Features Of Growth Hormone Deficiency Research Articles

Laron syndrome in South Indian children – A descriptive study

Objectives: The objectives of this study were to describe the clinical and biochemical features of five children with Laron syndrome (LS) from South India. Material and Methods: This is a prospective descriptive case series of five children with clinical and biochemical features of LS managed over 5 years. Results: Five children (two girls and three boys) with LS with the mean age group of 5.9 ± 1.7 years and the mean age at diagnosis of 2.7 ± 0.8 years are described. All children were born out of consanguinity and all had typical phenotypic facies of LS. The mean Z-scores of height, weight, and body mass index on follow-up for the cohort were −7.0 ± 1.6, −5.9 ± 2.8, and −0.1 ± 0.7, respectively, and they were within ± 2 SD of the mean for children in LS chart. The median basal growth hormone level for age was 13 ng/mL and the median growth hormone levels at 30 min, 60 min, 90 min, and 120 min post-stimulation test were 35 ng/mL, 35 ng/mL, 44 ng/mL, and 50 ng/mL, respectively. All of them had insulin-like growth factor-1 (IGF-1) levels less than the 3rd percentile and no increment during the IGF-1 generation test. The prevalence of micropenis was 100% and one child had symptomatic hypoglycemic episodes. Genetic analysis was performed in two boys and both harbored variants in the growth hormone receptor gene. Conclusion: LS should be suspected in children with clinical features of growth hormone deficiency along with elevated growth hormone levels and low IGF-1 levels with no increment of IGF-1 in the IGF-1 generation test.

Clinical profile of Laron dwarfism – experience from a tertiary care institute in Chennai

Laron dwarfism is a rare genetic disorder first reported among Israeli jewish children, subsequently about 350 cases cases have been reported worldwide. We aim to describe the clinical profile of nine children with Laron dwarfism from Institute of Child Health, Chennai. Analysis of case records from 2010 to 2018. Male:female ratio is 6:3. Mean age of the children at the time of diagnosis was 3 years. All children were extremely short, and mean height Z score (SD) was-7.7(0.8). All children had characteristic facies with no hypoglycaemic episodes. Microcephaly was present in four children out of which two had developmental delay. Three out of six boys had micropenis. All children had low insulin like growth factor-1 (IGF-1) and high basal growth hormone (GH) with a mean (SD) of 39.6 (11.2) ng/mL. Suspicion of Laron syndrome should be high when child presents with features of Growth Hormone Deficiency (GHD) with extreme stunting.

ODP386 Growth Velocity and Growth Hormone Deficiency During Puberty

Abstract Background A subnormal growth velocity (GV) is a characteristic feature of growth hormone deficiency (GHD). During puberty growth hormone (GH) levels increase markedly in response to sex hormone secretion. The normal range for GV declines during childhood, increases during puberty with peak levels at mid-puberty. Hence, pubertal status rather than age alone must be considered in the evaluation of GV in children and adolescents. In most cases, a diagnosis of GHD is established by a subnormal response in GH levels following a stimulation with two pharmacological agents. Objective We determined the reliability of GV as a predictor of GHD during puberty. Methods We conducted a retrospective study of pubertal children and adolescents who underwent a GH stimulation test in our pediatric endocrinology clinic. Seventy-nine subjects (57 boys and 22 girls) were included in this study. Bone age was determined for all patients. Serum levels of insulin like growth factor-1 (IGF-1) were obtained prior to GH stimulation test. Serum IGF-1 levels, expressed as a standard deviation score were compared to the IGF-1 levels expected chronological age (CA), height age (HA), and bone age (BA). Serum GH levels were determined following the administration of arginine and levodopa. GHD was established by a peak GH level <10 ng/mL. IBM SPSS Statistics software version 28. 0. 0. 0 (190) was used for data analysis. Results Subjects ranged in age from 7.3-17.9 years. Thirty-nine patients (49.4%) had GV < 10 th percentile for CA; Forty patients (50.6%) had GV <10 th percentile for BA. Sixty percent of patients with GV <10 th percentile for CA had GHD. A similar number (59%) of patients with normal GV for CA also had GHD. Among patients with GV <10 th percentile for BA, 72.5% of subjects had GHD. By contrast, the percentage of patients who had normal GV for bone age and GHD (46.2%) was significantly less than that of subjects with GV <10 th percentile for BA (p = 0. 015). Positive predictive value, negative predictive value, sensitivity and specificity for GV <10 th percentile for BA in the diagnosis of GHD were 72.5%, 53.8%, 61.7%, and 65.6%, respectively. With respect to the diagnostic value of serum IGF-1, when the area under the ROC curve was used to measure how well the serum IGF-1 standard deviation score distinguished between GHD and normal, serum IGF-1 standard deviation score for CA, HA, and BA were not predictive of GHD (p = 0.1, 0.47, and 0.27, respectively). Conclusions During puberty, slow growth velocity for bone age (but not slow growth velocity for chronological age) was useful to predict a diagnosis of growth hormone deficiency. Presentation: No date and time listed

SAT-LB58 Molecular Investigation of Recessive Inheritance by Exome Sequencing of Patients With Congenital Hypopituitarism

Background: Growth hormone deficiency (GHD) occurs in ~ 1/8000 individuals, and 14% of the patients have mutations in five major candidate genes. However, over 30 genes have been implicated in hypopituitarism. WES (Whole Exome Sequencing) is a promising approach for molecular diagnosis of patients with GHD because it offers the opportunity to screen for all known genes in addition to novel disease gene discovery. Methods: WES was performed for 13 unrelated patients with congenital hypopituitarism born from consanguineous parents. The variants were filtered assuming autosomal recessive inheritance, rare variants in population databases, in silico analysis predicted as deleterious and pituitary and/or hypothalamus gene expression. To determine whether variants in CDH2 that were predicted to be deleterious were functionally significant, L1 fibroblast lines that have no endogenous CDH2 protein were stably transfected with either human wild type or variant CDH2, the transfected cells were labelled with lipophilic dyes, and cell adhesion properties were assessed. Results: Homozygous pathogenic or likely pathogenic allelic variants were found in 2 of the 13 patients. First, a female patient with GH, TSH, ACTH and LH/ FSH deficiencies presenting ectopic posterior pituitary lobe, non-visualized stalk, and hypoplastic anterior pituitary lobe had two homozygous rare variants predicted as deleterious: PLA2G4A p.Asn703Lys and CDH2 c.865G>A (p.Val289Ile). Only CDH2 is known to be expressed in the pituitary, and Pla2g4a null mice have a pleiotropic phenotype without obvious hypopituitarism. The CDH2 variant is rare and classified as deleterious. Sanger sequencing of CDH2 in four family members of the affected proband revealed that the unaffected parents and two unaffected siblings were heterozygous carriers. The effect of the CDH2 variant on cell aggregation was assessed in cell culture. Large cell aggregates formed in cells transfected with wild type CDH2, but cell aggregates were small or absent in cells that were either non-transfected or transfected with the CDH2 variant. Second, a patient with isolated GHD and no MRI abnormalities was identified with a rare, likely deleterious, homozygous GH1 c.171delT (p. Phe 57Leufs*43) variant. He had a sister who died at the age of 5 and had features of GHD. Conclusion: In a cohort of congenital hypopituitarism from consanguineous parents we had 15% molecular diagnosis using WES. We identified a variant in a known gene, GH1 c.171delT and a variant in a novel gene, CDH2 p.Val289I.

The Concept of Growth Hormone Deficiency Affecting Clinical Prognosis in IVF.

The current understanding of human growth hormone (hGH; here GH) action is that the molecule is a 191-amino acid, single-chain polypeptide that is synthesized, stored and secreted by the somatotroph cells within the lateral wings of the anterior pituitary gland. It can be classified as a protein (comprising more than 50 amino acids) but true proteins have tertiary and quaternary chains creating a more complex structure, hence GH is usually classified as a polypeptide. GH is normally secreted at night during sleep and promotes skeletal, visceral and general body growth through the action of somatomedins or IGFs, notably IGF-1. In some tissues, GH action is directed via specific receptors GHRs; these are most abundant in liver, adipose and muscle tissues but have also been shown in granulosa cells, testicular tissues and on the oocyte, as well as in glandular cells of the luteal phase endometrium and decidua; such findings being recent and minimally researched to now. Following engagement with its receptor, the transduction process activates multiple signaling proteins. These all lead to extensive metabolic and mitogenic (growth promoting) responses. Clinically, GH is known to have an important role in pubertal development and is a key hormone for the vigor associated with adolescence and early adult life stages but has a faded presence and role for later adulthood, beyond age 30 years, and is minimally detected in advanced age, beyond 40 years. In association with the rapidly increasing trend for delaying reproduction beyond age 35 years, GH is being widely researched now as a potential adjuvant for infertility treatment in this group who, studies consistently show, have a poorer prognosis than younger females when relying on autologous oocytes. The idea that the age-related reduction in fertility prognosis is a feature of growth hormone deficiency is supported by our studies showing an elevated binding protein IGFBP-3/IGF-1 ratio and this can be reduced to a normal range (matching younger, good prognosis women) by the administration of GH as an adjuvant.

Design of the Growth hormone deficiency and Efficacy of Treatment (GET) score and non-interventional proof of concept study

BackgroundThe adverse effects of growth hormone (GH) deficiency (GHD) in adults (AGHD) on metabolism and health-related quality of life (HRQoL) can be improved with GH substitution. This investigation aimed to design a score summarising the features of GHD and evaluate its ability to measure the effect of GH substitution in AGHD.MethodsThe Growth hormone deficiency and Efficacy of Treatment (GET) score (0–100 points) assessed (weighting): HRQoL (40%), disease-related days off work (10%), bone mineral density (20%), waist circumference (10%), low-density lipoprotein cholesterol (10%) and body fat mass (10%). A prospective, non-interventional, multicentre proof-of-concept study investigated whether the score could distinguish between untreated and GH-treated patients with AGHD. A 10-point difference in GET score during a 2-year study period was expected based on pre-existing knowledge of the effect of GH substitution in AGHD.ResultsOf 106 patients eligible for analysis, 22 were untreated GHD controls (9 females, mean ± SD age 52 ± 17 years; 13 males, 57 ± 13 years) and 84 were GH-treated (31 females, age 45 ± 13 years, GH dose 0.30 ± 0.16 mg/day; 53 males, age 49 ± 15 years, GH dose 0.25 ± 0.10 mg/day). Follow-up was 706 ± 258 days in females and 653 ± 242 days in males. The GET score differed between the untreated control and treated groups with a least squares mean difference of + 10.01 ± 4.01 (p = 0.0145).ConclusionsThe GET score appeared to be a suitable integrative instrument to summarise the clinical features of GHD and measure the effects of GH substitution in adults. Exercise capacity and muscle strength/body muscle mass could be included in the GET score.Trial registrationNCT number: NCT00934063. Date of registration: 02 July 2009.

Геоэндемическая оценка клинико-эпидемиологических особенностей дефицита гормона роста у детей Одесского региона по результатам 15-летнего мониторирования

Геоэндемическая оценка клинико-эпидемиологических особенностей дефицита гормона роста у детей Одесского региона по результатам 15-летнего мониторирования

MRI features of growth hormone deficiency in children with short stature caused by pituitary lesions.

We verified the advantages of using magnetic resonance imaging (MRI) for improving the diagnostic quality of growth hormone deficiency (GHD) in children with short stature caused by pituitary lesions. Clinical data obtained from 577 GHD patients with short stature caused by pituitary lesions were retrospectively analyzed. There were 354 cases (61.3%) with anterior pituitary dysplasia; 45 cases (7.8%) of pituitary stalk interruption syndrome (PSIS); 15 cases (2.6%) of pituitary hyperplasia due to primary hypothyroidism; 38 cases (6.6%) of Rathke cleft cyst; 68 cases (11.8%) of empty sella syndrome; 16 cases (2.8%) of pituitary invasion from Langerhans cell histiocytosis; 2 cases (0.3%) of sellar regional arachnoid cyst and 39 cases (6.8%) of craniopharyngioma. MRI results showed that the height of anterior pituitary in patients was less than normal. Location, size and signals of posterior pituitary and pituitary stalk were normal in anterior pituitary dysplasia. In all cases pituitary hyperplasia was caused by hypothyroidism. MRI results showed that anterior pituitary was enlarged, and we detected upward apophysis and obvious homogeneous enhancement. There were no pituitary stalk interruption and abnormal signal. We also observed that after hormone replacement therapy the size of pituitary gland was reduced. Anterior pituitary atrophy was observed in Rathke cleft cyst, empty sella syndrome, sellar regional arachnoid cyst and craniopharyngioma. The microstructure of hypophysis and sellar region was studied with MRI. We detected pituitary lesions, and the characteristics of various pituitary diseases of GHD in children with short stature. It was concluded that in children with GHD caused by pituitary lesions, MRI was an excellent method for early diagnosis. This method offers clinical practicability and we believe it can be used for differential diagnosis and to monitor the therapeutic effects.

Xenograft of microencapsulated Sertoli cells as a therapy for experimental Laron syndrome.

Introduction and Aim The only treatment of Laron Syndrome (LS), caused by an inherited defect in the gene encoding the GH receptor resulting in the failure to generate IGF-1, consists of chronic administration of recombinant human IGF−1 (rhIGF-1) that is burdened side effects. Moreover, this approach is limited by the restricted availability of this drug for clinical use (orphan drug) which dramatically lowers number of treatable cases. It is known that IGF-1 represents one of the main growth factors produced by Sertoli cells (SC). Aim of our work was to assess if transplantation of barium alginate microencapsulated SC (BaMCs) would induce normalization of clinical features of growth hormone deficiency in “Laron mice”, the best animal model for human LS. Materials and Methods BaMCs were prepared from pre-pubertal piglets, according to our method and examined as far as: (a) SC morphology by light microscopy; (b) SC viability, by fluorescence microscopy after staining with ethidium bromide and fluorescein diacetate (EB+FDA); (c) SC in vitro function (α-aromatase activity and IGF-I secretion); (d) evaluation of growth parameters in Laron transplanted mice were concerned. Results BaMCs showed excellent features in terms of size, morphology, sphericity and coalescence. SC viability was very high (over 90%). Very good α-aromatase activity and IGF-I secretion were associated with the examined SC preparation. Intraperitoneal graft of BaMCs into Laron mice induced a significant increase in growth parameters in terms of weigth and nose-to-anus length as compared to untreated controls. Conclusions SC may be enveloped in BaMCs with no loss of their functional and morphological properties. Xenograft of BaMCs in Laron mice induced, an unprecedented, significant increase in growth parameters as compared to untreated controls. This result may open new perspectives for therapy of human LS.

Growth Hormone (GH) Substitution in GH-Deficient Patients Inhibits 11β-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression in Adipose Tissue

Local tissue activity of glucocorticoids is in part determined by the isoenzymes 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) and 11beta-HSD2, interconverting inert cortisone and active cortisol. Increased tissue activity of cortisol may play a central role in the features of GH deficiency and the metabolic syndrome. We investigated the effects of GH treatment on adipose tissue 11beta-HSD mRNA. A randomized placebo-controlled double-blind study design was used. Twenty-three GH-deficient patients (16 males and seven females) were randomized to 4 months of GH treatment (2 IU/m2) (n = 11) or placebo treatment (n = 12). Adipose tissue biopsies and blood samples were obtained before and after treatment. Biopsies were obtained from the abdominal sc depot at the level of the umbilicus and do not necessarily reflect the metabolically more important visceral adipose tissue. Gene expressions were determined by real-time RT-PCR. GH treatment decreased 11beta-HSD1 mRNA 66% [95% confidence interval (CI), 23-107%; P < 0.01] and increased 11beta-HSD2 mRNA 167% (95% CI, 33-297%; P < 0.05) in adipose tissue. Serum IGF-I and IGF-I mRNA increased in the GH-treated group by 187% (95% CI, 122-250%; P < 0.001) and 470% (95% CI, 88-846%; P < 0.01). The change in 11beta-HSD1 mRNA expression was negatively correlated with the change in serum IGF-I (R = -0.434; P < 0.05). In contrast, the change in 11beta-HSD2 mRNA expression was positively correlated with the change in serum IGF-I (R = 0.487; P < 0.05), and even stronger with the change in IGF-I mRNA expression (R = 0.798; P < 0.0001). GH treatment is able to decrease 11beta-HSD1 mRNA and increase 11beta-HSD2 and accordingly may be able to reduce the amount of locally produced cortisol in adipose tissue.

Long-term growth hormone replacement therapy in hypopituitary adults.

Growth hormone deficiency (GHD) in the adult has now been fully recognised as a clinical entity characterised by abnormal body composition, osteopenia, impaired quality of life, cardiac dysfunction and an adverse lipid profile. While short-term studies of GH replacement have demonstrated irrefutably a favourable effect on all if not most features of GHD, data on long-term administration spanning more than 2 years are still scarce. Experience of GH replacement up to 5 to 10 years indicate that the beneficial effects on body composition, predominantly a decrease in body fat and an increase in lean mass, is maintained during treatment. Long-term GH therapy also increases muscle strength and exercise performance. All data, with one exception, are consistent with a significant increase in bone mass during prolonged GH therapy. The most distinct effect on bone was observed in the worst affected individuals and in males. Improvement in quality of life is documented shortly after initiation of GH replacement and is maintained during long-term studies. This may explain the reduction in days of sick leave seen during GH therapy. The beneficial effect on cardiovascular risk factors is sustained over a prolonged period of time, revealing a reduction in intima wall thickness, and an improvement in serum lipid levels and clotting parameters. The increase in lipoprotein(a) levels with GH therapy in some studies may be disturbing, but difficulties in measuring this parameter and inconsistencies between the different studies makes it difficult to estimate its real impact. No data are yet available to show that GH replacement will normalise or even improve mortality rate and fracture rate. Adverse events associated with GH replacement therapy are mainly secondary to fluid retention as a result of excess dose administration. This can be adequately prevented by monitoring GH replacement according to serum insulin-like growth factor (IGF)-I levels. From what is currently known, GH replacement does not increase the prevalence of diabetes mellitus, and does not induce new neoplasms or recurrence of the primary brain tumour; however, longer follow-up studies are needed to provide definitive answers. In conclusion, it appears not only that long-term GH replacement therapy in adults with GHD is a procedure that can be safely used, but that GH replacement should be considered as a possible life-long therapy in order to maintain its benefits.

A Randomized, Double-Blind, Placebo-controlled Study of Growth Hormone in the Treatment of Fibromyalgia

PURPOSE: The cause of fibromyalgia (FM) is not known. Low levels of insulin-like growth factor 1 (IGF-1), a surrogate marker for low growth hormone (GH) secretion, occur in about one third of patients who have many clinical features of growth hormone deficiency, such as diminished energy, dysphoria, impaired cognition, poor general health, reduced exercise capacity, muscle weakness, and cold intolerance. To determine whether suboptimal growth hormone production could be relevant to the symptomatology of fibromyalgia, we assessed the clinical effects of treatment with growth hormone. METHODS: Fifty women with fibromyalgia and low IGF-1 levels were enrolled in a randomized, placebo-controlled, double-blind study of 9 months’ duration. They gave themselves daily subcutaneous injections of growth hormone or placebo. Two outcome measures—the Fibromyalgia Impact Questionnaire and the number of fibromyalgia tender points—were evaluated at 3-monthly intervals by a blinded investigator. An unblinded investigator reviewed the IGF-1 results monthly and adjusted the growth hormone dose to achieve an IGF-1 level of about 250 ng/mL. RESULTS: Daily growth hormone injections resulted in a prompt and sustained increase in IGF-1 levels. The treatment (n = 22) group showed a significant improvement over the placebo group (n = 23) at 9 months in both the Fibromyalgia Impact Questionnaire score ( P <0.04) and the tender point score ( P <0.03). Fifteen subjects in the growth hormone group and 6 subjects in the control group experienced a global improvement ( P <0.02). There was a delayed response to therapy, with most patients experiencing improvement at the 6-month mark. After discontinuing growth hormone, patients experienced a worsening of symptoms. Carpal tunnel symptoms were more prevalent in the growth hormone group (7 versus 1); no other adverse events were more common in this group. CONCLUSIONS: Women with fibromyalgia and low IGF-1 levels experienced an improvement in their overall symptomatology and number of tender points after 9 months of daily growth hormone therapy. This suggests that a secondary growth hormone deficiency may be responsible for some of the symptoms of fibromyalgia.

Metabolic Effects of Hypopituitarism and Acromegaly&lt;sup&gt;1&lt;/sup&gt;

Hypopituitarism is associated with reduced lean body mass and increased body fat, while in acromegaly the converse is true. Fasting plasma glucose is increased in acromegaly but fasting plasma insulin and C-peptide are increased in both groups. There is a positive association between fat mass and fasting serum insulin in hypopituitarism, suggesting insulin resistance. Hypoglycaemia unresponsiveness, rather than insulin sensitivity, is the feature of growth hormone deficiency. Basal metabolic rate (expressed per kg body weight) is increased in acromegaly and decreased in hypopituitarism but when expressed 'per kg lean body mass', is increased in both groups. There is a close correlation between fat mass and fasting free fatty acid and glycerol levels in obese but not normal weight patients with hypopituitarism; slim patients appear to metabolise and oxidise their fat stores more effectively than those who remain obese. Thus indirect evidence suggests that growth hormone has an important role in maintaining normal body composition and energy stores.

Diagnosis and treatment of children with growth hormone deficiency

Growth hormone deficiency embraces a heterogeneous group of disorders with multiple aetiologies. The biggest single division is between those children whose growth hormone deficiency is due to a structural lesion and those where it is not. In both cases other pituitary hormones may, or may not, be affected, although when a structural lesion is present multiple pituitary hormone deficiency is the rule rather than the exception. In the absence of structural lesions the pathogenesis of the condition in still largely obscure, although some mechanisms, such as cranial irradiation, are now well recognized. Birth trauma is also now a strong candidate as a predisposing factor. The prevalence of growth hormone deficiency is still uncertain, but is probably about 1 in 4000 live births. The clinical features of growth hormone deficiency are usually fairly clear, with short stature, low growth velocity, excess subcutaneous fat and delayed skeletal maturation being the principal clinical features. Laboratory investigation still largely depends upon the assessment of pituitary growth hormone secretion in response to a variety of provocation tests and is still in many ways unsatisfactory. Treatment consists of parenteral growth hormone replacement using material of human cadaveric origin. Non-primate growth hormones are of no value. Other endocrine abnormalities, when present, are treated appropriately, and with early diagnosis and optimal therapy the height prognosis is reasonably good. The principal aims for the future must be to ensure supplies of therapeutic growth hormone, improve some of the diagnostic procedures and ensure early ascertainment.