Isolated Growth Hormone Deficiency Research Articles

Evaluation of Asymmetric Dimethylarginine (ADMA) Levels in Children with Growth Hormone Deficiency

Ob­jec­ti­ve: To investigate serum asymmetric dimethylarginine (ADMA) levels in children with isolated growth hormone deficiency (GHD) and to determine the effect of GH replacement therapy on these levels.Methods: 31 patients diagnosed with isolated GHD and 29 age-and sex-matched healthy children were enrolled in the study. Height, weight and waist circumference were measured in all subjects. Fasting serum insulin-like growth factor-1 (IGF-1), IGF binding protein-3, glucose, insulin and lipid levels were evaluated. Serum ADMA levels were assessed using the enzyme-linked immunosorbent assay technique. The same evaluations were repeated on the 3rd and 6th months of treatment in 28 of the GHD cases.Results: There were no significant differences in ADMA levels between the patient and control groups [0.513±0.130 (0.291-0.820) µmol/L vs. 0.573±0.199 (0.241-1.049) µmol/L]. There was a positive correlation between serum ADMA and HbA1c levels in the control group. In the GHD cases, ADMA levels negatively correlated with high-density lipoprotein levels and positively correlated with low-density lipoprotein levels. There was also a significant increase in ADMA levels in patients receiving GH therapy compared to pre-treatment levels [serum ADMA level, 1.075±0.133 (0.796-1.303) µmol/L at the 3rd month and 0.923±0.121 (0.695-1.159) µmol/L at the 6th month of treatment]. There was a negative correlation between ADMA levels and homeostasis model assessment of insulin resistance values at the 6th month evaluation. There were no relationships between ADMA levels and age, sex, or pubertal state either before or during the treatment.Conclusion: Serum ADMA levels were found to be similar in patients with GHD and in healthy children. However, serum ADMA levels showed a significant increase in GHD patients following GH replacement therapy.

Clinical challenges in the management of isolated GH deficiency type IA in adulthood

SummaryIsolated GH deficiency type IA (IGHDIA) is an infrequent cause of severe congenital GHD, often managed by pediatric endocrinologists, and hence few cases in adulthood have been reported. Herein, we describe the clinical status of a 56-year-old male with IGHDIA due to a 6.7 kb deletion in GH1 gene that encodes GH, located on chromosome 17. We also describe phenotypic and biochemical parameters, as well as characterization of anti-GH antibodies after a new attempt made to treat with GH. The height of the adult patient was 123 cm. He presented with type 2 diabetes mellitus, dyslipidemia, osteoporosis, and low physical and psychological performance, compatible with GHD symptomatology. Anti-GH antibodies in high titers and with binding activity (>101 IU/ml) were found 50 years after exposure to exogenous GH, and their levels increased significantly (>200 U/ml) after a 3-month course of 0.2 mg/day recombinant human GH (rhGH) treatment. Higher doses of rhGH (1 mg daily) did not overcome the blockade, and no change in undetectable IGF1 levels was observed (<25 ng/ml). IGHDIA patients need lifelong medical surveillance, focusing mainly on metabolic disturbances, bone status, cardiovascular disease, and psychological support. Multifactorial conventional therapy focusing on each issue is recommended, as anti-GH antibodies may inactivate specific treatment with exogenous GH. After consideration of potential adverse effects, rhIGF1 treatment, even theoretically indicated, has not been considered in our patient yet.Learning points Severe isolated GHD may be caused by mutations in GH1 gene, mainly a 6.7 kb deletion.Appearance of neutralizing anti-GH antibodies upon recombinant GH treatment is a characteristic feature of IGHDIA.Recombinant human IGF1 treatment has been tested in children with IGHDIA with variable results in height and secondary adverse effects, but any occurrence in adult patients has not been reported yet.Metabolic disturbances (diabetes and hyperlipidemia) and osteoporosis should be monitored and properly treated to minimize cardiovascular disease and fracture risk.Cerebral magnetic resonance imaging should be repeated in adulthood to detect morphological abnormalities that may have developed with time, as well as pituitary hormones periodically assessed.

Defective minor spliceosome mRNA processing results in isolated familial growth hormone deficiency

The molecular basis of a significant number of cases of isolated growth hormone deficiency remains unknown. We describe three sisters affected with severe isolated growth hormone deficiency and pituitary hypoplasia caused by biallelic mutations in the RNPC3 gene, which codes for a minor spliceosome protein required for U11/U12 small nuclear ribonucleoprotein (snRNP) formation and splicing of U12-type introns. We found anomalies in U11/U12 di-snRNP formation and in splicing of multiple U12-type introns in patient cells. Defective transcripts include preprohormone convertases SPCS2 and SPCS3 and actin-related ARPC5L genes, which are candidates for the somatotroph-restricted dysfunction. The reported novel mechanism for familial growth hormone deficiency demonstrates that general mRNA processing defects of the minor spliceosome can lead to very narrow tissue-specific consequences.Subject Categories Genetics, Gene Therapy ' Genetic Disease; Metabolism

Isolated Growth Hormone Deficiency (GHD) in Childhood and Adolescence: Recent Advances

The diagnosis of GH deficiency (GHD) in childhood is a multistep process involving clinical history, examination with detailed auxology, biochemical testing, and pituitary imaging, with an increasing contribution from genetics in patients with congenital GHD. Our increasing understanding of the factors involved in the development of somatotropes and the dynamic function of the somatotrope network may explain, at least in part, the development and progression of childhood GHD in different age groups. With respect to the genetic etiology of isolated GHD (IGHD), mutations in known genes such as those encoding GH (GH1), GHRH receptor (GHRHR), or transcription factors involved in pituitary development, are identified in a relatively small percentage of patients suggesting the involvement of other, yet unidentified, factors. Genome-wide association studies point toward an increasing number of genes involved in the control of growth, but their role in the etiology of IGHD remains unknown. Despite the many years of research in the area of GHD, there are still controversies on the etiology, diagnosis, and management of IGHD in children. Recent data suggest that childhood IGHD may have a wider impact on the health and neurodevelopment of children, but it is yet unknown to what extent treatment with recombinant human GH can reverse this effect. Finally, the safety of recombinant human GH is currently the subject of much debate and research, and it is clear that long-term controlled studies are needed to clarify the consequences of childhood IGHD and the long-term safety of its treatment.

Hearing Status in Adult Individuals with Lifetime, Untreated Isolated Growth Hormone Deficiency

To evaluate the hearing status of growth hormone (GH)-naive adults with isolated GH deficiency (IGHD) belonging to an extended Brazilian kindred with a homozygous mutation in the GH-releasing hormone receptor gene. Cross-sectional. Divisions of Endocrinology and Otorhinolaryngology of the Federal University of Sergipe. Twenty-six individuals with IGHD (age, 47.6 ± 15.1 years; 13 women) and 25 controls (age, 46.3 ± 14.3 years; 15 women) were administered a questionnaire on hearing complaints and hearing health history. We performed pure-tone audiometry, logoaudiometry, electroacoustic immittance, and stapedial reflex. To assess outer hair cell function in the cochlea, we completed transient evoked otoacoustic emissions (TEOAEs). To assess the auditory nerve and auditory brainstem, we obtained auditory brainstem responses (ABRs). Misophonia and dizziness complaints were more frequent in those with IGHD than in controls (P = .011). Patients with IGHD had higher thresholds at 250 Hz (P = .005), 500 Hz (P = .006), 3 KHz (P = .008), 4 KHz (P = .038), 6 KHz (P = .008), and 8 KHz (P = .048) and mild high-tones hearing loss (P = .029). Stapedial reflex (P < .001) and TEOAEs (P = .025) were more frequent in controls. There were no differences in ABR latencies. Hearing loss in patients with IGHD occurred earlier than in controls (P < .001). Compared with controls of the same area, subjects with untreated, congenital lifetime IGHD report more misophonia and dizziness, have predominance of mild high-tones sensorineural hearing loss, and have an absence of stapedial reflex and TEOAEs.

Decreased retinal nerve fiber layer thickness in patients with congenital isolated growth hormone deficiency.

To evaluate the optic disc topography parameters of children with congenital isolated growth hormone deficiency (GHD) using the Heidelberg retina tomograph (HRT) in a controlled study. This prospective study included 32 eyes of 32 patients with congenital isolated GHD and 36 eyes of 36 healthy subjects. The topographic optic disc parameters (mean cup volume, rim volume, cup area, disc area, rim area, mean cup-to-disc ratio and cup depth, retinal nerve fiber layer thickness [RNFL]) were imaged in all subjects with HRT-III (software 3.01 a-M). Pearson correlation analysis was used to investigate the correlation between right and left eyes regarding the optic disc parameters. Differences between the 2 groups were evaluated by independent t test, Mann-Whitney U test, and chi-square test. The mean RNFL thickness in children with congenital isolated GHD was found to be statistically significantly thinner than in healthy subjects (p&lt;0.05). However, no statistically significant differences were found between the mean cup volume, rim volume, cup area, disc area, rim area, mean cup-to-disc ratio and cup depth, and mean sectorial RNFL thickness (p&gt;0.05). The results suggest that congenital GHD may lead to thinner RNFL thickness when compared with healthy subjects. This indicates that GH has an important role in the development of the neural retina.

A novel mutation in SOX3 polyalanine tract: a case of kabuki syndrome with combined pituitary hormone deficiency harboring double mutations in MLL2 and SOX3

Both duplications encompassing SOX3 and loss-of function mutations in SOX3 have been reported in a minor portion of X-linked isolated growth hormone deficiency (GHD) or combined pituitary hormone deficiency (CPHD) patients with or without mental retardation. We report a Japanese male patient with molecularly confirmed Kabuki syndrome who was found to have CPHD. We analyzed all coding exons and flanking introns of currently known nine genes responsible for CPHD by PCR-based sequencing. In this CPHD patient, we identified a novel hemizygous 21-base pair deletion, resulting in the loss of 7 alanine residues from polyalanine (PA) tracts of SOX3. The clinically and endocrinologically normal mother of the patient carried the same deletion in a heterozygous manner. In vitro experiments showed that the del 7A SOX3 had increased transactivation of the HESX1 promoter. Our study provides additional evidence that deletion in PA tracts of SOX3 is associated with hypopituitarism. Female carriers of SOX3 PA tract deletions will show a broad phenotypic spectrum, ranging from clinically normal to CPHD.

Long- But Not Short-Term Adult-Onset, Isolated GH Deficiency in Male Mice Leads to Deterioration of β-Cell Function, Which Cannot Be Accounted for by Changes in β-Cell Mass

Developmental models of GH deficiency (GHD) and excess indicate that GH is positively associated with β-cell mass. Therefore, the reduction in GH levels observed with age and weight gain may contribute to the age-related decline in β-cell function. To test this hypothesis, β-cell mass and function were assessed in a mouse model of adult-onset, isolated GHD (AOiGHD). β-Cell mass did not differ between low-fat (LF)-fed AOiGHD and controls. However, high fat-fed AOiGHD mice displayed impaired expansion of β-cell mass and a reduction of bromodeoxyuridine-labeled islet cells, whereas in vitro β-cell function (basal and glucose-stimulated insulin secretion [GSIS]) did not differ from controls. In contrast, duration of AOiGHD differentially altered in vitro β-cell function in LF-fed mice. Specifically, islets from young LF-fed AOiGHD mice showed significant reductions in insulin content and basal insulin secretion, but GSIS was similar to that of controls. A similar islet phenotype was observed in a developmental model of isolated GHD (GH-releasing hormone knockout). Given that LF- and high fat-fed AOiGHD mice, as well as GH-releasing hormone knockout mice, display improved insulin sensitivity, islet changes may be due to reduced insulin demand, rather than primary β-cell dysfunction. However, islets from older LF-fed AOiGHD mice exhibited impaired GSIS, associated with reduced expression of genes important to maintain glucose sensing, suggesting that factors secondary to AOiGHD can alter β-cell function with age. AOiGHD mice exhibited postprandial hypertriglyceridemia and increased pancreatic expression of lipid/inflammatory stress response genes (activating transcription factor 3 and peroxisome proliferator activator receptor β/δ). Therefore, we speculate that these changes may initially protect the AOiGHD β-cell, but with age, lipotoxicity may impair β-cell function.

Lifetime, untreated isolated GH deficiency due to a GH-releasing hormone receptor mutation has beneficial consequences on bone status in older individuals, and does not influence their abdominal aorta calcification

The GH/IGF-I axis has essential roles in regulating bone and vascular status. The age-related decrease in GH secretion ("somatopause") may contribute to osteoporosis and atherosclerosis, commonly observed in the elderly. Adult-onset GH deficiency (GHD) has been reported to be associated with reduced bone mineral density (BMD), increased risk of fractures, and premature atherosclerosis. We have shown the young adult individuals with isolated GHD (IGHD) due to a homozygous for the c.57+1G>A GHRH receptor gene mutation have normal volumetric BMD (vBMD), and not develop premature atherosclerosis, despite adverse risk factor profile. However, the bone and vascular impact of lifetime GHD on the aging process remains unknown. We studied a group of ten older IGHD subjects (≥60 years) homozygous for the mutation, comparing them with 20 age- and gender-matched controls (CO). Areal BMD was measured, and vBMD was calculated at the lumbar spine and total hip. Vertebral fractures and abdominal aortic calcifications (expressed as calcium score) were also assessed. Areal BMD was lower in IGHD, but vBMD was similar in the two groups. The percent of fractured individuals was similar, but the mean number of fractures per individual was lower in IGHD than CO. Calcium score was similar in the two groups. A positive correlation was found between calcium score and number of fractures. Untreated lifetime IGHD has beneficial consequences on bone status and does not have a deleterious effect on abdominal aorta calcification.

50 Years Ago in The Journal of Pediatrics: Hypoglycemia, Growth Retardation, and Probable Isolated Growth Hormone Deficiency in a 1-Year-Old Child

50 Years Ago in The Journal of Pediatrics: Hypoglycemia, Growth Retardation, and Probable Isolated Growth Hormone Deficiency in a 1-Year-Old Child

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic isolated GH deficiency

We assessed the characteristics of children initially diagnosed with idiopathic isolated GH deficiency (IGHD) who later developed additional (multiple) pituitary hormone deficiencies (MPHD). Data were analyzed for 5805 pediatric patients with idiopathic IGHD, who were GH-naïve at baseline and GH-treated in the multinational, observational Genetics and Neuroendocrinology of Short Stature International Study. Development of MPHD was assessed from investigator diagnoses, adverse events, and concomitant medications. Analyses were performed for all patients and for those who developed MPHD within 4.5 years or had ≥3.5 years, follow-up and continued to have IGHD (4-year cohort). MPHD developed in 118/5805 (2.0%) children overall, and in 96/1757 (5.5%) in the 4-year cohort. Patients who developed MPHD had more profound GHD, with decreased height SDS, IGF1 SDS and peak stimulated GH, and greater height decrement vs target, compared with children who continued to have IGHD (P<0.001 for each variable). Delivery complications, congenital anomalies, and perinatal/neonatal adverse events occurred more frequently in patients who developed MPHD. The most frequent additional deficiency was TSH (82 patients overall); four patients developed two pituitary hormone deficiencies and one developed three deficiencies. Multivariable logistic regression indicated that years of follow-up (odds ratio 1.55), baseline age (1.17), baseline height SDS (0.69), and peak stimulated GH (0.64) were associated with the development of MPHD. MPHD is more likely to develop in patients with more severe idiopathic IGHD. Older baseline age, lower baseline height SDS, and longer follow-up duration are associated with increased risk of development of MPHD.

How safe is growth hormone therapy? SAGhE and beyond

Although short term health on growth hormone treatment has been extensively studied, little is known of the long-term health of subjects treated with growth hormone in childhood. Approximately 40 000 children are treated with growth hormone in the European Union and several hundred thousands in the world and it is essential to address this important question. SAGhE is an European consortium aimed at addressing this question as well as to gain further insight in the long term effect of growth hormone both in terms of height and of significance on quality of life. Eight countries participate in SAGhE: Belgium, France, Germany, Italy, Netherlands, Sweden, Switzerland, United Kingdom and have recruited approximately 25 000 patients who were treated for the most part in the late 80's and 90's and who are currently adults. The results of the SAGhE study as a whole are expected to be available to the investigators at the end of 2012 and will be disseminated in 2013. However, the study did not start synchronously in all countries and results from France and from 3 other countries have been made disseminated in late 2010 and published in early 2012. In the report from France, 6928 children with idiopathic isolated GH deficiency (n = 5162), neurosecretory dysfunction (n = 534) idiopathic short stature (n = 871) or born short for gestational age (n = 335) who started treatment between 1985 and 1996 were followed on vital status up to September 2009 for 94.7% of the patients. In this population of patients, all-cause mortality was increased with a standardized mortality ratio (SMR) of 1.33. 95% CI 1.08–1.64). In multivariate analysis adjusted for height, the use of GH doses >50 µg/kg/day was associated with mortality rates using external and internal references (SMR 2.94, 95%CI 1.22–7.07, HR 2.79, 95%CI 1.14–6.82). All type cancer-related mortality was not increased. Bone tumor-related mortality was increased (SMR 5.00, 95%CI 1.01–14.63). An increase in mortality due to diseases of the circulatory system (SMR 3.07, 95%CI 1.40–5.83), subarachnoid or intracerebral hemorrhage (SMR 6.66, 95%CI 1.79–17.05) was observed. Mortality rates were therefore increased in this population of adults treated as children with recombinant GH, particularly in those who had received the highest doses. In a parallel report, 3 additional countries (Belgium, Netherlands, Sweden) the cause of death from a cohort of 2543 patients could be identified and no cancer- or cardiovascular disease-related deaths were found. These results highlight the need for additional studies of long-term mortality and morbidity after GH treatment in childhood but do not change the risk benefit balance of growth hormone treatments, after careful evaluation by Medicine Agencies. Consolidated results of the SAGhE study are expected to be available at the end of 2012 and to be disseminated during 2013.

Isolated GH Deficiency due to a GHRH Receptor Mutation Causes Hip Joint Problems and Genu Valgum, and Reduces Size but not Density of Trabecular and Mixed Bone

The GH/IGF-I axis is important for bone growth, but its effects on joint function are not completely understood. Adult-onset GH-deficient individuals have often reduced bone mineral density (BMD). However, there are limited data on BMD in adult patients with untreated congenital isolated GH-deficient (IGHD). We have shown that adult IGHD individuals from the Itabaianinha, homozygous for the c.57+1G>A GHRHR mutation, have reduced bone stiffness, but BMD and joint status in this cohort are unknown. The goal is to study BMD, joint function, and osteoarthritis score in previously untreated IGHD adults harboring the c.57+1G>A GHRHR mutation. This is a cross-sectional study. Areal BMD by dual-energy X-ray absorptiometry was measured in 25 IGHD and 23 controls (CO). Volumetric BMD (vBMD) was calculated at the lumbar spine and total hip. Joint function was assessed by goniometry of elbow, hips, and knees. X-rays were used to measure the anatomic axis of knee and the severity of osteoarthritis, using a classification for osteophytes (OP) and joint space narrowing (JSN). Genu valgum was more prevalent in IGHD than CO. The osteoarthritis knees OP score was similar in both groups, and knees JSN score showed a trend to be higher in IGHD. The hips OP score and JSN score were higher in IGHD. Areal BMD was lower in IGHD than CO, but vBMD was similar in the two groups. Range of motion was similar in elbow, knee, and hip in IGHD and CO. Untreated congenital IGHD due to a GHRHR mutation causes hip joint problems and genu valgum, without apparent clinical significance, reduces bone size, but does not reduce vBMD of the lumbar spine and hip.

Effects of isolated GH deficiency on adipose tissue, feeding and adipokines in mice

ObjectiveGrowth hormone deficiency (GHD) leads to growth failure and changes in body composition including increased fat accumulation and reduced lean body mass in both humans and rodents. The aim of this study was to characterize the consequences of isolated GHD (IGHD) on adiposity, total body weight (TBW), and food intake in a mouse model of autosomal recessive IGHD due to targeted ablation of the GH-releasing hormone (GHRH) gene [GHRH knockout (GHRHKO)]. Animals were also analyzed with respect to leptin, adiponectin and visfatin circulating levels and gene expression in both intra-abdominal and subcutaneous fat. DesignWe studied 8 male mice homozygous for GHRHKO allele (−/−) and 8 heterozygous (+/−) animals as controls. Feeding and TBW data were collected weekly from 3 through 5months of age. Animals were then euthanized for measurement of body length and intra-abdominal (epididymal and retroperitoneal) and subcutaneous (interscapular, axillary, gluteal and inguinal) fat weights, and for blood collection for leptin, adiponectin and visfatin measurement. Gene expression of leptin, adiponectin and visfatin in adipose tissue was evaluated by real-time reverse transcription polymerase chain reaction. ResultsGHRHKO mice had significantly increased relative intra-abdominal (P<0.01) and subcutaneous (P<0.0001) fat, accompanied by significantly increased food intake per TBW (P<0.01), whereas – despite 40% higher food consumption – TBW change was not different from controls over the 2month period. Adiponectin and visfatin mRNA levels were decreased in both intra-abdominal (P<0.001) and subcutaneous fat (P<0.0001), while leptin mRNA levels were not different from controls. Conversely, serum adiponectin levels were higher in GHRHKO mice (P<0.0001), whereas serum visfatin and leptin did not significantly differ from controls. ConclusionsIGHD due to targeted ablation of the GHRH gene in mice is associated with increased relative subcutaneous and intra-abdominal fat mass and higher food consumption which is not related to changes in circulating leptin.

Presence of GH1 and absence of GHRHR gene mutations in a large cohort of Argentinian patients with severe short stature and isolated GH deficiency

Fil: Juanes, Matias Hernan. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatria Juan P. Garrahan; Argentina

The Effect of Recombinant Human Growth Hormone Therapy on Left-Ventricular Chamber Size and Function in Children With Growth Hormone Deficiency

This study was designed to assess the effect of recombinant human growth hormone (rhGH) therapy on left-ventricular (LV) chamber size and function in children with idiopathic isolated growth hormone deficiency (GHD) using conventional echocardiography and tissue Doppler imaging (TDI). Thirty patients (19 boys and 11 girls) with idiopathic isolated GHD were followed-up for 12 months. Mean age of patients was 11.0 ± 2.6 years (range 6.3-15.5). At baseline and at 3, 6, and 12 months of treatment, the structure of the left ventricle was assessed by conventional echocardiography and myocardial rates and time intervals by TDI. There was a significant increase in LV mass (LVM) compared with pretreatment values. Like LVM, relative wall thickness (RWT) was also increased significantly. The significant increase in LVM indexed to body surface area and RWT became apparent at month 3 of treatment with a significant increase in LVM indexed to height(2.7) at treatment month 6. Normalized LVM increased as early month 3 of treatment, and a steady increase was observed until month 12. However, no patient had LVM > +2 standard deviation scores at month 12 of treatment. No significant differences were observed in functional parameters of the left ventricle and the interventricular septum. The results of this study showed that rhGH therapy causes an increase in myocardial mass without changing the geometry or function of the myocardium. Therefore, the increase in myocardial mass appears to be concentric, thus causing remodeling instead of hypertrophy.

Endoplasmic Reticulum Stress and Apoptosis Contribute to the Pathogenesis of Dominantly Inherited Isolated GH Deficiency Due to GH1 Gene Splice Site Mutations

Dominantly inherited isolated GH deficiency is mainly caused by a heterozygous donor site mutation of intron 3 in the GH1 gene. An exon 3 deletion in GH (del32-71 GH) is produced from a mutant allele, whereas wild-type GH is produced from the other allele. Several studies have demonstrated a dominant negative effect of del32-71 GH on wild-type GH secretion, but the precise molecular mechanisms remain unclear. We hypothesized that unfolded del32-71 GH accumulates in the endoplasmic reticulum (ER) and causes ER stress and apoptosis in somatotrophs, promoting GH deficiency. To evaluate del32-71 GH-mediated ER stress, we established GH4C1 cell lines with doxycycline (dox)-controlled del32-71 GH expression. In 20 of 23 dox-controlled cell lines, the concentration of wild-type GH in the culture medium significantly decreased with del32-71 GH induction, demonstrating the dominant negative effect of this mutant. Cell viability, mRNA abundance of ER stress-response genes, caspase activation, and DNA fragmentation were evaluated in 5 dox-controlled cell lines selected as cellular models. In 4 of the 5 cell lines, del32-71 GH induction decreased cell viability, increased expression of 3 major ER stress response pathways (PRKR-like endoplasmic reticulum kinase [PERK], activating transcription factor-6 [ATF6], and inositol requirement 1 [IRE1]), and induced caspase-3 and caspase-7 activation. In 1 of the 4 cell lines, DNA fragmentation was demonstrated. Finally, overexpression of XBP1(S), a nuclear transcription factor downstream of IRE1, completely reversed the observed caspase activation. These data suggested that del32-71 GH-mediated ER stress and apoptosis contributed to the decrease in wild-type GH secretion observed in GH deficiency due to the GH1 gene slice-site mutations.

Lifetime congenital isolated GH deficiency does not protect from the development of diabetes

ObjectivesAdult subjects with untreated, lifetime, isolated GH deficiency (IGHD) due to a homozygous GHRH receptor gene mutation (MUT/MUT) residing in Itabaianinha, Brazil, present with lower BMI, higher prevalence of impaired glucose tolerance (IGT), increased insulin sensitivity (IS), and reduced β-cell function (βCF) when compared with non-BMI-matched homozygous normal controls. However, the prevalence of diabetes mellitus (DM) in this cohort is unknown. Comparing their IS and βCF with BMI-matched individuals heterozygous for the same mutation (MUT/N) may be useful to elucidate the role of the GH–IGF1 axis in IS and βCF. The purposes of this work were to verify the prevalence of IGT and DM in adult MUT/MUT subjects from this kindred and to compare IS and βCF in MUT/MUT and MUT/N.DesignCross-sectional study.MethodsWe studied most (51) of the living IGHD adults of this kindred who are GH naive. The oral glucose tolerance test (OGTT) could be performed in 34 subjects, fasting glucose was measured in 15, while two had a previous diagnosis of DM. The OGTT results of 24 MUT/MUT subjects were compared with those of 25 BMI-matched MUT/N subjects. IS was assessed by homeostatic model assessment of insulin resistance (HOMA–IR), quantitative IS check index, and oral glucose IS index for 2 and 3 h. βCF was assayed by HOMA-β, insulinogenic index, and the area under the curve of insulin:glucose ratio.ResultsThe prevalence of DM and IGT in IGHD was 15.68 and 38.23% respectively. IS was increased and βCF was reduced in MUT/MUT in comparison with MUT/N.ConclusionsLifetime, untreated IGHD increases IS, impairs βCF, and does not provide protection from diabetes.

Novel compound heterozygous mutations of the growth hormone-releasing hormone receptor gene in a case of isolated growth hormone deficiency

ObjectiveTo elucidate the pathogenesis of isolated growth hormone (GH) deficiency in a Japanese girl without consanguinity. DesignA 2-year-old girl of height 77.2cm (−3.0 SD for Japanese girls) was found to have an insulin-like growth factor (IGF)-1 level of 7ng/mL and IGF binding protein-3 (IGFBP-3) level of 0.41μg/mL. GH responded modestly to a series of pharmacological stimulants, increasing to 2.81ng/mL with insulin-induced hypoglycemia, 3.78ng/mL with arginine, and 3.93 with GH-releasing hormone (GHRH). Following direct sequencing of the GHRH receptor (GHRHR) gene, evaluation by the luciferase reporter assay, immunofluorescence study, and in vitro splicing assay with minigene constructs was conducted. ResultsNovel compound heterozygous GHRHR gene mutations were identified in the patient. A p.G136V substitution elicited no luciferase activity increment in response to GHRH stimulation, with normal membranous expression. Splicing assay demonstrated that the IVS2+3a>g mutation would lead to aberrant splicing. ConclusionsA case of isolated GH deficiency due to novel GHRHR gene mutations was identified.

The effects of growth hormone replacement therapy on insulin, lipid profile and calcium in children with growth hormone deficiency

Background: Growth hormone has multiple effects on the overall form and function of growing body. Aside from these growth stimulating functions, it has marked effects on energy metabolism, it acts on fat cells to reduce the amount of stored fats, promotes protein synthesis in cells and plays a role in regulating the sugar levels in the blood.&#x0D; Objective: to investigate the effect of growth hormone replacement on lipid profile, insulin level, glucose and calcium level in patients with growth hormone deficiency (GHD).&#x0D; Method: A prospective study of 49 children; 37 boys and 12girls with a mean age(13.5±3.3)years attending the Children Welfare Teaching Hospital/ department of endocrinology with short stature proved to have an isolated growth hormone deficiency (other causes of short stature were excluded), with 20 healthy children as control were studied over a period of 11 months( from Oct. 2007 to Aug 2008). . Insulin level ,serum lipid ,blood glucose and serum calcium were estimated for control group and for those with isolated( GHD) prior to and post 11 months of growth hormone replacement therapy(GHRT) .&#x0D; Result: Insulin levels were ( 8.1 µIU/L) in patients with GHD and elevated significantly to( 17.4 µIU/L) after GHRT, without any unfavorable effects on blood glucose. Pre treatment lipid profile values were higher (total cholesterol T-C 4.1 mmol/L ,triglyceride TG 1.5 mmol/L ,low density lipoprotein LDL 2.5 mmol/L, very low density lipoproteins VLDL 0.7mmol/L, than the control group ( T-C 3.9, TG 1, LDL 1.8, VLDL 0.5) .&#x0D; Significant improvement was occurred after treatment (T-C=3.6 , TG=1.2, LDL=1.6 , VLDL=0.5); while pretreatment high density lipoproteins HDL was significantly lower (1 mmol/L) than in control (1.6) which improved significantly post treatment to (1.5) mmol/L.&#x0D; Significant decrement of Post-treatment serum Ca mmol/L (2) noticed as compared to controls (2.3) and to its baseline values (2.2). Significant improvement of height= -3.7 and body mass index {BMI} =-1.1 Z score to-2.9and 0, 7 respectively were noticed post- treatment. &#x0D; Conclusion: Several metabolic derangements are associated with (GHD) which could be managed effectively with (GHRT).