Influence of growth hormone (GH) receptor deletion of exon 3 and full-length isoforms on GH response and final height in patients with severe GH deficiency

CONTEXT: A polymorphism of the GH receptor (GHR) gene resulting in genomic deletion of exon 3 (GHR-d3) has been associated with responsiveness to GH therapy. However, the data reported so far do vary according to the underlying condition, replacement dose, and duration of the treatment. OBJECTIVE, DESIGN: The aim of this study was to analyze the impact of the GHR genotypes in terms of the initial height velocity (HV) resulting from treatment and the impact upon adult height in patients suffering from severe isolated GH deficiency. CONTROLS, PATIENTS, SETTING: A total of 181 subjects (peak stimulated GHGHR genotype frequency was compared with a healthy adult control group. INTERVENTIONS: Based on the various GHR genotypes, HV, effect of recombinant human GH dose used, and final height were analyzed. MAIN OUTCOME MEASURES, RESULTS: In the 181 subjects after the first two yr on recombinant human GH treatment, HV sd score (SDS) as well as height gain were significantly greater in subjects with the GHR-d3/d3 genotype when compared with the subjects presenting with the GHR-full-length/full-length genotype (P<0.05). A GHR-d3 allele dose-dependent effect was found for both HV SDS (r=0.72) and height gain (r=0.77). However, there was no significant difference in final adult height and height SDS according to the exon-3 genotypes. CONCLUSIONS: Our results indicate that in patients with severe isolated GH deficiency, although the GHR genotype might play a role in GH responsiveness, at least at the beginning of treatment, there is no effect on final height.

A 2-year multicentre, open-label, randomized, controlled study of growth hormone (Genotropin(®) ) treatment in very young children born small for gestational age: Early Growth and Neurodevelopment (EGN) Study

OBJECTIVE In Europe, growth hormone (GH) treatment for children born small for gestational age (SGA) can only be initiated after 4 years of age. However, younger age at treatment initiation is a predictor of favourable response. To assess the effect of GH treatment on early growth and cognitive functioning in very young (<30 months), short-stature children born SGA. DESIGN A 2-year, randomized controlled, multicentre study (NCT00627523; EGN study), in which patients received either GH treatment or no treatment for 24 months. PATIENTS Children aged 19-29 months diagnosed as SGA at birth, and for whom sufficient early growth data were available, were eligible. Patients were randomized (1:1) to GH treatment (Genotropin(®) , Pfizer Inc.) at a dose of 0·035 mg/kg/day by subcutaneous injection, or no treatment. MEASUREMENTS The primary objective was to assess the change from baseline in height standard deviation score (SDS) after 24 months of GH treatment. RESULTS Change from baseline in height SDS was significantly greater in the GH treatment vs control group at both month 12 (1·03 vs 0·14) and month 24 (1·63 vs 0·43; both P < 0·001). Growth velocity SDS was significantly higher in the GH treatment vs control group at 12 months (P < 0·001), but not at 24 months. There was no significant difference in mental or psychomotor development indices between the two groups. CONCLUSIONS GH treatment for 24 months in very young short-stature children born SGA resulted in a significant increase in height SDS compared with no treatment.

Association of the (CA)n repeat polymorphism of insulin-like growth factor-I and -202 A/C IGF-binding protein-3 promoter polymorphism with adult height in patients with severe growth hormone deficiency

A number of mathematical models for predicting growth and final height outcome have been proposed to enable the clinician to 'individualize' growth-promoting treatment. However, despite optimizing these models, many patients with isolated growth hormone deficiency (IGHD) do not reach their target height. The aim of this study was to analyse the impact of polymorphic genotypes [CA repeat promoter polymorphism of insulin-like growth factor-I (IGF-I) and the -202 A/C promoter polymorphism of IGF-Binding Protein-3 (IGFBP-3)] on variable growth factors as well as final height in severe IGHD following GH treatment. DESIGN, PATIENTS AND CONTROLS: One hundred seventy eight (IGF-I) and 167 (IGFBP-3) subjects with severe growth retardation because of IGHD were studied. In addition, the various genotypes were also studied in a healthy control group of 211 subjects.

The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency

Total body water (TBW) is reduced in adult GH deficiency (GHD) largely due to a reduction of extracellular water. It is unknown whether total blood volume (TBV) contributes to the reduced extracellular water in GHD. GH and insulin-like growth factor I (IGF-I) have been demonstrated to stimulate erythropoiesis in vitro, in animal models, and in growing children. Whether GH has a regulatory effect on red cell mass (RCM) in adults is not known. We analyzed body composition by bioelectrical impedance and used standard radionuclide dilution methods to measure RCM and plasma volume (PV) along with measuring full blood count, ferritin, vitamin B12, red cell folate, IGF-I, IGF-binding protein-3, and erythropoietin in 13 adult patients with GHD as part of a 3-month, double blind, placebo-controlled trial of GH (0.036 U/kg.day). TBW and lean body mass significantly increased by 2.5 +/- 0.53 kg (mean +/- SEM; P < 0.004) and 3.4 +/- 0.73 kg (P < 0.004), respectively, and fat mass significantly decreased by 2.4 +/- 0.32 kg (P < 0.001) in the GH-treated group. The baseline RCM of all patients with GHD was lower than the predicted normal values (1635 +/- 108 vs. 1850 +/- 104 mL; P < 0.002). GH significantly increased RCM, PV, and TBV by 183 +/- 43 (P < 0.006), 350 +/- 117 (P < 0.03), and 515 +/- 109 (P < 0.004) mL, respectively. The red cell count increased by 0.36 +/- 0.116 x 10(12)/L (P < 0.03) with a decrease in ferritin levels by 39.1 +/- 4.84 micrograms/L (P < 0.001) after GH treatment. Serum IGF-I and IGF-binding protein-3 concentrations increased by 3.0 +/- 0.43 (P < 0.001) and 1.3 +/- 0.15 (P < 0.001) SD, respectively, but the erythropoietin concentration was unchanged after GH treatment. No significant changes in body composition or blood volume were recorded in the placebo group. Significant positive correlations could be established between changes in TBW and TBV, lean body mass and TBV (r = 0.78; P < 0.04 and r = 0.77; P < 0.04, respectively), and a significant negative correlation existed between changes in fat mass and changes in TBV in the GH-treated group (r = -0.95; P < 0.02). We conclude that 1) erythropoiesis is impaired in GHD; 2) GH stimulates erythropoiesis in adult GHD; and 3) GH increases PV and TBV, which may contribute to the increased exercise performance seen in these patients.

The consequences of growth hormone deficiency in adulthood, and the effects of growth hormone replacement

The availability of recombinant human growth hormone (GH) has resulted in investigation of the role of GH in adulthood and the effects of GH replacement in the GH-deficient adult. These studies have led to the recognition of a specific syndrome of GH-deficiency, characterized by symptoms, signs and investigative findings. Adults with long-standing growth hormone deficiency are often overweight, have altered body composition, with reduced lean body mass (LBM), increased fat mass (FM), reduced total body water and reduced bone mass. In addition, there is reduced physical and cardiac performance, altered substrate metabolism and an abnormal lipid profile predisposing to the development of cardiovascular disease. Adults with GH deficiency report reduced psychological well-being and quality of life. These changes may contribute to the morbidity and premature mortality observed in hypopituitary adults on conventional replacement therapy. GH treatment restores LBM, reduces FM, increases total body water and increases bone mass. Following GH therapy, increases are recorded in exercise capacity and protein synthesis, and "favourable" alterations occur in plasma lipids. In addition, psychological well-being and quality of life improve with replacement therapy. GH is well tolerated; adverse effects are largely related to fluid retention and respond to dose adjustment. It is likely that GH replacement will become standard therapy for the hypopituitary adult in the near future. The benefits of GH replacement in the GH-deficient adult have been unequivocally demonstrated in studies lasting up to 3 years. The results of longer term studies are awaited to determine whether these benefits are sustained over a lifetime.

Natural history of growth hormone deficiency in a pediatric cohort.

BACKGROUND/AIMS Controversies still exist regarding the evaluation of growth hormone deficiency (GHD) in childhood at the end of growth. The aim of this study was to describe the natural history of GHD in a pediatric cohort. METHODS This is a retrospective study of a cohort of pediatric patients with GHD. Cases of acquired GHD were excluded. Univariate logistic regression was used to identify predictors of GHD persisting into adulthood. RESULTS Among 63 identified patients, 47 (75%) had partial GHD at diagnosis, while 16 (25%) had complete GHD, including 5 with multiple pituitary hormone deficiencies. At final height, 50 patients underwent repeat stimulation testing; 28 (56%) recovered and 22 (44%) remained growth hormone (GH) deficient. Predictors of persisting GHD were: complete GHD at diagnosis (OR 10.1, 95% CI 2.4-42.1), pituitary stalk defect or ectopic pituitary gland on magnetic resonance imaging (OR 6.5, 95% CI 1.1-37.1), greater height gain during GH treatment (OR 1.8, 95% CI 1.0-3.3), and IGF-1 level <-2 standard deviation scores (SDS) following treatment cessation (OR 19.3, 95% CI 3.6-103.1). In the multivariate analysis, only IGF-1 level <-2 SDS (OR 13.3, 95% CI 2.3-77.3) and complete GHD (OR 6.3, 95% CI 1.2-32.8) were associated with the outcome. CONCLUSION At final height, 56% of adolescents with GHD had recovered. Complete GHD at diagnosis, low IGF-1 levels following retesting, and pituitary malformation were strong predictors of persistence of GHD.

Transient MR changes and symptomatic epilepsy following gamma knife treatment of a residual GH-secreting pituitary adenoma in the cavernous sinus

To report a rare side effect of gamma knife treatment of pituitary macroadenoma.

Insulin-like growth factor-I treatment in primary growth hormone insensitivity: effect of recombinant human IGF-I (rhIGF-I) and rhIGF-I/rhIGF-binding protein-3 complex

Growth hormone insensitivity syndrome (GHIS) is a rare cause of growth retardation characterized by high serum GH levels, and low serum insulin-like growth factor I (IGF-I) levels associated with a genetic defect of the GH receptor (GHR) as well post-GHR signaling pathway. Based on clinical, as well as biochemical characteristics, GHIS can be genetically classified as classical/Laron's syndrome and nonclassical/atypical GHIS. Recombinant human IGF-I (rhIGF-I) treatment is effective in promoting growth in subjects who have GHIS. Further, pharmacological studies of a IGF-I compound containing a 1:1 molar complex of rhIGF-I and rhIGF-binding protein-3 (BP-3) demonstrated that the complex was effective in increasing levels of circulating total and free IGF-I and that the administration in patients with GHIS should be safe, well-tolerated and more effective than rhIGF-I on its own.

Anti-Müllerian hormone levels in girls and adolescents with Turner syndrome are related to karyotype, pubertal development and growth hormone treatment

In girls and adolescents with Turner syndrome (TS), is there a correlation between serum AMH levels and karyotype, spontaneous puberty and other biochemical markers of ovarian function, or growth hormone (GH) therapy? SUMMARY ANSWER: Serum anti-Müllerian hormone (AMH) correlates with karyotype, pubertal development, LH, FSH and are measurable in a higher percentage of TS patients under GH therapy. WHAT IS KNOWN ALREADY: Most girls with TS suffer from incomplete sexual development, premature ovarian failure and infertility due to abnormal ovarian folliculogenesis. Serum AMH levels reflect the ovarian reserve in females, even in childhood. STUDY DESIGN, SIZE, DURATION: Cross-sectional study investigating 270 karyotype proven TS patients aged 0-20 years between 2009 and 2010. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Studies were conducted at three University Children's hospitals in Europe. Main outcome measures were clinical data concerning pubertal development as well as laboratory data including karyotype, serum AMH, LH, FSH, estradiol (E2), inhibin B and IGF. RESULTS AND THE ROLE OF CHANCE: Serum AMH was detectable in 21.9% of all TS girls and correlated strongly with karyotypes. A measurable serum AMH was found in 77% of TS girls with karyotype 45,X/46,XX, in 25% with 'other' karyotypes and in only 10% of 45,X TS girls. A strong relationship was also observed for measurable serum AMH and signs of spontaneous puberty such as breast development [adjusted odds ratio (OR) 19.3; 95% CI 2.1-175.6; P = 0.009] and menarche (crude OR 47.6; 95% CI 4.8-472.9; P = 0.001). Serum AMH correlated negatively with FSH and LH, but did not correlate with E2 and inhibin B. GH therapy increased the odds of having measurable AMH in TS (adjusted OR 4.1; 95% CI 1.9-8.8; P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The cross-sectional design of the study does not allow longitudinal interpretation of the data; for that further studies are needed. High percentage of non-measurable AMH levels in the cohort of TS require categorized analysis. WIDER IMPLICATIONS OF THE FINDINGS: Serum AMH levels are a useful marker of the follicle pool and thus ovarian function in pediatric patients with TS. These findings are in line with the published literature. The finding that GH therapy may affect AMH levels is novel, but must be confirmed by future longitudinal studies.

Towards optimal treatment with growth hormone in short children and adolescents: evidence and theses

Treatment with growth hormone (GH) has become standard practice for replacement in GH-deficient children or pharmacotherapy in a variety of disorders with short stature. However, even today, the reported adult heights achieved often remain below the normal range. In addition, the treatment is expensive and may be associated with long-term risks. Thus, a discussion of the factors relevant for achieving an optimal individual outcome in terms of growth, costs, and risks is required. In the present review, the heterogenous approaches of treatment with GH are discussed, considering the parameters available for an evaluation of the short- and long-term outcomes at different stages of treatment. This discourse introduces the potential of the newly emerging prediction algorithms in comparison to other more conventional approaches for the planning and evaluation of the response to GH. In rare disorders such as those with short stature, treatment decisions cannot easily be deduced from personal experience. An interactive approach utilizing the derived experience from large cohorts for the evaluation of the individual patient and the required decision-making may facilitate the use of GH. Such an approach should also lead to avoiding unnecessary long-term treatment in unresponsive individuals.

Ectopic growth hormone-releasing hormone secretion by a metastatic bronchial carcinoid tumor: a case with a non hypophysial intracranial tumor that shrank during long acting octreotide treatment

Ectopic acromegaly represents less than 1% of the reported cases of acromegaly. Although clinical improvement is common after treatment with somatostatin (SMS) analogs, the biochemical response and tumor size of the growth hormone-releasing hormone (GHRH)-producing tumor and its metastases are less predictable. Subject A 36-year-old male was referred because of a 3-year history of acromegaly related symptoms. He had undergone lung surgery in 1987 for a "benign" carcinoid tumor. Endocrine evaluation confirmed acromegaly Plasma IGF-1: 984 ng/ml (63-380), GH: 49.8 ng/ml (<5). MRI showed a large mass in the left cerebellopontine angle and diffuse pituitary hyperplasia. Pulmonary, liver and bone metastases were shown by chest and abdominal CT scans. Ectopic GHRH secretion was suspected. Methods Measurement of circulating GHRH levels by fluorescence immunoassay levels and immunohistochemical study of the primary lung tumor and metastatic tissue with anti-GHRH and anti-somatostatin receptor type 2 (sst2A) antibodies. Results Basal plasma GHRH: 4654 pg/ml (<100). Pathological study of liver and bone biopsy material and lung tissue removed 19 years earlier was consistent with an atypical carcinoid producing GHRH and exhibiting sst2A receptor expression. Treatment with octreotide LAR 20-40 mg q. month resulted in normalization of plasma IGF-1 levels. Circulating GHRH levels decreased dramatically. The size of the left prepontine cistern mass, with SMS receptors shown by a radiolabeled pentetreotide scan, decreased by 80% after 18 months of therapy. Total regression of pituitary enlargement was also observed. No changes were observed in lung and liver metastases. After 24 months of therapy the patient is asymptomatic and living a full and active life.

Systemic response of the GH/IGF-I axis in timely versus delayed fracture healing

The GH-IGF axis has profound effects on the local and systemic regulation of bone metabolism and may be important for quality of fracture healing. To test the hypothesis that deficiency of the GH/IGF axis may play a role in the pathogenesis of fracture non-union we investigated whether alterations of serum concentrations of the GH-IGF axis could be related to failed fracture healing compared to timely fracture healing in trauma patients. Serum probes were prospectively collected from 186 patients with surgical treatment of long bone fractures up to 6 months after surgery. Samples from 14 patients with atrophic type of non-union have been compared to 14 matched patients with normal bone healing. Postoperative time courses of serum concentrations have been analyzed using commercially available chemiluminescence sandwich assays (GH), fully automated assay systems (IGF-I, IGFBP-3) or sandwich immunometric assays (ALS). Comparison between both collectives revealed significantly lower serum concentrations of GH dependent ALS during early (1st week after surgery) and of both IGFBP-3 and ALS during late stages of fracture healing (6 and 8 weeks after surgery) in non-union patients, coinciding clinically with failed fracture healing. Tendentially lower serum levels of IGF-I in the non-union group over the entire investigation period were statistically not significant. We have been able to show time courses of serum concentrations of the GH/IGF-I axis during normal and failed fracture healing in humans. An impairment of the GH/IGF-I axis might be involved in the biochemical mechanisms determining delayed or failed fracture healing.

Effects of growth hormone (GH) replacement therapy on low-density lipoprotein apolipoprotein B100 kinetics in adult patients with GH deficiency: a stable isotope study

GH replacement therapy has been shown to improve the dyslipidemic condition in a substantial proportion of patients with adult GH deficiency. The mechanisms are not yet fully elucidated. Low-density lipoprotein (LDL) apolipoprotein B100 (apoB) formation and catabolism are important determinants of plasma cholesterol concentrations. This study examined the effect of GH replacement therapy on LDL apoB metabolism using a stable isotope turnover technique. LDL apoB kinetics was determined in 13 adult patients with GH deficiency before and after 3 months GH/placebo treatment in a randomized, double-blind, placebo-controlled study. LDL apoB (13)C-leucine enrichment was determined by isotope-ratio mass spectrometry. Plasma volume was assessed by standardized radionuclide dilution technique. GH replacement therapy significantly decreased LDL cholesterol, LDL apoB concentrations, and LDL apoB pool size compared with placebo. Compared with baseline, GH replacement therapy resulted in a significant increase in plasma volume and fractional catabolic rate, whereas LDL formation rate remained unchanged. LDL lipid content did not significantly change after GH and placebo. This study suggests that short-term GH replacement therapy decreases the LDL apoB pool by increasing removal of LDL particles without changing LDL composition or LDL apoB production rate. In addition, it is possible that the beneficial effects of GH on the cardiovascular system contribute to these findings.

IGF-I treatment in adults with type 1 diabetes: effects on glucose and protein metabolism in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp

Type 1 diabetes is associated with abnormalities of the growth hormone (GH)-IGF-I axis. Such abnormalities include decreased circulating levels of IGF-I. We studied the effects of IGF-I therapy (40 microg x kg(-1) x day(-1)) on protein and glucose metabolism in adults with type 1 diabetes in a randomized placebo-controlled trial. A total of 12 subjects participated, and each subject was studied at baseline and after 7 days of treatment, both in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp. Protein and glucose metabolism were assessed using infusions of [1-13C]leucine and [6-6-2H2]glucose. IGF-I administration resulted in a 51% rise in circulating IGF-I levels (P < 0.005) and a 56% decrease in the mean overnight GH concentration (P < 0.05). After IGF-I treatment, a decrease in the overnight insulin requirement (0.26+/-0.07 vs. 0.17+/-0.06 U/kg, P < 0.05) and an increase in the glucose infusion requirement were observed during the hyperinsulinemic clamp (approximately 67%, P < 0.05). Basal glucose kinetics were unchanged, but an increase in insulin-stimulated peripheral glucose disposal was observed after IGF-I therapy (37+/-6 vs. 52+/-10 micromol x kg(-1) x min(-1), P < 0.05). IGF-I administration increased the basal metabolic clearance rate for leucine (approximately 28%, P < 0.05) and resulted in a net increase in leucine balance, both in the basal state and during the hyperinsulinemic amino acid clamp (-0.17+/-0.03 vs. -0.10+/-0.02, P < 0.01, and 0.25+/-0.08 vs. 0.40+/-0.06, P < 0.05, respectively). No changes in these variables were recorded in the subjects after administration of placebo. These findings demonstrated that IGF-I replacement resulted in significant alterations in glucose and protein metabolism in the basal and insulin-stimulated states. These effects were associated with increased insulin sensitivity, and they underline the major role of IGF-I in protein and glucose metabolism in type 1 diabetes.