rhGH Dose Research Articles

Decreased Thyroxine Levels during rhGH Therapy in Children with Growth Hormone Deficiency.

Background: Hypothyroidism in children leads to growth retardation. However, there is some evidence that recombinant human growth hormone (rhGH) therapy could suppress thyroid function. The most common observation in rhGH-treated patients is a decrease in thyroxine levels, which is reported as transient, but the studies in the field are inconsistent. We aimed to evaluate thyroid function in initially euthyroid children with idiopathic isolated GH deficiency during long-term rhGH therapy and to determine who is at a higher risk of thyroid function alterations during the therapy. Methods: The study group consisted of 101 children treated with rhGH for at least three years. Serum TSH and fT4 levels were determined at baseline, after the first six months and after each full year of therapy. The associations between changes in thyroid hormone levels during rhGH therapy and GH deficit, insulin-like growth factor-1 levels and growth response were investigated. Results: A significant decrease in fT4 levels (p = 0.01) was found as early as after the first six months of rhGH therapy. This effect persisted in the subsequent years of treatment without any significant changes in TSH values and tended to be rhGH dose related. Children with a greater fT4 decrease after the initiation of rhGH therapy were older, had higher bone age and responded to that therapy worse than children with lower fT4 changes. Conclusions: Our study revealed a long-term decrease in fT4 levels during rhGH therapy in initially euthyroid GHD children. The decrease in fT4 levels was associated with a lower growth response to rhGH therapy.

Analysis of the Influence of High-Dose rhGH Therapy on Serum Vitamin D and IGF-1 Levels in School-Age Children with Idiopathic Short Stature.

Objective To discuss the influence of high-dose recombinant human growth hormone (rhGH) therapy on serum vitamin D and insulin-like growth factor-1 (IGF-1) levels in school-age children with idiopathic short stature (ISS). Method A total of 103 school-age children with ISS were selected from June 2016 to June 2020 in our hospital. The enrolled cases were divided into the low-dose group (n = 59) and high-dose group (n = 44) according to the treatment dose of rhGH. After the treatment, the height (Ht), height standard deviation score (Ht SDS), growth velocity (GV), and other indicators were recorded. The serum 25-hydroxy vitamin D [25-(OH)D] and IGF-1 levels of the two groups were tested, and the occurrence of adverse reactions was recorded. Results After treatment, the high-dose group outperformed the low-dose group in various growth effect indicators such as Ht, Ht SDS, and GV (P < 0.05). After treatment, the serum 25-(OH)D of children with ISS in the two groups increased significantly, but there was no significant difference between the two groups (P > 0.05). After treatment, the serum IGF-1 of children with ISS in the two groups increased significantly, but there was no significant difference between the two groups (P > 0.05). For children with ISS, adverse reactions induced by rhGH therapy were very rare. There was no significant difference in the incidence of adverse reactions induced by different doses of rhGH in the treatment of ISS (P > 0.05). Conclusion rhGH has definite efficacy in the treatment of ISS children, for it can significantly increase the annual growth rate of ISS children in a dose-dependent manner. High-dose rhGH for ISS has a better therapeutic effect. At the same time, regardless of the dose level of rhGH, serum 25-(OH)D and IGF-1 levels in children with ISS were increased, with less adverse reactions and higher safety.

The Auxological and Metabolic Consequences for Children Born Small for Gestational Age.

'Small for gestational age' (SGA) is an auxological and not an etiological definition that characterizes children born small based upon low-birth-weight and/or birth-length criteria [≥ 2 standard deviations (SD) below the mean for gestational age]. Most SGA children exhibit catch-up growth into the normal range within 6 mo of age. Overall SGA children are 4cm shorter than expected based upon midparental height and being born SGA is a common cause of adult short stature. Recombinant human growth hormone (rhGH) has been shown to improve adult height by 0.9 SDs and is a safe treatment. Surprisingly, a higher rhGH dose (67 μgm/kg/d) did not lead to a greater adult height than a conventional dose (33 μgm/kg/d). At least 85% of SGA children treated through childhood with rhGH achieve a height within the normal adult range. Other long-term consequences for children born SGA include insulin resistance, abdominal adiposity, dyslipidemia, type 2 diabetes mellitus, and metabolic syndrome. Cross-sectional studies have found reduced insulin sensitivity in the neonatal, childhood, and young adult periods. Increased abdominal fat has been shown in preschool SGA children and is more evident in young adults. Increased adiposity markedly accentuates reduction in insulin sensitivity. Many SGA children have suffered from in utero nutritional restriction that leads to long-term growth restriction and adverse metabolic sequelae.

Safety and Effectiveness of Recombinant Human Growth Hormone in Children with Turner Syndrome: Data from the PATRO Children Study

Introduction: PATRO Children is an international, observational, postmarketing surveillance study for a biosimilar recombinant human growth hormone (rhGH; somatropin, Omnitrope®; Sandoz), approved by the European Medicines Agency in 2006. We report safety and effectiveness data for patients with Turner syndrome (TS). Methods: The study population included infants, children, and adolescents with TS who received Omnitrope® treatment according to standard clinical practice. Adverse events (AEs) were monitored for safety evaluation, and height velocity (HV), height standard deviation score (HSDS), and HVSDS were calculated to evaluate treatment effectiveness. Results: As of August 2019, 348 TS patients were enrolled from 130 centers. At baseline, 314 patients (90.2%) were prepubertal and 284 patients (81.6%) were rhGH treatment naïve. The mean (range) age at baseline was 9.0 (0.7–18.5) years, and mean (SD) treatment duration in the study was 38.5 (26.8) months. Overall, 170 patients (48.9%) reported AEs, which were considered treatment related in 25 patients (7.2%). One treatment-related serious AE was reported (intracranial hypertension). Mean ΔHSDS after 3 years of therapy was +1.17 in treatment-naïve prepubertal patients and +0.1 in pretreated prepubertal patients. In total, 51 patients (31.1%) reached adult height (AH), 35 of whom were rhGH treatment naïve; in these patients, mean (SD) HSDS was −2.97 (1.03) at the start of Omnitrope® treatment, and they achieved a mean (SD) AHSDS of −2.02 (0.9). Conclusion: These data suggest that biosimilar rhGH is well tolerated and effective in TS patients managed in real-life clinical practice. Optimization of rhGH dose may contribute to a higher AH.

Etiology and Treatment of Growth Delay in Noonan Syndrome.

Noonan syndrome is characterized by multiple phenotypic features, including growth retardation, which represents the main cause of consultation to the clinician. Longitudinal growth during childhood and adolescence depends on several factors, among them an intact somatotrophic axis, which is characterized by an adequate growth hormone (GH) secretion by the pituitary, subsequent binding to its receptor, proper function of the post-receptor signaling pathway for this hormone (JAK-STAT5b and RAS/MAPK), and ultimately by the production of its main effector, insulin like growth factor 1 (IGF-1). Several studies regarding the function of the somatotrophic axis in patients with Noonan syndrome and data from murine models, suggest that partial GH insensitivity at a post-receptor level, as well as possible derangements in the RAS/MAPK pathway, are the most likely causes for the growth failure in these patients. Treatment with recombinant human growth hormone (rhGH) has been used extensively to promote linear growth in these patients. Numerous treatment protocols have been employed so far, but the published studies are quite heterogeneous regarding patient selection, length of treatment, and dose of rhGH utilized, so the true benefit of GH therapy is somewhat difficult to establish. This review will discuss the possible etiologies for the growth delay, as well as the outcomes following rhGH treatment in patients with Noonan syndrome.

Treatment with recombinant growth hormone in children with Turner syndrome: a study from a tertiary university center

Introduction : Turner syndrome (TS) is a rare disease with typical phenotype manifestations and short stature. Part of the therapy in TS patients is the recombinant human growth hormone (rhGH) that leads to improved height velocity and final height. Aim : The aim of the current study is to summarize the results of the diagnosis and treatment with rhGH of the TS patients followed up at a tertiary university center from 2011 to 2020. Patients and Methods : The study design is a retrospective cohort evaluation. All study participants had at least one full year of observation at the center. A total of 28 children with genetically confirmed TS or TS variation karyotype, aged between 2 and 18 years, 92.9 % of whom were girls, participated in the study. Results : The mean age at diagnosis was 9.6±3.7 years. Therapy with rhGH was started at 9.27±3.4 years in 22 (78.5%) of them with a mean rhGH dose of 0.035±0.006 mg/kg/d, which led to height gain of 8.0±1.3 cm for the first year. With a similar rhGH dose for the 2 nd year of treatment (0.033±0.007 mg/kg/d), height velocity of 6.8±1.1 cm was achieved (p&lt;0.005). A positive change in SDS height was observed for the first year of therapy (-2.75±1.2 vs. -2.27±1.2, p=0.005). SDS IGF -1 before and after one treatment year increased significantly (-0.74±1.1 vs.1.57±1.4, p=0.001), without exceeding 2.0 SD. Conclusion : The achieved growth in the presented TS cohort is suboptimal though consistent with the international guidelines for treatment of TS, and could help optimize future treatment approach to TS patients in our center.

Testicular Growth and Pubertal Onset in GH-Deficient Children Treated With Growth Hormone: A Retrospective Study.

The prevalence of idiopathic oligozoospermia has been esteemed as high as 75%. An Italian survey has reported bilateral testicular hypotrophy in 14% of final-year high school students. The search for determinants of testicular growth in childhood is important for the primary prevention of spermatogenic failure. Therefore, this retrospective study aimed to evaluate the testicular growth and pubertal onset in deficient children treated recombinant human growth hormone (rhGH). To accomplish this, the clinical charts of 93 patients with GH deficiency (GHD) were carefully reviewed. Their mean age at the time of diagnosis was 11.2 ± 2.4 years. rhGH was administered for 44.0 ± 22.4 months, and the onset of puberty was recorded after a mean of 25.8 ± 22.4 months from the first rhGH administration. As expected, serum insulin-like growth factor 1 (IGF1) levels increased significantly after treatment. Before rhGH therapy, the Tanner stage was I in 59 out of 70 boys (84.3%), II in 8/70 (11.4%), III in 3/70 (4.3%). No one was on stage IV or V. The mean Tanner stage was 1.19 ± 0.51. At the last visit, the Tanner stage was I in 8/72 boys (11.1%), II in 6/72 (8.3%), III in 6/72 (8.3%), IV in 16/72 (22.2%), and V in 36/72 (50.0%). After a mean of 44.0 ± 22.4 months of rhGH treatment, the mean Tanner stage was 4.05 ± 1.30. Patients treated with rhGH showed a significant testicular volume (TV) growth over time, whereas no growth was observed in age-matched but not yet treated patients, even when the age was compatible with a spontaneous start of puberty. The multivariate regression analysis showed that the duration of treatment and the mean rhGH dose significantly predicted the percentage of TV increase. In contrast, age, serum FSH, and IGF1 levels, and final rhGH dose did not impact TV growth over time. In conclusion, these findings suggest that GH may play a role in testicular growth and pubertal onset, despite the descriptive nature of this study. Further properly designed studies are needed to confirm these findings. This knowledge may be useful to implement the diagnostic-therapeutic algorithm in case of a lack of testicular growth in childhood.

Impact of adherence on growth response during the first 2 years of growth hormone treatment

Adherence to growth hormone (GH) treatment impacts clinical outcomes. The aim of this study is to assess the impact of adherence to rhGH treatment (2 years) on auxological outcomes. Multicentric, retrospective observational study in rhGH-naïve GHD/SGA children treated with Saizen® during ≥2 years. Growth response was assessed by evaluating the change in height standard deviation score (ΔH SDS) and the index of responsiveness (IoR). Adherence was monitored using EasyPod™ Connect device. A total of 110 patients (3 Spanish centers) were evaluable (GHD n = 76, SGA n = 34). Adherence was 95.6 and 93.9% (year 1, 2). SGA and GHD children showed an increase of 0.6 cm/year and 1.1 cm/year for each 10% adherence modification. Lower adherence was observed in patients with lower pretreatment height velocity (HV) and in patients whose parents had a lower level of education. A positive correlation between index of responsiveness (IoR) during the first and second years with HV SDS during the second year and between IoR2 and adherence (year 1, 2) was observed. The frequency of patients with HV > 1 SD was higher (p = 0.025) among patients with adherence >90%. The best model to predict the height gain(cm) reaching an adjusted R squared of 0.489 involved percentage of adherence, Tanner stage, pretreatment HV, dose of rhGH, and whether the treatment was initiated before or after puberty. Adherence during the first 2 years of response was very high >90% and showed a negative association with age, pretreatment HV and treatment duration and a positive correlation with the level of parent education.

Growth response and metabolic effects of growth hormone therapy in appropriate-for-gestational-age growth hormonedeficient children in relation to birth size and gestational age: A preliminary study.

The aim of the study was to investigate the influence of birth weight (BW), birth length (BL) and gestational age (GA) on growth pattern and metabolic profile in appropriate-for-gestational-age (AGA) growth hormone-deficient children before and during recombinant human growth hormone (rhGH) therapy. Forty children with isolated idiopathic growth hormone deficiency underwent auxological and biochemical assessment at baseline and after 6 and 12 months of rhGH therapy. Biochemical analysis included: insulin-like growth factor I (IGF-I), adiponectin, resistin, fasting glucose, fasting insulin, total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and glycated haemoglobin (HbA1c). There was a tendency for positive association between BW and baseline height standard deviation score (SDS). GA correlated with baseline weight SDS (p=0.019) and BMI SDS (p=0.039). GA was associated with baseline fasting glucose (p=0.031), fasting insulin (p=0.027), HOMA-IR (p=0.010) and QUICKI (p=0.016). BW correlated with baseline HbA1c (p=0.032). After the initiation of rhGH therapy we did not find any significant relationships between birth size parameters or GA and metabolic profile of the studied children. In conclusion, our results suggest that AGA GH-deficient children born with higher birth size parameters and higher GA had better first-year growth response to rhGH therapy and better baseline metabolic profile, especially parameters of carbohydrate metabolism. In order to optimize the effects of rhGH therapy, higher rhGH doses should be considered in those GH-deficient children who were born with lower birth size and GA.

Premature Adrenarche in Children with Prader-Willi Syndrome Treated with Recombinant Human Growth Hormone Seems to Not Influence the Course of Central Puberty and the Efficacy and Safety of the Therapy.

Puberty in children with Prader-Willi syndrome (PWS) is usually delayed and/or incomplete but in some patients premature/early adrenarche is observed. We assessed the premature adrenarche (PA) in PWS patients during the recombinant human growth hormone (rhGH) therapy and influence of PA on the course of central puberty (CP), rhGH efficacy and safety, and patients’ metabolic state. Forty-nine PWS patients were treated with rhGH, 11 presented with PA (group 1) and 14 had normal course of adrenarche (group 2). PA was observed in 22.5% of the PWS children treated with rhGH. The mean time between the rhGH start and the adrenarche, the rhGH dose, the growth velocity and the insulin-like growth factor 1 SD (IGF1 SD) during the treatment, as well as the time of CP, final height SD and BMI SD were similar in both groups. There were also no significant differences in the metabolic assessment—the oral glucose tolerance test (OGTT) and lipid profile results. PA may be a part of the clinical picture of PWS, apart from hypogonadotrophic hypogonadism and it seems to have no influence on CP in PWS patients. The rhGH efficacy and safety were comparable in the patients with PA and the normal course of adrenarche.

Individual sensitivity to growth hormone replacement in adults.

The metabolic actions of growth hormone (GH) last a lifetime and involve several physiological functions associated with the control of body composition, energy metabolism, water regulation, immune response, cardiovascular performance, physical and mental work. Adult patients with GH deficiency (GHD) present a constellation of clinical findings, which include increased total and visceral body fat, low bone and muscle mass, reduced muscle strength, impaired anaerobic physical capacity, unfavorable cardiovascular profile, and poor quality of life. Recombinant human GH (rhGH) therapy has been proved to reverse or improve many abnormalities associated with GHD in adult life, but the therapeutic response is highly variable among patients and influenced by multiple factors, which are the main focus of this narrative review. Given the individual sensitivity of adult GHD patients to rhGH replacement, dose regimens evolved from weight-based to individualized dose-titration strategies, which improved efficacy and reduced the frequency of adverse events. Individual tailoring and maintenance doses of rhGH are mainly influenced by age, age at GHD onset, sex, body mass index, baseline GH status, quality of life and other pituitary hormone replacements. In addition, genetic background and poor adherence due to patient or product-related factors might play a role in the responsiveness to rhGH therapy. There have been attempts to develop predictive mathematical models to distinguish good and poor responders to rhGH therapy, but thus far none of them have been prospectively tested and validated in a large cohort of adult GHD individuals.

SUN-348 Growth Hormone Replacement in Adults During 8 Years Leads to Sustained Increase in Bone Mineral Density

Introduction: Adult growth hormone deficiency (AGHD) is associated with lower bone mass and likely with increased risk of fragility fractures. GH replacement leads to increase in bone mineral density (BMD).However, only few studies longer than 2 years exist. Aim: To assess long-term effect of recombinant GH replacement on BMD and bone turnover markers duringperiod of 8 years. Patients & Methods: Prospective follow-up of all (N=63) AGHD patients at one single center. All patients with adult GHD followed at single center. All participants were replaced with daily injection of recombinant human (rh) GH in IGF-1 normalizing regimen according to Endocrine Society Guidelines. Every 2 years, lumbar spine (L-spine) and total hip (TH) BMD using dual X-ray absorptiometry on Hologic Discovery device, was assessed. All patients were assessed for bone turnover markers; carboxy-terminal collagen crosslinks (CTx) and osteocalcin (OC), and 25(OH)D levels. Deficiencies of other pituitary axes were treated if necessary. All patients were supplemented with 800 IU /day of cholecalciferol and 1000-1200mg/day of calcium as recommended by International Osteoporosis Foundation. Results: Study group consisted of 38 males and 25 females (35 with adult onset (AO) /28 with childhood onset (CO); mean age at diagnosis 25,1 yrs) AGHD patients. All patients ended 8 years follow-up period without any treatment discontinuation during this period. Treatment was well tolerated, without any serious adverse event. IGF-1 has reached the normal ranges during first 6 months and remains normal during whole study period documenting good adherence to treatment (average dose of rhGH=0,4 mg/day). Both, L-spine and TH BMD increased significantly after 8 years of GH replacement (+8 % for L-spine BMD, +7,7% for TH BMD, both p<0,01). The highest peak of BMD was observed after 6 years of treatment. CTx increased by 35% (p<0,05) and remain stable, and no significant change in OC was observed during study period. Levels of 25(OH)D increased by 32% (p<0,05) from baseline. No clinical fractures were observed. Conclusion: Long-term GH replacement in adult GHD together with sufficient levels of vitamin D levels led to increase in BMD and CTx. This study supported fact that GH has sustained effect on bone mass and bone turnover and is safe and well -tolerated for the long time period.

SAT-096 Response to RHGH Therapy in Children with Isolated Short Stature with or Without an Identified Genetic Cause

Introduction: Children with isolated (former known as idiopathic) short stature (ISS) have been treated with rhGH with a variable response. Objectives: To evaluate the short-term response to rhGH therapy in children with ISS with or without a genetic diagnosis. Methods: We analyzed retrospectively the growth rate and height SDS change in the first year of rhGH treatment according to the presence or absence of defects in genes that regulate growth plate. The decision to start rhGH treatment was based on clinical features and the genetic results were obtained during the follow-up. Patients were enrolled in several previous genetic studies using gene candidate approach or multigene sequencing analysis. Results: A total of 51 prepubertal children (36 boys) with ISS were treated with rhGH. Thirteen of these children start puberty during the treatment and three of them were concomitant treated with GnRH analog. Basal characteristics of these children were 7.7 ± 3.2 years of age, height SDS -2.5 ± 0.8; sitting height/height (SH/H) SDS 1.2 ± 1.4; BMI SDS 0 ± 1.0 and mild delay of bone age (-1.6 ± 1.3 y). The mean target height SDS was -1.2 ± 0.9y, 18 (35%) of these children have at least one parent with height SDS < -2 and 3 (6%) both parents are short. Consanguinity was present in 3 (6%) cases. Among this cohort, fifteen children had pathogenic or likely pathogenic allele variants in genes that regulate growth plate: IHH (n = 4), SHOX (n = 9) and NPR2 (n = 2). Seven (47%) of these variants were inherited from a short stature parent. Children with or without an identified genetic cause have similar age and height SDS at the start of the treatment. A higher BMI and SH/H SDS were observed in children with genetic defects than in those without (BMI SDS 0.5 ± 1.1 vs. -0.15 ± 0.9, p = 0.02; SH/H SDS 2.0 ± 1.4 vs. 0.9 ± 1.3, p = 0.006). Additionally, children with genetic defects had a less marked bone age delay (-1.0 ± 1.3 vs. -1.9 ± 1.2; p = 0.02). Both groups were treated with similar rhGH dose (50 μg/kg/day). Patients with and without an identified genetic cause had similar improvement in growth velocity during the first year of therapy: 4.8 ± 1.6 to 8.9 ± 1.7 cm/y for patients with molecular diagnosis vs. 4.6 ± 1.2 to 8.5 ± 2.3 cm/y for those without. This resulted in similar height SDS change during this period for both groups (0.6 ± 0.3 vs. 0.6 ± 0.5 SDS for children with or without a genetic cause, respectively). Age at the start of treatment was the main variable that explains growth response variability during this first year (r2 = 0.17, p = 0.009). Conclusion: The presence or absence of an identified genetic cause, involving genes that regulate growth plate, did not significantly influence the short-term growth response to rhGH therapy of children with ISS. Long-term follow-up is still needed to assess the final height of these children and possibly to assess whether there is a different growth rate related to each known affected gene.

Uniparental disomy and pretreatment IGF-1 may predict elevated IGF-1 levels in Prader-Willi patients on GH treatment

Pediatric patients with Prader-Willi syndrome (PWS) can be treated with recombinant human GH (rhGH). These patients are highly sensitive to rhGH and the standard doses suggested by the international guidelines often result in IGF-1 above the normal range. We aimed to evaluate 1 the proper rhGH dose to optimize auxological outcomes and to avoid potential overtreatment, and 2 which patients are more sensitive to rhGH. In this multicenter real-life study, we recruited 215 patients with PWS older than 1 year, on rhGH at least for 6 months, from Italian Centers for PWS care. We collected auxological parameters, rhGH dose, IGF-1 at recruitment and (when available) at start of treatment. The rhGH dose was 4.3 (0.7/8.4) mg/m2/week. At recruitment, IGF-1 was normal in 72.1% and elevated in 27.9% of the patients. In the group of 115 patients with IGF-1 available at start of rhGH, normal pretreatment IGF-1 and uniparental disomy were associated with elevated IGF-1 during the therapy. No difference in height and growth velocity was found between patients treated with the highest and the lowest range dose. The rhGH dose prescribed in Italy seems lower than the recommended one. Normal pretreatment IGF-1 and uniparental disomy are risk factors for elevated IGF-1. The latter seems to be associated with higher sensitivity to GH. In case of these risk factors, we recommend a more accurate titration of the dose to avoid overtreatment and its potential side effects.

Treatment with Growth Hormone in Noonan Syndrome Observed during 25 Years of KIGS: Near Adult Height and Outcome Prediction

Background/Aims: There is little information how rhGH treatment affects height in NS. This study aims to analyze data from the NS patients assembled in KIGS over 25 years. Patients/Methods: Of 613 (389 m/224 f) NS patients documented, 476 (302 m/174 f) were treated for 1 year, 237 (160 m/77 f) of which served to develop a 1st year height velocity (HV) prediction algorithm. One-hundred and forty (74 m/66 f) had reached near adult height (NAH). Factors affecting NAH on rhGH were determined. Results: At the start of rhGH, the NAH groups were (median, m, f) 11.0 and 10.3 years, with a height SDS of –3.2 and –3.8 SDS (Prader), respectively. The total gain after 6.3 and 5.6 years on rhGH (0.27 and 0.30 mg/kg/week) was 1.2 and 1.3 SDS. Age at the start of rhGH (negative), height at the start of rhGH, rhGH dose, number of rhGH injections/wk and birth weight (all positive) explained 36% of the variability of 1st year HV. Height at the start of rhGH, 1st year growth on rhGH, birth weight, and gender explained 74% of the variability of NAH. Causes for rhGH treatment discontinuation and adverse events were also analyzed. Conclusion: rhGH treatment increases NAH in NS. Prediction algorithms may optimize treatment in the future.

Short- and long-term responsiveness to low dose growth hormone (GH) in adult GH deficiency: Role of GH receptor polymorphism.

In patients with growth hormone (GH) deficiency (GHD), low doses of recombinant human GH (rhGH) have a similar or better long-term clinical effect than higher doses. Pharmacogenetic studies suggest that GH receptor (GHR) polymorphism only influences some metabolic parameters. Nonetheless, there is no clear scientific evidence proving the effects of lower rhGH dose regimens on metabolic parameters. The aim of our prospective study was to evaluate the effects of GHR polymorphism in adult GHD patients treated with low rhGH dose during short- (6 and 12months) and long-term (5years) follow-up. Sixty-nine GHD adult patients were studied, before and during treatment with rhGH, using a standardised low-dose protocol calculated on the basis of body weight (0.01-0.03mgkg-1 week-1 ) and monitored by an insulin-like growth factor (IGF)-I plasma assay, as well as anthropometric and metabolic parameters. The GHR genotype (flfl, fld3 or d3d3) was determined from the peripheral blood. d3-GHR carriers showed a more effective short- and long-term response to low rhGH dose with respect to low-density lipoprotein reduction, body composition and blood pressure (homozygous patients only); d3-GHR homozygosity is related to a significant IGF-I increase during short-term follow-up. Regression analysis demonstrated that rhGH dose, age at diagnosis and GHR genotype are the major determinants of IGF-I increase at 6 and 12months of replacement therapy. The d3d3-GHR genotype may influence some metabolic effects during the short- and long-term follow-up of low rhGH dose and could be an independent determinant of the increase of IGF- I during short-term follow-up.

Growth Hormone Treatment for Idiopathic Short Stature.

ISS is the commonest cause of short stature and poor growth and is arbitrarily defined as a height < -2 SDS without an identified cause. ISS consists largely of normal children with the remainder unrecognised conditions, mainly syndromes and genetic (monogenic and polygenic) causes. Growth response to rhGH is widely variable reflecting the heterogeneity of ISS. Further identification of genetic causes of ISS will better characterise treatment response. rhGH during childhood has been shown in RCTs to improve adult height by approximately 4 cm which is less than seen in other treated growth disorders. Factors that influence response include; younger age, longer birth length, lower height compared to mid-parental height, delayed bone age and larger rhGH dose. The evidence that short stature is associated with psychological well-being and quality of life is minimal and that rhGH could improve this is scant. Further research in this area is urgently required.

The relationship between alkaline phosphatase and bone alkaline phosphatase activity and the growth hormone/insulin-like growth factor-1 axis and vitamin D status in children with growth hormone deficiency.

The relationships between bone turnover, the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and vitamin D are complex, but still not fully explained. The GH/IGF-1 axis and vitamin D can mutually modulate each other's metabolism and influence the activation of cell proliferation, maturation, and mineralization as well as bone resorption. The aim of this study was to evaluate the reciprocal associations between bone formation markers [alkaline phosphatase (ALP), bone alkaline phosphatase (BALP)], the GH/IGF-1 axis and 25-hydroxyvitamin D [25(OH)D] in children with growth hormone deficiency at baseline and during recombinant human growth hormone (rhGH) therapy. ALP, BALP, 25(OH)D and IGF-1 levels were evaluated in 53 patients included in this prospective three-year study. ALP, BALP and IGF-1 increased during rhGH therapy. Baseline ALP activity correlated positively with baseline height velocity (HV). ALP and BALP activity at 12 months correlated positively with HV in the first year of therapy. We found positive correlations between ALP and IGF-1 at baseline and during the first year of therapy, between BALP activity at 12 months and rhGH dose in the first year of therapy, and between doses of cholecalciferol in the first year of rhGH therapy and early changes in BALP activity during rhGH therapy. Our results indicate that vitamin D supplementation enhances the effect of rhGH on bone formation process, which could improve the effects of rhGH therapy. ALP and BALP activity are useful in the early prediction of the effects of rhGH therapy, but their utility as long-term predictors seemed insufficient.

Effect of recombinant human growth hormone therapy on blood lipid and carotid intima-media thickness in children with growth hormone deficiency

BackgroundReports on the association between growth hormone deficiency (GHD) and cardiovascular risk factors in children are limited. We aim to investigate the effect of different doses of recombinant human growth hormone (rhGH) therapy on blood lipid and carotid intima-media thickness (cIMT) in Chinese GHD children.MethodsNinety children, including sixty isolated GHD children and thirty healthy children, were enrolled. GHD children were randomly divided into two groups (A and B) according to the rhGH dose given: group A received 0.23 mg/kg/week and group B received 0.35 mg/kg/week for 12 months. The TC, TG, LDL-C, HDL-C, and cIMT at baseline and after treatment were measured.ResultsThe height, weight, and height velocity improved significantly over 12 months of rhGH therapy in all GHD children. At baseline, GHD children in both the treatment groups showed significantly higher total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), cIMT, and lower high-density lipoprotein-cholesterol (HDL-C) than healthy children (all P≤0.033). After the 12-month rhGH therapy, a significant decrease in the TC, TG, LDL-C, and cIMT, as well as a significant increase in the HDL-C (P≤0.046), was observed in the GHD children, with change in the group B being even more marked.ConclusionsThe RhGH replacement therapy in GHD children can improve both the blood lipid profile and carotid intima-media thickness, with higher-dose rhGH therapy showing superior effects.

Effect of recombinant human growth hormone on rotator cuff healing after arthroscopic repair: preliminary result of a multicenter, prospective, randomized, open-label blinded end point clinical exploratory trial

This study evaluated the effect of systemic injection of recombinant human growth hormone (rhGH) on outcomes after arthroscopic rotator cuff repair. This multicenter, prospective, randomized, comparative trial, randomized patients who underwent arthroscopic repair of large-sized rotator cuff tears into 3 groups: rhGH 4 mg group (n = 26), rhGH 8 mg group (n = 24) , and control group (n = 26). Sustained release rhGH was injected subcutaneously once weekly for 3 months postoperatively. The healing failure rate (primary end point), fatty infiltration, and atrophy of the supraspinatus muscle, and functional scores (Constant and American Shoulder and Elbow Surgeons scores) were evaluated at 6 months. Range of motion, pain visual analog scale, and serum insulin-like growth factor-1 level were measured at each follow-up. The healing failure rate was similar between groups (rhGH 4 mg group, 30.8%; rhGH 8 mg group, 16.7%; and control group, 34.6%; all P > .05) The proportion of severe fatty infiltration (Goutallier grade ≥3) was 20.8% in the rhGH 8 mg group, 23.1% in the rhGH 4 mg group, and 34.6% in the control group (P > .05). Functional outcomes, range of motion, and pain visual analog scale were similar between groups (all P > .05). The rhGH 8 mg group showed more increased peak insulin-like growth factor-1 level (279.43 ng/mL) than the rhGH 4 mg group ((196.82 ng/mL) and control group (186.31 ng/mL), which was not statistically different (all P > .05). No rhGH injection-related major safety issues occurred. This preliminary study showed no statistically significant improvement in healing or outcomes related to the treatment of rhGH after rotator cuff repair. However, further study with more enrolled patients after resetting the rhGH dose or daily administration protocol would be mandatory.