a transient DNA damage and mitogenic impairment in PBL. The analysis of DNA damage should be explored as useful tool in monitoring the mid to long-term effects of high rhGH treatment or abuse.

Determination of Recent Growth Hormone Abuse Using a Single Dried Blood Spot.

Although it is being increasingly applied, blood collection for drug testing in sport presents some logistic issues that complicate full applicability on a large scale. The use of dried blood spots (DBS) could benefit compliant blood testing considerably owing to its simplicity, minimal invasiveness, analyte stability, and reduced costs. The aim of this study was to evaluate the applicability of DBS to the methodology approved by the World Anti-Doping Agency (WADA) for detection of doping by recombinant human growth hormone (rhGH) in serum. A protocol for a single DBS analysis using the hGH isoforms differential immunoassays (kit 1 and kit 2) was developed and validated. A clinical study with healthy volunteers injected for 3 consecutive days with a low subcutaneous dose (0.027 mg · kg(-1) · day(-1) · person(-1)) of rhGH was conducted. Finger prick DBS and paired-time serum samples from arm venipuncture were compared. The analysis of the DBS-based protocol indicated that with only a single blood spot it was possible to detect positivity for growth hormone abuse. In spite of the low rhGH dose administered and independently of the kit used, the window of detection for DBS was confirmed in all analyzed samples up to 8 h after rhGH administration and extended up to 12 h in 50% of the cases. Serum positivity was detected in all studied samples for 12 h after administration. These results support the usefulness of DBS as a biological matrix for testing recent growth hormone abuse.

Comparative pharmacokinetic and pharmacodynamic evaluation between a new biosimilar and reference recombinant human growth hormone

ObjectiveTo extend available dosing options in the treatment of growth hormone deficiency, a comparative pharmacokinetic and pharmacodynamic phase-1 clinical study involving subcutaneous administration of growth hormone was conducted. DesignThe test formulation (biosimilar recombinant human growth hormone; r-hGH; Somatotropin) and reference formulation (Genotropin®) were tested in 38 adult healthy subjects after their subcutaneous administration of 12.8IU in an open label, single dose, randomized, two period cross over study separated with a washout period of 11days. Endogenous growth hormone release was suppressed by a continuous Octreotide infusion up to 24h after r-hGH administration. All the subjects were evaluated for local tolerance using Wong-Baker Faces pain rating scale and an injection site reaction (ISR) score. Detection of serum levels of r-hGH, insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) was done by suitable validated bio-analytical methods. Assessment of bioequivalence for pharmacokinetic parameters was done using log-transformed area under the curve (AUC) and maximum concentration (Cmax) for r-hGH. The pharmacodynamic assessment was done by comparing the area under the effect-time curve (AUEClast) and maximum measured effect concentration (Emax) of IGF-1 and IGFBP-3. ResultsThe biosimilar formulation of recombinant human growth hormone fulfilled the predefined bioequivalence criteria for pharmacokinetic and pharmacodynamic parameters. ConclusionThe new biosimilar recombinant human growth hormone bears the potential to become an alternative option for the treatment of growth hormone deficiency.

Height Outcome of Recombinant Human Growth Hormone Treatment in Achondroplasia Children: A Meta-Analysis

Background/Aims: Although recombinant human growth hormone (rhGH) is not approved to treat short stature of achondroplasia (ACH), some studies suggested growth improvement during short-term rhGH treatment. Methods: A meta-analysis of rhGH therapy efficacy in ACH children was performed. Results: From 12 English-language studies, 558 (54.0% males) rhGH-treated ACH children were enrolled. Administration of rhGH (median dosage 0.21 mg/kg/ week; range 0.16-0.42 mg/kg/week) improved height (Ht) from baseline [-5.069 standard deviation score (SDS; 95% CI -5.109 to -5.029); p < 0.0001] to 12 [-4.325 SDS (95% CI -4.363 to -4.287); p < 0.0001] and 24 months [-4.073 SDS (95% CI -4.128 to -4.019); p < 0.0001]. Then, Ht remained approximately constant up to 5 years [-3.941 SDS (95% CI -4.671 to -3.212); p < 0.0001]. Conclusions: In ACH children, rhGH treatment increased Ht from -5.0 to -4.0 SDS during 5 years, but insufficient data are available on both the adult Ht and the changes of body proportions.

Supra-physiological rhGH administration induces gender-related differences in the hypothalamus-pituitary-thyroid (HPT) axis in healthy individuals.

The use of recombinant human growth hormone (rhGH) is a common habit among athletes. While the effects of rhGH administration have been described with contrasting results in males, no data exist in females to date. The aim of the present study was to evaluate the effects of rhGH administration on TSH, FT4 and FT3 levels and the time requested to return to baseline values after treatment withdrawal. Twenty-one healthy trained male and female athletes were treated with 0.03mg rhGH/kg body mass 6days/week for 3weeks. We collected blood samples immediately before the first daily rhGH administration, at 3, 4, 8, 15 and 21days of treatment and at 3 and 9days after rhGH withdrawal. In males, rhGH administration induced a significant (p<0.01) early and stable TSH decrease and IGF-I increase, and a delayed FT4 reduction without FT3 modification, suggesting a central regulatory mechanism. In females, rhGH administration induced a significant (p<0.01) early and transient TSH decrease and IGF-I increase, and a transient reduction in FT4 without any changes in FT3 concentrations. rhGH withdrawal was associated with a prompt normalization of TSH and FT4 levels in males, while in females the effects of rhGH treatment had already disappeared during the last period of treatment. We suggest that rhGH inhibits TSH at central level both in males and females. The pattern of normalization was different in the two genders probably due to gonadal steroids modulation on GH-IGF-I axis.

Genetic and protein biomarkers in blood for the improved detection of GH abuse

Human Growth Hormone (hGH, somatotropin) is one of the relevant forbidden substances to be detected in sport drug testing. Since the appearance of recombinant hGH (rhGH) in the 80’s, its expansion and availability through the black market have increased, so the detection of its abuse continues to be a challenge at present. New techniques or biomarkers that are robust, reliable, sensitive and allowing a large detection time window are welcome. rhGH produces an increase of insulin-like growth factor 1 (IGF-1). FN1 (fibronectin 1) and RAB31 (member of RAS oncogene family) genes have been suggested as two potential biomarkers for IGF-1 abuse. Following this line, in the present study some genetic and proteomic approaches have been performed with fourteen healthy male subjects treated with rhGH (which produces increase of IGF-1 concentrations) to study FN1 gene, FN1 protein, RAB31 gene and RAB31 protein as potential biomarkers for rhGH abuse. The results showed that both, RAB31 and FN1 genes and FN1 protein could be potential biomarkers for rhGH administration. Preliminary assessments of gender, age, acute sport activities and GHRP-2 (pralmorelin, a rhGH releasing peptide) influence suggest they are not relevant confounding factors. Thus, the selected markers present high sensitivity and a larger detection window for rhGH detection than IGF-1 itself.

The Efficacy of GnRHa Alone or in Combination with rhGH for the Treatment of Chinese Children with Central Precocious Puberty.

The addition of recombinant human growth hormone (rhGH) to GnRH agonist (GnRHa) to treat central precocious puberty (CPP) is controversial. We systemically reviewed and evaluated the efficacy and safety of the rhGH and GnRHa adjunctive therapy in Chinese children with CPP and assessed the influence of age and therapy duration on the efficacy of the combined treatment. A total of 464 patients were included from 14 studies. Compared with baseline, administration of GnRHa plus rhGH led to a significant increase in height, predicted adult height (PAH) and height standard deviation for bone age (HtSDS-BA), corresponding to a weighted mean difference (WMD) (95%CI) of 9.06 cm (6.41, 11.70), 6.5 cm (4.47, 8.52), and 0.86 (0.58, 1.14) respectively. Subgroup analysis showed the combined therapy had increased efficacy in subjects with initial treatment age younger than 10 years old or with treatment lasting over 12 months. Compared with GnRHa alone treatment, the combined treatment led to a significant increase in height, PAH and HtSDS-BA, corresponding to a WMD (95% CI) of 3.56 cm (2.54, 4.57), 3.76 cm (3.19, 4.34) and 0.56 (0.43, 0.69). The combined treatment exhibited no safety concerns. Our findings may aid clinicians in making treatment decisions for children with CPP.

The effects of growth hormone on clinical outcomes after frozen-thawed embryo transfer.

To evaluate the effects of recombinant human growth hormone (rhGH) on clinical outcomes of frozen-thawed embryo transfer (FET). A prospective study was conducted among 240 patients (aged ≤38years) who underwent FET cycles at a center in Hefei, China, between November 2011 and October 2012. Patients were divided into three groups on the basis of visit order: those in group A received hormone-replacement therapy (HRT) for endometrial preparation, those in group B received HRT plus simultaneous rhGH, and those in group C received rhGH on day8 of HRT. Ten cycles were cancelled; 230 FET cycles were analyzed (77 in group A, 77 in group B, 76 in group C). The rates of clinical pregnancy, embryo implantation, and live birth were significantly higher in group B than in group A, as were the serum levels of estradiol and insulin-like growth factor-1 (P≤0.033 for all comparisons). Endometrial thickness and serum levels of vascular endothelial growth factor were significantly higher in group B than in groups A and C, whereas pulsatility index, resistance index, and peak systolic velocity/end diastolic velocity of the uterine arcuate artery were significantly lower (P≤0.017 for all comparisons). Simultaneous administration of rhGH with HRT could improve clinical outcomes after FET by increasing endometrial blood perfusion and expression of cytokines related to endometrial receptivity.

Effect of Recombinant Human Growth Hormone and Rosiglitazone for HIV-Associated Abdominal Fat Accumulation on Adiponectin and other Markers of Inflammation

Background/Objective: In a previous report of HIV-infected patients with fat redistribution, we found that recombinant human growth hormone (rhGH) therapy reduced visceral adipose tissue (VAT) but increased insulin resistance, and that the addition of rosiglitazone reversed the negative effects of rhGH on insulin sensitivity. In this study, we sought to determine the effects of rhGH and rosiglitazone therapy on an array of inflammatory and fibrinolytic markers.Methods: 72 patients with HIV-associated abdominal obesity and insulin resistance were randomized to treatment with rhGH, rosiglitazone, the combination of rhGH and rosiglitazone, or placebo for 12 weeks. Subjects with plasma and serum samples available at weeks 0 (n = 63) and 12 (n = 46–48) were assessed for adiponectin, C-reactive protein, homocysteine, interleukin-1, interleukin-6, tumor necrosis factor alpha, interferon gamma, fibrinogen, plasminogen activator inhibitor-1 antigen, and tissue plasminogen activator antigen.Results: Treatment with both rosiglitazone alone and the combination of rosiglitazone and rhGH for 12 weeks resulted in significant increases in adiponectin levels from baseline. Adiponectin levels did not change significantly in the rhGH arm alone . There were no significant changes in the other biomarkers among the different treatment groups.Discussion: In this study of HIV-infected patients with altered fat distribution, treatment with rosiglitazone had beneficial effects on adiponectin concentrations, an effect that was also seen with a combination of rosiglitazone and rhGH. RhGH administration alone, however, did not demonstrate any significant impact on adiponectin levels despite reductions in VAT.

Comparative Analysis of Human Growth Hormone in Serum Using SPRi, Nano-SPRi and ELISA Assays

Sensitive and selective methods for the detection of human growth hormone (hGH) over a wide range of concentrations (high levels of 50-100 ng ml−1 and minimum levels of 0.03 ng ml−1) in circulating blood are essential as variable levels may indicate altered physiology. For example, growth disorders occurring in childhood can be diagnosed by measuring levels of hGH in blood. Also, the misuse of recombinant hGH in sports not only poses an ethical issue it also presents serious health threats to the abuser. One popular strategy for measuring hGH misuse, relies on the detection of the ratio of 22 kDa hGH to total hGH, as non-22 kDa endogenous levels drop after exogenous recombinant hGH (rhGH) administration. Surface plasmon resonance imaging (SPRi) is an analytical tool that allows direct (label-free) monitoring and visualization of biomolecular interactions by recording changes of the refractive index adjacent to the sensor surface in real time. In contrast, the most frequently used colorimetric method, enzyme-linked immunosorbent assay (ELISA) uses enzyme labeled detection antibodies to indirectly measure analyte concentration after the addition of a substrate that induces a color change. To increase detection sensitivity, amplified SPRi uses a sandwich assay format and near infrared quantum dots (QDs) to increase signal strength. After direct SPRi detection of recombinant rhGH in spiked human serum, the SPRi signal is amplified by the sequential injection of detection antibody coated with near-infrared QDs (Nano-SPRi). In this study, the diagnostic potential of direct and amplified SPRi was assessed for measuring rhGH spiked in human serum and compared directly with the capabilities of a commercially available ELISA kit.

A Child with Local Lipohypertrophy following Recombinant Human Growth Hormone Administration.

Local lipohypertrophy due to recombinant human growth hormone (rhGH) administration is a rare phenomenon. Here, we report a case of an 11-year-old girl who presented with a paraumbilical swelling, approximately one year after the start of rhGH treatment for short stature due to the presumed diagnosis of partial growth hormone insensitivity. Ultrasound imaging revealed an asymmetric distribution of subcutaneous fat tissue at the rhGH administration site, indicating local lipohypertrophy. After sparing her routine injection site and alternating other sites, the swelling disappeared within 6 months. Although the precise cause of local lipohypertrophy resulting from rhGH administration is still unclear, it might be related to the presumed diagnosis of partial growth hormone insensitivity.

Self-administration of Recombinant Human Growth Hormone with an Electronic Device: Clinical, Economic and Management Benefits of Objective Adherence Monitoring

Purpose: The aim was to identify factors affecting treatment adherence and to assess the clinical, economic and management impact of growth hormone deficiency treatment using an electronic auto-injector for recombinant human growth hormone (r-hGH) administration in children. Patients and Methods: A literature review was conducted in PubMed up to 31JUL2013, including the following search terms: “growth hormone deficiency”, “human-recombinant growth hormone” and “treatment adherence”. An economic model was developed to estimate the economic benefits of using an electronic injection device. In order to quantify this benefit, potential savings due to growth hormone cartridge optimization were analyzed. Results: From the literature review, the following key factors were found to affect treatment adherence: type of device used, discomfort, complexity of treatment regimens, long-term treatment, age and patient or family understanding of treatment benefits were assessed. A better adjustment to prescribed daily dose (accuracy up to 0.01 mg) with the electronic device results in a better optimization of vials and could save an average of 5% of total treatment costs in terms of doses not wasted, amounting to €245 of potential savings per patient and year of treatment. Conclusion: The use of an electronic device for r-hGH administration and monitoring may provide a better identification of responder and adherent patients. It may also generate savings in annual r-hGH consumption by hospitals and regional healthcare services.

Height outcome of short children with hypochondroplasia after recombinant human growth hormone treatment: a meta-analysis.

Hypochondroplasia (HCH) is a genetic skeletal dysplasia, characterized by rhizomelic short height (Ht) with facial dysmorphology and lumbar hyperlordosis. Albeit there are concerns that HCH children may not achieve optimal long-term outcome in response to recombinant human growth hormone (rhGH), anecdotal experiences suggested at least short-term Ht improvement. After thorough search of published studies, meta-analysis of rhGH use in HCH children was performed. In 113 HCH children, rhGH administration (median 0.25 mg/kg/week) progressively improved Ht pattern with 12 months catch-up growth (p < 0.0001). Then, Ht improvement resulted constant until 36 months (p < 0.0001), but stature remained subnormal. While bone age chronologically progressed, no serious adverse events were reported. In conclusion, our meta-analysis indicates that rhGH treatment progressively improved Ht outcome of HCH subjects.

A pilot study of growth hormone administration in boys with predicted adult short stature and near-ending growth

ContextThe growth-promoting effect of starting recombinant human growth hormone (rhGH) at the time of near-ending growth has not been studied in sexually mature boys who will have idiopathic short stature (ISS) as adults because it is believed that such an advanced stage of puberty would preclude favorable results. Objectives1) To explore the effects of starting rhGH administration at time of near-ending growth in boys with ISS. 2) To search for predictors of response to rhGH. SubjectsFifteen boys aged 15.5±1years terminating puberty were growing at a rate <2cm/6months towards a predicted adult height (PAH) <−2.5 SDS. MethodsParticipants received 0.50±0.06mg/kg·wk of rhGH according to a target-to-treat protocol. When growth became less than 0.5cm in 3months or when height has reached 169cm, rhGH was ceased. Testosterone, growth velocity (GV), height, serum IGF-1, bone age (BA) at hand–wrist and knee score were measured at onset; IGF-1 and height were monitored every 3months. A formula for PAH was developed. Height increment (HI, adult height-starting height) and height gain (HG, adult height-PAH) were calculated. ResultsFollowing rhGH administration for 11.1±4.8months, GV-SDS increased from −2.5±1.7 to 3.5±4.3 (P=2×10−4), HI=8.5±3.7cm, HG=6.8±4.8cm and adult height was −1.8±0.9 SDS, compared to a PAH of −2.9±0.6 SDS (P=4×10−4). Knee score (P=2×10−3), GV at rhGH onset (P=8×10−3) and rhGH dose (P=8×10−3) were identified as predictors of HI and HG, but BA was not. ConclusionsOur study suggests that 1) a short period of rhGH administration can increase true adult height significantly in boys with ISS at time of near-ending growth; and 2) knee score rather than BA should be used to identify rhGH responders. These preliminary observations await confirmation by larger randomized trials.

Growth Hormone Bioavailability, Insulin-Like Growth Factor-I and IGFBinding-Protein-3 Release in Japanese and Caucasian Subjects

Context: The pharmacokinetics (PK) of the recombinant human GH (rhGH) is poorly documented for the Japanese adult population, and a study comparing the PK, insulin-like growth factor-I (IGF-I) and IGF-bindingprotein- 3 (IGFBP-3) release between Japanese and Caucasian subjects after rhGH administration has previously not been reported. Objective: To compare the profiles of serum GH concentrations and the IGF-I and IGFBP-3 responses after administration of identical doses of rhGH to healthy Japanese and Caucasian subjects. Design and Setting: A randomised, double-blind, placebo-controlled, parallel-group study. Participants and Intervention: A total of 80 healthy male subjects (40 Japanese and 40 Caucasians) completed the study. A single dose of rhGH or placebo was administered subcutaneously, and blood samples were drawn up to 24 hours post-administration. Main Outcome Measures: Standard PK parameters, including the area under the GH concentration–time curve from 0 to 24 hours (AUC[0-24h]) and maximum GH concentration from 0 to 24 hours (Cmax). The IGF-I and IGFBP-3 levels were measured at various timepoints during the sampling period. Results: The bioavailabilities for Japanese and Caucasian subjects in terms of AUC(0–24 h) and Cmax were considered equivalent. The time to maximum GH concentration from 0–24 hours (tmax) was not statistically different for Japanese and Caucasian subjects. No differences in IGF-I or IGFBP-3 levels were observed. Conclusion: The bioavailabilities of rhGH for Japanese and Caucasian subjects are considered equivalent. Basal circulating IGF-I and IGFBP-3 levels and the release of IGF‑I and IGFBP-3 after administration of rhGH were similar between the two ethnic populations.

Whether the administration of thyroid hormones may play a role in the treatment of short stature?

Normal thyroid hormone secretion or optimal substitution of L-thyroxine is necessary for the proper functioning of the hypothalamic-pituitary-IGF-I axis. Over 30 years ago Cacciari et al. [1] indicated a slight risk of inducing an alteration of thyroid function in patients with GH deficiency during hGH therapy and recovery of thyroxine (T4) and trijodthyronine (T3) values to normal limits during follow-up. The rGH therapy might disclose previously unrecognised thyroid insufficiency rather than induce hypothyroidism [2,3]. The phenomenon of unmasking central hypothyroidism after the beginning of rGH therapy in some children with previous diagnosis of isolated GH-deficiency was described. Changes in TSH secretion during initial phase of the rGH therapy are less evident than fluctuations of FT4 concentration. The possibility of a decrease of TSH in terms of rhGH administration has been explained by an increase of somatostatin, a natural TSH inhibitor. The most frequently quoted mechanism of changes in thyroid hormone levels is GH-mediated increase of peripheral T4 to T3 deiodination. The potential role of IGF-I in stimulating that process has been postulated. Chernausek et al. [4] documented that IGF-I concentrations were diminished in hypothyroid patients. The mechanism of this phenomenon remained unclear. Diminished GH secretion or direct effects of hypothyroidism upon IGF-I production were considered. It is well documented that in patients with congenital hypothyroidism and caused by thyroiditis L-T4 replacement led to physiological increase of IGF-I and IGFBP3 secretion. It was proven that in children with neglected congenital hypothyroidism, even after a long period of hypothyroidism, L-T4 replacement improved the growth rate, leading to a partial recovery of the GH-IGF-I axis [5]. In GH-deficient children from the beginning of rhGH therapy - in euthyroid status - has not been recommended the obligatory L-T4 supplementation due a little evidence for the development of clinically significant hypothyroidism in most of previously euthyroid patients and spontaneous recovery to pre-treatment thyroid function in most patients [6]. Maintaining euthyroid status is important for the best effectiveness of rhGH therapy. The incidence of revealing hypothyroidism should be taken into account while starting rhGH therapy, as hypothyroidism may worsen the poor response to the therapy. It seems that assessment of TSH and FT4 concentration after rhGH therapy onset should be performed earlier and more often - for example every 3 months. It seems important to establish, if possible, the threshold values of pre-rhGH treatment TSH and/or FT4 levels for revealing hypothyroidism during rhGH therapy [7].

Effects of recombinant human growth hormone (rhGH) administration on body composition and cardiovascular risk factors in obese adolescent girls.

BackgroundObesity is associated with a relative deficiency of growth hormone, which is predictive of greater visceral fat and markers of cardiovascular risk. The study’s purpose was to use recombinant human growth hormone (rhGH) as a physiologic probe to assess the effects of reversing obesity-related GH deficiency on body composition, cardiovascular risk markers, and insulin resistance.Methods22 obese girls 13–21 years old were followed for a randomized 6-month trial of rhGH vs. placebo/no treatment. At baseline and 6-months, DXA was performed for body composition, MRI to measure visceral, subcutaneous and total adipose tissue (VAT, SAT and TAT), and fasting blood drawn for IGF-1, inflammatory cardiovascular risk markers [soluble intercellular adhesion molecule (sICAM), high sensitivity CRP], lipids and HbA1C. An oral glucose tolerance test (OGTT) was performed. Twelve girls completed the 6-month visit. Baseline and mean 6-month change were compared between the groups using the Student t-test and the relationship between variables was determined through multiple regression analysis.ResultsAfter 6-months, the rhGH group maintained IGF-1 levels, and had decreases in total cholesterol (p = 0.03), sICAM-1 (p = 0.04) and HbA1C (p = 0.03) compared to placebo/no treatment. The rhGH group trended towards greater decreases in LDL and 2-hour OGTT glucose. Glucose tolerance did not worsen with rhGH administration.ConclusionsAdministering rhGH in small doses is able to stabilize IGF-1 levels in obesity. We have also shown that rhGH administration leads to an improvement in some markers of cardiovacular risk with without adversely affecting glucose tolerance.Trial registrationClinical Trial Registration Number: NCT01169103.

A novel soluble supramolecular system for sustained rh-GH delivery.

Methoxy-poly(ethylene glycol)s bearing a terminal cholanic moiety (mPEG(5kDa)-cholane, mPEG(10kDa)-cholane and mPEG(20kDa)-cholane) were physically combined with recombinant human growth hormone (rh-GH) to obtain supramolecular assemblies for sustained hormone delivery. The association constants (Ka) calculated by Scatchard analysis of size exclusion chromatography (SEC) data were in the order of 10(5)M(-1). The complete rh-GH association with mPEG(5kDa)-cholane, mPEG(10kDa)-cholane and mPEG(20kDa)-cholane was achieved with 7.5 ± 1.1, 3.9 ± 0.4 and 2.6 ± 0.4 w/w% rh-GH/mPEG-cholane, respectively. Isothermal titration calorimetry (ITC) yielded association constants similar to that calculated by SEC and showed that rh-GH has 21-25 binding sites for mPEG-cholane, regardless the polymer molecular weight. Dialysis studies showed that the mPEG-cholane association strongly delays the protein release; 80-90% of the associated rh-GH was released in 200 h. However, during the first 8h the protein formulations obtained with mPEG(10kDa)-cholane and mPEG(20kDa)-cholane showed a burst release of 8 and 28%, respectively. Circular dichroism (CD) analyses showed that the mPEG(5kDa)-cholane association does not alter the secondary structure of the protein. Furthermore, mPEG(5kDa)-cholane was found to enhance both the enzymatic and physical stability of rh-GH. In vivo pharmacokinetic and pharmacodynamic studies were performed by subcutaneous administration of rh-GH and rh-GH/mPEG(5kDa)-cholane to normal and hypophysectomised rats. The study showed that mPEG(5kDa)-cholane decreases the maximal concentration in the blood but prolongs the body exposure of the protein, which resulted in 55% bioavailability increase. Finally, rh-GH formulated with mPEG(5kDa)-cholane yielded prolonged weight increase of hypophysectomised rats as compared to rh-GH in buffer or formulated with mPEG(5kDa)-OH. After the second administration the weight of the animals treated with rh-GH formulated with mPEG(5kDa)-cholane was about 2 times higher than that obtained with equal dose of non-formulated rh-GH.

Growth hormone enhances fat-free mass and glutamine availability in patients with short-bowel syndrome: an ancillary double-blind, randomized crossover study , ,

Benefits of recombinant human growth hormone (rhGH) alone or combined with glutamine in patients with intestinal failure because of short-bowel syndrome remain controversial. We explored effects of rhGH on whole-body protein metabolism in patients with short-bowel syndrome with intestinal failure (SBS-IF) to gain insight into its mechanism of action. Eight stable hyperphagic patients with severe SBS-IF received, in a double-blind, randomized crossover study, low-dose rhGH (0.05 mg · kg⁻¹ · d⁻¹) and a placebo for two 3-wk periods. Leucine and glutamine kinetics under fasting and fed conditions, fat-free mass (FFM), and serum insulin were determined on the final day of each treatment. rhGH increased FFM and nonoxidative leucine disposal (NOLD; an index of protein synthesis) (P < 0.02), whereas FFM and NOLD were correlated in the fed state (r = 0.81, P = 0.015). With rhGH administration, leucine release from protein breakdown (an index of proteolysis) decreased in the fed compared with fasting states (P = 0.012), which was not observed with the placebo. However, the fast-to-fed difference in leucine release from protein breakdown was not significantly different between rhGH and placebo (P = 0.093). With rhGH, the intestinal absorption of leucine and glutamine increased (P = 0.036) and correlated with serum insulin (r = 0.91, P = 0.002). rhGH increased glutamine de novo synthesis (P < 0.02) and plasma concentrations (P < 0.03) in both fasting and fed states. In SBS-IF patients, feeding fails to decrease proteolysis in contrast to what is physiologically observed in healthy subjects. rhGH enhances FFM through the stimulation of protein synthesis and might decrease proteolysis in response to feeding. Improvements in de novo synthesis and intestinal absorption increase glutamine availability over the physiologic range, suggesting that beneficial effects of rhGH in hyperphagic patients might be achieved without glutamine supplementation.