Recombinant Growth Hormone Research Articles

Floating-Harbor Syndrome in a Korean Patient with Short Stature and Early Puberty: A Case Report.

Floating-Harbor syndrome (FHS) is a rare autosomal dominant genetic disorder characterized by proportionately short stature, lack of expressive language, and distinctive facial features, including a large nose, long eyelashes, deeply set eyes, and a triangular face. We present a case of an 11-year-old Korean girl who was initially suspected of having Noonan-like syndrome but was later diagnosed with Floating-Harbor syndrome. The patient exhibited short stature, developmental language delay, dysmorphic facial features, and early puberty. Targeted exome sequencing revealed a heterozygous mutation, c.7303C>T (p.Arg2435Ter), in the SRCAP gene, confirming a diagnosis of Floating-Harbor syndrome. She responded well to human recombinant growth hormone and gonadotropin-releasing hormone (GnRH) agonist, effectively suppressing bone maturation and improving her height SDS from -4.6 to -2.4.

Auxological and metabolic effects of long-term treatment with recombinant growth hormone in children born small for gestational age: a retrospective study.

Children born small for gestational age (SGA) not showing catch-up during the first two years of life reportedly show an impaired growth rate and adult height, as well as a worse metabolic outcome, mainly in terms of glycemic and lipid profile, compared to general population. In SGA children with short stature, treatment with recombinant growth hormone (GH) is currently recommended until adolescence; therefore, it may last long-term. The aim of the current study was to evaluate the auxological and metabolic effects and the safety of long-term recombinant GH treatment in SGA children. The study included 15 SGA children (5 F, 10 M; mean age: 6.78 yrs) treated with GH for at least 48 months. Growth and metabolic parameters, including glycemic and lipid profile, transaminases, and urycemia, were collected every six months. Compared to baseline, SGA children showed a significant improvement in height, weight, and growth rate after four yaers of treatment with GH (p ≤ 0.002), being already evident after six months of treatment (p < 0.001). Noteworthy, patients showed a constant, significant improvement in height throughout the treatment, as it was significantly higher at each follow-up compared to the previous one, until 42 months of treatment, except at 30 months of treatment (p < 0.001 T6VST12; p < 0.01 T12VST18, T18VST24; p < 0.05 T30VST36, T36VST42). Considering metabolic parameters, compared to baseline, a recurring increase in glycemia (p ≤ 0.028 vs T30, T36, and T48) and decrease in AST (p ≤ 0.035 vs T36, T42, and T48) and an occasional decrease in LDL cholesterol (p ≤ 0.04 vs T24 and T42) and triglycerides (p = 0.008 vs T18) and increase in urycemia (p = 0.034 vs T42). Considering safety profile, treatment was well tolerated, as the most frequently reported adverse event was poor compliance (20%); no hyperglycemia, hypercholesterolemia or hyperstransaminasemia occurred throughout the treatment, CONCLUSIONS: Long-term GH treatment showed to be effective in improving height and growth rate in SGA children, with a positive impact of metabolic profile and a safety profile, although glycemia should be carefully monitored over time.

Assessment of adenohypophysis function and ghrelin level in children with biologically inactive growth hormone syndrome

Background. Mutations in the growth hormone (GH) gene cause various forms of biologically inactive growth hormone (BIGH) syndrome. Ghrelin potentiates the secretion of GH. Ade­nohypophysis hormones take part in human growth mechanisms. Insulin-like growth factor 1 (IGF-1) level is a criterion of GH activity. The purpose of the study was to assess the adenohypo­physis functions and to determine the role of ghrelin in patients with BIGH syndrome to optimize the diagnosis and treatment. Materials and methods. Anthropometric parameters were evalua­ted in 158 children with BIGH syndrome whose average age was 7.83 ± 1.23 years. The function of the adenohypophysis was evalua­ted accor­ding to the levels of somatotropin, thyroid-sti­mulating, adrenocorticotropic, luteinizing, follicle-stimulating hormone and their corresponding peripheral hormones, which were determined by radioimmunological methods and chemiluminescent immunoassay. A statistical analysis of the results was carried out. Results. The release of GH against the background of clonidine and insulin tests in patients with BIGH syndrome was higher than 10 ng/ml, the basal level of IGF-1 was significantly lower than the reference values. After a 4-day test for sensitivity to GH, the level of IGF-1 increased more than 2 times. Against the background of treatment with recombinant GH, serum thyroid-stimulating, adrenocorticotropic hormone, and cortisol indicators changed significantly, but their levels fluctuated within the reference values. Significant changes in ghrelin content were detected 120 minutes after falling asleep. Most children with BIGH syndrome had timely sexual development, precocious puberty was revealed in 19 children, the smallest was the group with delayed puberty (5 children). Gonadotropin-releasing hormone ana­logues were added to the GH treatment in case of unsatisfactory final growth. Conclusions. Normal/high levels of GH and reduced IGF-1 are characteristic of children with BIGH syndrome. In addition, these children have a significant increase in ghrelin in the first hours after falling asleep. The test for sensitivity to GH is a reliable diagnostic method. Thyroid and adrenal disorders were not found in patients with BIGH syndrome. Children with BIGH syndrome have normal sexual development with a tendency to precocious puberty. The simultaneous use of gonadotropin-releasing hormone analogues in combination with GH preparations significantly improves patients’ final growth.

IGF-2-mediated hypoglycemia: a case series and review of the medical therapies for refractory hypoglycemia.

Non-islet cell tumour hypoglycemia (NICTH), typically mediated by insulin-like growth factor 2 (IGF-2), is a rare but highly morbid paraneoplastic syndrome associated with tumours of mesenchymal or epithelial origin. Outside of dextrose administration and dietary modification which provide transient relief of hypoglycemia, resection of the underlying tumour is the only known cure for NICTH. Available medical therapies to manage hypoglycemia include glucocorticoids, recombinant growth hormone, and pasireotide. We report two cases of IGF-2 mediated hypoglycemia. The first was managed surgically to good effect, highlighting the importance of a timely diagnosis to maximise the likelihood of a surgical cure. The second patient had unresectable disease and was managed medically, adding to a growing number of cases supporting the efficacy of glucocorticoids and recombinant growth hormone in NICTH. Recurrent fasting hypoglycemia in the setting of a malignancy should raise suspicion of non-islet cell tumour hypoglycemia (NICTH), which is typically mediated by IGF-2. The initial workup for NICTH should include a serum glucose, C-peptide, insulin, insulin antibodies, beta-hydroxybutyrate, IGF-2, IGF-1, and sulphonylurea screen during a spontaneous or induced hypoglycemic episode. An IGF-2/IGF-1 ratio above 10 is highly suggestive of IGF-2-mediated hypoglycemia if the IGF-2 level is normal or elevated. False positives may be seen with sepsis and cachexia as both IGF-2 and IGF-1 are subnormal in these cases. A low IGF binding protein 3 (IGFBP3), such as in renal failure, may also result in a falsely normal or low IGF-2/IGF-1 ratio. Surgical resection of the associated tumour is curative in most NICTH cases. When the tumour is unresectable, moderate-dose glucocorticoids, low-dose glucocorticoids in combination with recombinant growth hormone, and pasireotide are medical therapies with promising results in controlling NICTH.

Expressão extracelular, purificação e produção em biorreator do hormônio de crescimento de tambaqui (Colossoma macropomum) na levedura Komagataella phaffii (anteriormente Pichia pastoris)

ABSTRACT Due to its zootechnical importance, the gene encoding growth hormone (GH) from several fish species has been isolated and expressed in heterologous systems. In this study, we isolated the cDNA sequence of GH of tambaqui (Colossoma macropomum), a species native to the Amazon basin and considered promising for Brazilian fish farming, and expressed it in the yeast Komagataella phaffii GS115. Heterologous expression was regulated by the AOX1 promoter and recombinant tambaqui GH (rtGH) secreted to the culture supernatant via the alpha factor of Saccharomyces cerevisiae. The rtGH was successfully expressed in shaken flask and bioreactor systems and purified using affinity chromatography. In the bioreactor, the production reached 250 mg L-1. This is the first report of the heterologous expression, purification and production of rtGH in a bioreactor. Our results contribute to making tambaqui a target species for future biotechnological innovations based on the significant levels of rtGH obtained in the bioreactor and the future zootechnical applications of this protein, which can be exploited in aquaculture.

Effect of treatment with growth hormone on body composition and metabolic profile of short children born small for gestational age.

To assess the effect of recombinant growth hormone (rGH) on body composition and metabolic profile of prepubertal short children born small for gestational age (SGA) before and after 18 months of treatment. It is a clinical, non-randomized, and paired study. Children born SGA, with birth weight and/or length <-2 standard deviations (SD) for gestational age and sex, prepubertal, born at full term, of both genders, with the indication for treatment with rGH were included. The intervention was performed with biosynthetic rGH at doses ranging from 0.03 to 0.05 mg/kg/day, administered subcutaneously, once a day at bedtime. Total lean mass (LM) and total fat mass (FM) were carried out using dual-energy X-ray absorptiometry (DXA), and the metabolic profile was assessed for insulin, glycemia, IGF-1 levels and lipid profile. Twelve patients (nine girls, 8.17±2.39 y) were evaluated; three patients dropped out of the study. There was an increase of LM adjusted for length (LMI) (p=0.008), LMI standard deviation score (SDS) adjusted for age and sex (p=0.007), and total LM (p<0.001). The percentage of body fat (BF%) and abdominal fat (AF) remained unaltered in relation to the beginning of treatment. Among the metabolic variables, blood glucose remained within normal levels, and there was a reduction in the number of participants with altered cholesterol (p=0.023). The effect of rGH treatment was higher on LM than in FM, with increased LM adjusted for length and standardized for age and sex. Glycemia remained within the normal limits, and there was a decreased number of children with total cholesterol above the recommended levels.

Indications for genetic diagnosis in children with growth hormone deficiency and born small for gestational age.

The aim of the study is to analyze patients who do not respond adequately to human recombinant growth hormone (rhGH) treatment. Four boys were analyzed: three patients diagnosed with SNP at the ages of 1) 8 years and 2 months, 2)13years and 2 months, 3) 16 years and 6 months, and patient 4) at the age of 6 years and 11 months - born small for gestational age (SGA). They underwent rhGH treatment. The expected growth improvement was not observed in all boys. Patient 1 was diagnosed with aortic coarctation, and after each attempt to increase the rhGH dose, nocturnal vomiting occurred - epilepsy was diagnosed. Patient 2 had severe foot pain. Patient 3 had delayed puberty - hypogonadotropic hypogonadism was diagnosed. Patient 4 had dysmorphic features. Genetic tests revealed the following: 1) mixed gonadal dysgenesis - modifying treatment; 2) Fabry disease - enzyme treatment and rhGH improved growth; 3)Kallmann syndrome - discontinuing rhGH for testosterone supplementation; 4) KBG syndrome. 1. The presence of dysmorphic features and symptoms atypical for growth hormone deficiencies could warrant genetic diagnostics before initiating treatment. 2. Lack of significant improvement in growth is an indication for reevaluation of patients who have not completed growth. 3. Genetic studies in this patient group often elucidate the causes of slow growth rate. 4. The case authors have developed aproposal for amulticentre program aimed at establishing indications for genetic diagnosis in children diagnosed with SNP and SGA treated with rhGH.

Familial Combined Pituitary Hormone Deficiency by a Mutation in PROP1 – a Case Report

Objective This paper aimed to emphasize the importance of considering the diagnosis of PROP1 mutation in all cases where multiple members of the same family are affected by combined pituitary hormone deficiencies (CPHD).Case Report − We describe two brothers of unrelated parents with a mutation in the PROP1 gene. Both brothers presented with growth impairment - the older one at the age of 2.5 years, and the younger one at the age of 3.3 years. Central hypothyroidism and GH deficiency were established in both of them. Replacement therapy was started using levothyroxine and recombinant growth hormone. Pituitary magnetic resonance imaging was normal. Genetic analysis identified a pathogenic homozygous frameshift variant c.301_302delAG in the PROP1 gene.Conclusion − Patients with PROP1 mutation must be closely followed up to reveal other possible hormonal defects and to avoid possible life-threatening adrenal crisis in the future. PROP1 mutation should be considered in all familial forms of CPHD and in all patients who have a deficiency of two or more pituitary hormones.

GROWTH HORMONE, IMMUNOSENESCENCE AND VACCINATION FAILURE IN THE ELDERLY

In the aging population, the longitudinal decrease in the secretion of steroidal and polypeptides growth hormones is directly associated with accumulation of senescent cells in tissues and organs. The cellular hypo-replicative senescence state is caused by metabolic stress and persistent DNA damage, which lead to the activation of the p16INK4a cell-cycle inhibitor, retinoblastoma and p53 pathways. Aging increases the susceptibility to physical frailty, sarcopenia, diabetes, atherosclerosis, infectious disease and cancer in the older adults. As a consequence of immunosenescence and reduced immunoreactivity of the innate and adaptive systems, seniors have a weak response to vaccination. The high doses of vaccines have been recommended to boost growth and activation of memory T and B cells in non-responsive older individuals, but it is not sufficient for long-term protection. The treatment with recombinant human growth hormone has been shown to regenerate thymus and increase the repertoire of naive T cells CD4+ and CD8+ T cell and B cell subsets in people with age-related diseases, chronic viral infection and immunodeficiencies. This review presents an update on senescence biology and their clinical immunological manifestations in the elderly. We describe possible immune mechanisms by which personalized recombinant growth hormone therapy could act to prolong the effectiveness of the vaccines recommended to older adults.

Ambulatory blood pressure monitorisation in children with recombinant growth hormone treatment.

It is safe to use recombinant growth hormone in children. Studies have shown it to be effective and safe, except for a few side effects in the short and long term after treatment. The present study investigated the presence of hypertension in pediatric patients receiving growth hormone treatment using 24 h ambulatory blood pressure monitoring (ABPM). This study is a single-center, retrospective study. Eighty-four patients aged 5-16 years who received growth hormone treatment for at least 3months, who underwent 24 h ABPM were analyzed. They were compared with 67 patients who had no risk factors for hypertension. In the study, 84 rhGH-treated patients (45.2 % male, 54.8 % female) and 67 healthy control groups (49.3 % male, 50.7 % female) were analyzed. The mean age of the patient group was 10.83±2.85 years and the mean age of the healthy control group was 13.1±2.93 years. The diagnostic classification of the patients receiving treatment was as follows: 66.6 % (n=56) partial growth hormone deficiency, 22.6 % (n=19) growth hormone deficiency, 7.1 % (n=6) bioactive growth hormone, 2.3 % (n=2) idiopathic short stature, 1.1 % (n=1) low birth weight for gestational age (SGA). Body mass index was significantly lower in the treated group (p=0.013). The duration of treatment was 6.04±4.9months. Daytime diastolic blood pressure was significantly lower in the treated group (p=0.001). There was no correlation between BMI and ABPM parameters in the treatment group and the control group. The present study shows that growth hormone treatment is safe in terms of high blood pressure.

Cloning, Sequencing and Expression of Goonch Bagarius bagarius (Hamilton, 1822) Growth Hormone

Abstract Goonch Bagarius bagarius (Hamilton, 1822) is one of the largest and fastest-growing catfish of the Indus River found at Taunsa Barrage, Pakistan. The full-length cDNA of the growth hormone gene (600 bp) was amplified by reverse transcription of mRNA isolated from the pituitary gland of B. bagarius. The full-length growth hormone gene encodes a putative polypeptide of 200 amino acids with a molecular mass of 22.58 kDa. The precursor of B. bagarius growth hormone (GH) is composed of 22 amino acids as a signal peptide and 178 amino acids of a mature peptide. There were six conserved Cys residues in GH protein (20, 71, 135, 173, 190 and 198) that maintain the structural integrity of this protein. One putative N-glycosylation site was present at the 197th amino acid. The total number of positively charged (Arg and Lys) and negatively charged (Asp and Glu) residues is 42 and 31, respectively. The B. bagarius GH gene shows more than 90% sequence homology with other catfishes. The mature protein GH gene was expressed in Escherichia coli using pET-28 expression vector, and the recombinant protein of 19.5 kDa was detected through SDS-PAGE analysis. This study suggests that cloning and expression of B. bagarius GH gene would provide basic information for transgenic studies aimed at a faster growth rate. This recombinant GH may be produced on a large scale to exploit its growth-promoting function in other cultured fishes.

THU211 Novel SIN3A Loss-Of-Function Variant As Potentially Pathogenic For Hypogonadotropic Hypogonadism In Witteveen-Kolk Syndrome

Abstract Disclosure: L.M. Correa Brito: None. A.C. Keselman: None. N.M. Sanguineti: None. P.A. Scaglia: None. M. Esnaola Azcoiti: None. F. Villegas: None. M. Maier: None. I. Bergada: None. M.G. Ropelato: None. R.A. Rey: None. Witteveen-Kolk Syndrome (WITKOS, MIM #613406) is an autosomal dominant disorder characterized by short stature, typical facial dysmorphism, microcephaly and mild intellectual disability, initially associated with 15q24 microdeletions encompassing SIN3A gene. Subsequently, WITKOS was found in individuals with loss-of-function (LOF) variants in SIN3A. Central or hypogonadotropic hypogonadism (HH) has been described in patients with WITKOS due to 15q24 microdeletions, but whether HH was due to haploinsufficiency of SIN3A or of any of the other five genes located in the shortest region of overlap (∼260 kb) of 15q24 could not be ascertained. A 6-year-old girl was referred to us for short stature. She had a history of intrauterine growth retardation and presented with microcephaly, broad forehead, wide nasal base, prominent nasal bridge, short philtrum, overfolded helix, clinodactyly of the 5th finger, joint laxity, neurodevelopmental delay, attention deficit hyperactivity disorder (ADHD), sensorineural hearing impairment, bicuspid aortic valve and ulcerative proctitis. She was treated with recombinant growth hormone, with good response. At the age of 14, she showed absence of thelarche and was evaluated for delayed puberty. Serum estradiol was undetectable, and gonadotropins were low after a GnRH infusion test (LH basal 0.2 IU/L, peak 0.7 IU/L; FSH basal 0.1 IU/L, peak 0.6 IU/L). HH was diagnosed. An MRI scan revealed a bilateral agenesis of the olfactory bulbs and olfactometry detected anosmia, leading to the clinical diagnosis of Kallmann syndrome (HH with anosmia). Whole exome sequencing (WES) identified a novel heterozygous frameshift variant, NM_001145358.2:c.3045_3046dup, NP_001138830.1:p.(Ile1016ArgfsTer6) in SIN3A. The insertion creates a frameshift expected to lead to a stop codon and a loss of function due to nonsense-mediated mRNA decay. Her mother, who had no history of HH, was while type for SIN3A. Unfortunately, his father was not available. The variant was absent in GnomAD, and has not been reported in dbSNP, ClinVar and Uniprot. It was classified as pathogenic according to the ACMG criteria, with a score of 10 points (8 points for PVS1_very strong, 1 point for PM2_supporting and 1 point for PP4_supporting). No other variant was found in 82 genes potentially related to HH. This is the first case report of a patient with WITKOS and HH carrying a pathogenic single nucleotide variant in SIN3A. Our results are strongly suggestive that HH in patients with WITKOS is due to SIN3A haploinsufficiency, thus ruling out a contiguous gene syndrome as causative for HH. Presentation: Thursday, June 15, 2023

THU169 Role Of Growth Hormone (GH) Therapy In Short Children With Skeletal Dysplasias And Pathogenic Variants In The COL2A1 Gene

Abstract Disclosure: L.D. Cellin: None. K.G. Guimaraes: None. N.L. Menezes De Andrade: None. G.A. Vasques: None. E.D. Goiano: None. M. Akkari: None. C. Santili: None. A.A. Jorge: None. A.C. Malaquias: None. Introduction: COL2A1 is the primary collagen synthesized by chondrocytes and plays a critical structural role in regulating cell growth, differentiation, and migration. Mutations in the COL2A1 gene may cause heterogeneous phenotypes ranging from skeletal dysplasia to nonsyndromic short stature. Clinical characteristics in COL2A1-related disorders are abnormalities in the ocular, skeletal, oro-facial, and audiological systems. Unfortunately, data were scarce about GH treatment in short children with pathogenic variants in COL2A1.Objective: To evaluate recombinant growth hormone (GH) treatment in short children carrying mutations in the COL2A1 gene. Methods: Retrospectively, we selected 8 prepubertal patients with short stature and pathogenic variants in the COL2A1 gene who were treated with GH (mean dose of 45.8 ± 7.9 µg/kg/d at the start). The primary outcomes were changes in height SDS and growth velocity in the 1st year and at the end of treatment. Results: Five patients were male; 3 were disproportionate, and 5 showed skeletal dysplasia signs. Two had familial short stature. At the start of the treatment, the mean calendar age was 8.1 ± 3.9 yr, and bone age was 6.9 ± 4.2 yr. The mean height SDS was -4.0 ± 0.9 for the CDC reference. In the 1st year of therapy, the growth velocity (GV) increased from baseline values of 5.2 ± 1.9 cm/yr to 7.4 ± 1.4cm/yr, an increment of 2.2 ± 2.2cm (p=0.02). GV SDS increased from -1.2 ± 1.5 to 1.2 ± 1.8 in the whole cohort during the 1st year of treatment (p=0.02). Height SDS showed a modest improvement after one year of therapy (from -4.0 ± 0.9 to -3.5 ± 0.9; p=0.005). To improve adult height, we treated two patients with GnRH analogs associated with GH. After a mean duration of therapy of 5.5 ± 2.5 years, 5 patients ended the treatment with rhGH (one prematurely stopped therapy due to poor growth response). No increment was observed in height SDS at the end of treatment (from -3.8 ± 0.9 to -3.4 ± 1.3; p=0.2). Four patients achieved adult height after 6.4 ± 1.7 years of therapy (height SDS ranging from -3.4 ± 0.4 to -2.9 ± 0.8; p=0.08). The mean gain in adult height SDS was 0.5 ± 0.4 (ranging from zero to 0,97). Conclusions: Our patients with COL2A1-associated disorders showed no response to GH therapy to improve adult height as a group. However, we need more studies to determine which patient will benefit from this treatment once there is considerable phenotype heterogeneity. GnRH analogs may help to improve adult height in association with GH. Also, alternative therapies might be evaluated to treat short children with these disorders. Presentation: Thursday, June 15, 2023

A combined top-down and bottom-up LC-HRMS/MS method for the quantification of human growth hormone in plasma and serum

ObjectiveThe precise and accurate quantification of human growth hormone (GH) in plasma/ serum is crucial for the diagnosis and treatment of diseases like GH deficiency or acromegaly. However, the ligand-binding assays (LBAs) currently used for routine testing show considerable methodological variability. Here, we present a complementary, combined top-down and bottom-up LC-MS-based method to quantify (intact) GH in plasma and serum, which concurrently provides a basis for a MS-based analysis of GH in doping controls. DesignExtraction of GH from plasma/ serum was accomplished by protein precipitation, followed by an immunocapture step using protein A-coupled magnetic beads and a polyclonal anti-GH antibody. The intact protein was subsequently analyzed top-down on a 2D-LC-HRMS/MS system. In addition, sample extracts were digested with trypsin and analyzed for signal peptides corresponding to ‘total’, 22 kDa and 20 kDa GH (bottom-up). Both assays were validated according to current guidelines and compared to the GH isoform differential immunoassay used in routine doping control analysis. GH concentrations in serum samples of healthy adults, patients with acromegaly, and in samples obtained after administration of recombinant GH were analyzed as proof-of-principle. ResultsThe intact monomeric 22 kDa isoform of GH was selectively quantified in a representative working range of 0.5 to 10 ng/ml by top-down LC-HRMS/MS. Subsequent bottom-up analysis provided additional data on ‘total’ and 20 kDa GH. Top-down and bottom-up assay results for the 22 kDa isoform correlated well with the corresponding immunoassay results (R2 > 0.95). For a possible application of the method in an anti-doping context, the ratio between 22 kDa and ‘total’ GH was evaluated, indicating differences between the various donor groups, but only with limited significance. ConclusionThe top-down and bottom-up LC-HRMS/MS method developed here presents a valuable tool for the quantification of GH in plasma/ serum complementary to established LBAs used at present in clinical measurements. Albeit the examination of the GH isoform proportions by the LC-MS method does not yet allow for the assessment of GH abuse, the obtained findings provide an important basis to enable LC-MS-based GH analysis of doping control samples in the future.

Long acting growth hormone (LAGH), an update.

In 1957, Maurice Raben at Yale was able to isolate and purify growth hormone from cadaveric pituitary glands. Pituitary growth hormone was the only way to treat children with growth hormone (GH) deficiency, until 1985 when recombinant GH became available for daily subcutaneous injection. For many years, the pediatric endocrine community longed for a long-acting recombinant GH formulation that would decrease the inconvenience of daily injections. Several mechanisms were employed to develop a GH that is rapidly absorbed into the blood stream after subcutaneous injection, but provides slow removal from the circulatory system to potentially optimize patient adherence to GH therapy. Four long-acting growth hormones are currently available in the world, or are close to regulatory approval. They are: (1) Pegylated formulations, (2) Prodrug formulations which are converted into active drug, (3) Nonvalent transient albumin binding GH compounds and (4) GH fusion proteins where a protein si fused with GH. All four formulations have undergone detailed phase 3 studies and were found to show non-inferiority in these clinical studies. All four demonstrate a safety and tolerability profile that is comparable to that of daily somatropin with an excellent adherence profile.

Impact of growth hormone on physical performance

Growth hormone (GH) is an anabolic hormone produced by the pituitary gland. The action of growth hormone is not only to promote growth in children, but it has a significant effect on metabolism and body composition also in adults. Growth hormone deficiency (GHD) leads to physical impairment (worsen muscle strength, aerobic and anaerobic capacity) and altered body composition - with increased fat and reduced lean body mass, particularly reduced skeletal muscle mass. On the other hand, GH excess in patients with acromegaly impairs physical function, especially aerobic capacity and muscle strength irrespective of GH-dependent muscle hypertrophy. There is unclear data about GH impact on physical performance among healthy populations. Some studies showed improvement in anaerobic capacity during recombinant human GH (rh-GH) administration, others showed no significant difference. Muscle strength did not improve after rh-GH administration among healthy adults. However, recombinant GH is abused by professional and recreational athletes to improve their physical performance.

Adult height and health-related quality of life in patients born small for gestational age treated with recombinant growth hormone

Adult height and health-related quality of life in patients born small for gestational age treated with recombinant growth hormone

Longitudinal assessment of bone health index as a measure of bone health in short-statured children before and during treatment with recombinant growth hormone.

The aim of our study was the longitudinal assessment of bone health index (BHI) in short-statured children during growth hormone (GH) treatment to estimate changes in their bone health. 256 short-statured children (isolated GH deficiency (IGHD) n=121, multiple pituitary hormone deficiency (MPHD) n=49, intrauterine growth retardation (small for gestational age (SGA)) n=52, SHOX (short stature homeobox gene) deficiency n=9, Ullrich Turner syndrome (UTS) n=25) who started with GH between 2010 and 2018 were included. Annual bone ages (Greulich and Pyle, GP) and BHI were, retrospectively, analysed in consecutive radiographs of the left hand (BoneXpert software) from GH therapy start (T0) up to 10 years (T10) thereafter, with T max indicating the individual time point of the last available radiograph. The results are presented as the median (25 %/75 % interquartile ranges, IQR) and statistical analyses were performed using non-parametric tests as appropriate. The BHI standard deviation scores (SDS) were reduced (-0.97,-1.8/-0.3) as bone ages were retarded (-1.6 years,-2.31/-0.97) in all patients before start of GH and were significantly lower in patients with growth hormone deficiency (GHD) (-1.04,-1.85/-0.56; n=170) compared to non-GHD patients (-0.79,-1.56/-0.01; n=86; p=0.022). BHISDS increased to-0.17 (-1/0.58) after 1 year of GH (T1, 0.5-1.49, p<0.001) and to-0.20 (-1/-0.50, p<0.001) after 5.3 years (T max, 3.45/7.25). BHI SDS are reduced in treatment-naive short-statured children regardless of their GH status, increase initially with GH treatment while plateauing thereafter, suggesting sustained improved bone health.

The Effect of Immersion Duration of java barb larvae (Barbornymus gonionotus) in the combination of thyroxine hormone and recombinant growth hormone (rGH) on the egg yolk absorption and growth

Java barb (Tawes) is one of the endemic freshwater fish in Indonesia which has being widely cultivated. The time rearing of Java barb from larva to market size is generally 5-6 months. Egg yolk absorption rate and growth of Java barb fish can be increased by hormonal manipulation using thyroxine hormone and recombinant growth hormone (rGH). The length of immersion time affects the performance of hormones in the fish’s body. The purpose of this study is to determine the effect of immersion duration and the best immersion time in a combination of thyroxine and rGH on the egg yolk absorption and the growth of Java barb larvae. This research was conducted on 23 August-1 November 2021 at Laboratorium Pengujian Kesehatan Ikan dan Lingkungan (LPKIL) in Muntilan, Magelang regency. The testing fishes used were early hatched Java barb fish larvae that still had egg yolks. The method used was a completely random design (CRD) with 4 treatments and 3 replications and each was done with a combination of 0.1 mg/l thyroxine hormone and 2.5 mg/l rGH with treatments A (control), B (1 hour immersion time), C (2 hours immersion time) and D (3 hours immersion time). The results showed that the effect of immersion duration in combination of thyroxine and rGH had a significant effect on the rate of egg yolk absorption and the growth of Java barb fish larvae. The best immersion time was treatment D (3 hours immersion duration) which resulted in 4%/hour of the absorption rate of egg yolk absorption rate, 12.53±0.15 mm absolute length growth, 0.047±0.002 g absolute weight growth, 13.82±0.15 % of specific growth rate, and 54.67±4.62 % survival rate.

Novel pathogenic NPR2 variants in short stature patients and the therapeutic response to rhGH

ObjectiveHeterozygous loss-of-function variants in the NPR2 gene cause short stature with nonspecific skeletal abnormalities and account for about 2 ~ 6% of idiopathic short stature. This study aimed to analyze and identify pathogenic variants in the NPR2 gene and explore the therapeutic response to recombinant growth hormone (rhGH).MethodsNPR2 was sequenced in three Chinese Han patients with short stature via exome sequencing. In vitro functional experiments, homology modeling and molecular docking analysis of variants were performed to examine putative protein changes and the pathogenicity of the variants.ResultThree patients received rhGH therapy for two years, and two NPR2 heterozygous variants were identified in three unrelated cases: c.1579 C > T,p.Leu527Phe in patient 1 and c.2842dupC,p.His948Profs*5 in patient 2. Subsequently, a small gene model was constructed, and transcriptional analysis of the synonymous variant (c.2643G > A) was performed in patient 3, which revealed the deletion of exon 17 and the premature formation of a stop codon (p.His840Gln*). Functional studies showed that both NPR2 variants, His948Profs*5 and His840Gln*, failed to produce cGMP in the homozygous state. Furthermore, the Leu527Phe variant of NPR2 was almost unresponsive to the stimulatory effect of ATP on CNP-dependent guanylyl cyclase activity. This loss of response to ATP has not been previously reported. The average age of patients at the start of treatment was 6.5 ± 1.8 years old, and their height increased by 1.59 ± 0.1 standard deviation score after 2 years of treatment.ConclusionIn this report, two novel variants in NPR2 gene were described. Our findings broaden the genotypic spectrum of NPR2 variants in individuals with short stature and provid insights into the efficacy of rhGH in these patients.