d3‐GHR genotype does not explain heterogeneity in GH responsiveness in hypopituitary adults

Objective Heterogeneity in growth hormone (GH) responsiveness in adult hypopituitary patients receiving recombinant human GH (rhGH) is poorly understood; doses vary up to fourfold between individuals. Deletion of exon 3 in the GH receptor (d3‐GHR) has been linked to enhanced rhGH responsiveness in children. We investigated the role of the d3‐GHR polymorphism in determining adult rhGH responsiveness. Methods One hundred and ninety‐four patients treated with an identical rhGH dosing protocol in a single centre were genotyped for the d3‐GHR, and the results correlated with changes in serum IGF‐I and clinical parameters of GH responsiveness after 6 and 12 months of GH replacement therapy. Results Allele frequencies for homozygous full length (fl/fl), heterozygous d3 (fl/d3) and homozygous d3 (d3/d3) were 52%, 38·7% and 9·3%, respectively, and were in Hardy–Weinberg equilibrium. Baseline IGF‐I and ΔIGF‐I at 6 months were comparable between groups. ΔIGF‐I at 12 months was significantly greater in the d3/d3 group (P = 0·028). No difference was detected between fl/d3 and fl/fl groups. Regression analyses of ΔIGF‐I at 12 months and ΔIGF‐I/rhGH dose confirmed a significant relationship of d3/d3 genotype on rhGH response. There was no difference between groups in maintenance rhGH dose between genotypes. Conclusion Homozygosity for d3‐GHR confers a marginal increase in GH responsiveness at 12 months but without a detectable change in maintenance rhGH dose required. Both d3 alleles are required to achieve this response; given that only 10% of the population are d3 homozygotes, the d3GHR does not explain the marked heterogeneity of GH responsiveness in hypopituitary adults.     

Ascites from patients with alcoholic liver cirrhosis contains higher IGF‐I bioactivity than serum

Objective Patients with liver cirrhosis have diminished hepatic IGF‐I generation, resulting in low circulating levels, whereas data on IGF‐I in ascites are sparse. Therefore, we compared the IGF‐system in serum and ascites from cirrhotic patients. Design and patients The study comprised 43 patients (12 females) with ascites and liver function of 58 ± 10% of normal. Serum and ascites were collected concomitantly in the fasting state. In 11 patients, second serum and ascitic samples were collected within the first week. Eleven matched controls were also included. All samples were assayed for IGF‐related parameters by immunoassays and by cell‐based IGF‐I bioassay. Results As compared with controls, serum total IGF‐I, total IGF‐II, pro‐IGF‐II and bioactive IGF‐I were reduced in liver patients, whereas IGF‐binding protein 1 (IGFBP‐1), IGFBP‐2 and the soluble IGF‐II receptor were elevated (P < 0·005 for all). In ascites, all IGF‐related peptides but pro‐IGF‐II were further reduced as compared with serum (P < 0·001). By contrast, bioactive IGF‐I was fourfold elevated in ascites as compared with serum (2·20 ± 0·33 vs. 0·55 ± 0·08 μg/l, P < 0·001). In ascites, the IGF‐I bioactivity signal was completely blocked by addition of IGFBP‐3. Repetitive measurements (n = 11) in ascites showed that all peptides but IGFBP‐1 remained unchanged within 1 week. Conclusions It is a novel observation that the in vitro bioactivity of IGF‐I can be higher in fluids from an extravascular compartment than in serum, in contrast to immunoreactive levels. This supports different roles for endocrine and paracrine/autocrine IGF‐I, but the pathophysiological significance of our observation remains to be clarified.     

ORIGINAL ARTICLE: Associations of the growth hormone receptor (GHR) gene polymorphisms with adiposity and IGF‐I activity in adolescents

Objective: To explore the genetic effect of the GH receptor (GHR) on obesity and related metabolic parameters in Hong Kong Chinese adolescents. Context: Obesity is a growing global epidemic. Increasing evidence suggests that the GH‐IGF‐I axis plays an important role in regulating adiposity and insulin sensitivity. Design: We examined the associations of genetic variants of GHR with serum IGF‐I and IGFBP‐3 levels as well as obesity‐related metabolic traits in Hong Kong Chinese adolescents. Patients: Nine hundred and eighty‐one randomly selected Hong Kong Chinese adolescents from 14 schools. Measurements: We genotyped 17 single nucleotide polymorphisms (SNP) at GHR and measured serum IGF‐I and IGFBP‐3 levels as well as obesity‐related metabolic traits including fasting plasma glucose, insulin and lipid levels. Results: There were significant associations between rs4410646 and the body composition (P = 0·0044) and blood pressure factor scores (P = 0·00017). Carriers of the CC genotype had lower body mass index, percentage body fat, waist and hip circumferences than AC and AA genotype carriers (P = 0·00030–0·0094). There was also association between rs7703713 and the IGF‐I activity factor score (P = 0·0033). The GA and AA carriers of rs7703713 had higher serum IGF‐I, higher serum IGFBP‐3 and higher IGF‐I/IGFBP‐3 molar ratio (P = 0·00069–0·025). Haplotype analysis did not increase the significance of associations. Conclusion: Our results support the role of GHR gene polymorphisms in modulating adiposity and IGF‐I activity in adolescents. Examination of interactions of these SNPs with lifestyle, environmental and perinatal factors may provide further insights into their long‐term effects on obesity and metabolic risks.     

Changes and relationships of IGFS and IGFBPS and cytokines in coeliac disease at diagnosis and on gluten-free diet

Objective To evaluate changes and relationships of IGFs and IGFBPs, serum interleukin 6 (IL‐6) and tumour necrosis factor (TNF)‐α, and auxological parameters at diagnosis of coeliac disease (CD) and at 6 months and 12 months after starting a gluten‐free diet (GFD), compared with a control population. Patients Twenty patients were enrolled at diagnosis (9 male, 11 female; age 9·6 ± 0·8 years). A healthy population of 18 subjects (5 male, 13 female; age 11·3 ± 0·6 years) comparable for age, sex and pubertal status served as controls at baseline. Measurements Blood samples were taken at diagnosis, and at 6 months and 12 months after starting the GFD. Serum IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐2, IGFBP‐3, IL‐6 and TNF‐α were measured using commercial kits. Height (Ht) standard deviation score (SDS), body mass index (BMI) SDS and Ht velocity SDS were evaluated at diagnosis and at 6 months and 12 months after starting GFD. Results In CD patients, both Ht SDS and BMI SDS increased during the first year of treatment, and Ht velocity SDS increased during the second 6 months of follow‐up (P < 0·05). At diagnosis, IGF‐I, IGF‐II and IGFBP‐3 were lower compared with controls, IGFBP‐1 was similar, IGFBP‐2, IL‐6 and TNF‐α were higher (P < 0·05). When on GFD, all peptides normalized and IGFBP‐1 decreased. The IGF‐I/IGFBP‐2 and IGF‐I/IGFBP‐3 molar ratios were significantly reduced at diagnosis compared with those of controls, but were increased for both groups when on GFD. Although there was no apparent abnormality at diagnosis, the IGF‐II/IGFBP‐2 molar ratio increased significantly on GFD. Ht velocity SDS was positively correlated with IGFBP‐3 (P < 0·05) and with the IGF‐I/IGFBP‐2 molar ratio (P < 0·05). Serum IL‐6 was negatively correlated with IGF‐I and positively with IGFBP‐1 (P < 0·05). Conclusions The data obtained from this study confirm changes in the IGF and cytokine systems at diagnosis of CD which tend to normalize on the gluten‐free diet. The two systems show relationships with each other and with linear growth.     

IGF system and peripheral arterial disease: relationship with disease severity and inflammatory status of the affected limb

Objectives IGF‐1 and its binding proteins are involved in the pathogenesis of atherosclerosis. We designed this study to unravel the relationship of the IGF system with peripheral arterial disease (PAD). Design Case‐control, cross‐sectional study. Measurements Serum levels of IGF‐1, IGFBP‐3 and acid labile subunit (ALS) were measured in 96 PAD patients and 89 controls. In 28 patients who underwent peripheral angiography, C‐reactive protein (CRP), IGF‐1, IGFBP‐3 and ALS were measured in blood from femoral vein of the affected limb and aorta. Results Compared to controls, PAD patients showed lower levels of IGFBP‐3 (3569 ± 115 vs. 3106 ± 107 µg/l, P < 0·01), and ALS (12·2 ± 0·5 vs. 8·3 ± 0·5 mg/l, P < 0·01). In PAD, concentrations of IGFBP‐3 and ALS were significantly lower in patients with ankle/brachial index less than median than in those with a less severe PAD. In the affected limb, CRP venous‐arterial difference correlated negatively with that of IGF‐1 (ρ = ?0·57, P < 0·01), and positively with that of IGFBP‐3 (ρ = 0·63, P < 0·01). At multivariate analysis, a high transfemoral gradient of CRP was independently associated with a low transfemoral gradient of IGF‐1 (β coefficient = ?0·48, P < 0·01), and a high transfemoral gradient of IGFBP‐3 (β coefficient = 0·22, P < 0·05). Conclusions This study is the first to demonstrate that the systemic levels of IGF axis components are associated with the presence and severity of PAD, and that the inflammatory status of the ischaemic limb affects the transfemoral concentrations of IGF‐1 and IGFBP‐3. Due to the importance of IGF axis in modulating atherosclerotic plaque progression, our data may contribute to a better understanding of PAD pathophysiology.     

The IGF system and cytokine interactions and relationships with longitudinal growth in prepubertal patients with cystic fibrosis

Objective Growth delay is a feature of patients with cystic fibrosis (CF). CF is a condition characterized by chronic inflammation that has been shown to modify the IGF system, which is essential for normal growth, and is related to pulmonary function in CF patients. We aimed to verify whether circulating levels of tumour necrosis factor (TNF)‐α, interleukin (IL)‐6, insulin and the IGF system were related and/or had relationships with linear growth in children with CF. Design and patients Seventeen prepubertal CF patients (nine males and eight females) in a stable clinical condition were enrolled. Auxological parameters, pulmonary function and the Shwachman–Kulczycki (S‐K) score were assessed, and serum samples were drawn at baseline and after 12 months. Measurements TNF‐α, IL‐6, IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐2, IGFBP‐3 and insulin were assayed using specific commercial kits. Results At baseline, TNF‐α serum concentration was related to serum IGF‐I concentration (R = 0·53), IGF‐II bioactivity (IGF‐II/IGFBP‐3 molar ratio, R = +0·52) and insulin concentration (R = +0·63). Changes in serum IL‐6 and IGFBP‐2 concentrations during the 12‐month observation were positively correlated (R = +0·63). Changes in height standard deviation score (Ht SDS) were correlated with IGF‐I serum concentrations at baseline (R =+0·67) and after 12 months (R = +0·70), with IGF‐I bioavailability and with IGFBP‐1 serum concentrations (R = –0·88). Body mass index (BMI) SDS correlated with IGF bioavailability. Conclusions This study showed a relationship between inflammatory status and the IGF system, and an effect of these interactions on longitudinal growth. Moreover, a role for insulin in growth was identified. Better control of inflammation and preservation of insulin secretion could benefit these patients.     

Dexamethasone administration inhibits skeletal muscle expression of the androgen receptor and IGF‐1 – implications for steroid‐induced myopathy

Context Glucocorticoids are a well‐recognized cause of muscle weakness. The early effects of glucocorticoids on skeletal muscle (SkM) androgen and IGF‐1 pathways have not been previously investigated in human subjects. Objective To determine if administration of the potent glucocorticoid dexamethasone down‐regulates SkM androgen receptor and the IGF‐1 signalling pathway. Methods and subjects Twenty‐four subjects (12 men and 12 women), including 12 with type 2 diabetes and 12 nondiabetics were enrolled. Venous blood sampling and biopsy of vastus lateralis were performed before and after administration of oral dexamethasone 4 mg/day for 4 days. Main outcome measures Changes in plasma testosterone and IGF‐1, SkM androgen receptor mRNA, SkM IGF‐1mRNA and SkM IGF‐1 receptor mRNA by quantitative RT‐PCR after dexamethasone. Results Relative expression of SkM androgen receptor was similar in male (1·63 ± 0·37) vs. female (1·57 ± 0·30) subjects, despite the significant difference in plasma testosterone levels. Plasma IGF‐1 and SkM expression of IGF‐1 and IGF‐1 receptor were also similar between males and females. Following dexamethasone, there was a significant down‐regulation of SkM androgen receptor (1·60 ± 0·23 vs. 1·11 ± 0·16, P < 0·05) and IGF‐1 (1·72 ± 0·29 vs. 1·06 ± 0·14, P < 0·05) mRNA, but no change in expression of the IGF‐1 receptor. Plasma testosterone fell significantly in both sexes (male: 15·0 ± 1·3 vs. 11·3 ± 1·2 nmol/l, P < 0·01, female: 1·8 ± 0·5 vs. 0·5 ± 0·1 nmol/l, P < 0·05). Conclusions Exogenous steroid excess results in relative androgen deficiency at two levels, reduced circulating testosterone and SkM androgen receptor mRNA, along with reduced SkM IGF‐1 mRNA. These defects may contribute to the development of steroid‐induced myopathy.     

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

Objective 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. Results The frequency of the individual IGF‐I (CA)_n repeats ranging from 10 to 24, with the most frequent allele containing CA₁₉, was similar in controls and in IGHD subjects. However, in controls, the pooled CA₁₉ and CA₂₀ as well as ?202 A IGFBP‐3 alleles were significantly (P < 0·01 and P < 0·001) more common in the taller [≥2 to 0 standard deviation score (SDS)] when compared with the shorter subgroup (<0 to ≤?2 SDS). Overall, the effect of recombinant human growth hormone (rhGH) replacement did not reveal any difference between the various genotypes in terms of final height. Independent of their genotype, all subjects showed a slightly lower adult height SDS compared with midparental height SDS. Conclusion Our results indicate that in patients with severe IGHD, although the various IGF‐I and IGFBP‐3 genotypes may play a role in GH responsiveness, there was no effect on final height.     

A randomized phase I/II trial of HQK‐1001, an oral fetal globin gene inducer,in β‐thalassaemia intermedia and HbE/β‐thalassaemia

β‐thalassaemia intermedia (BTI) syndromes cause haemolytic anaemia, ineffective erythropoiesis, and widespread complications. Higher fetal globin expression within genotypes reduces globin imbalance and ameliorates anaemia. Sodium 2,2 dimethylbutyrate (HQK‐1001), an orally bioavailable short‐chain fatty acid derivative, induces γ‐globin expression experimentally and is well‐tolerated in normal subjects. Accordingly, a randomized, blinded, placebo‐controlled, Phase I/II trial was performed in 21 adult BTI patients (14 with HbE/β⁰ thalassaemia and seven with β⁺/β⁰ thalassaemia intermedia, to determine effective doses for fetal globin induction, safety, and tolerability. HQK‐1001 or placebo were administered once daily for 8 weeks at four dose levels (10, 20, 30, or 40 mg/kg per day), and subjects were monitored for laboratory and clinical events. Pharmacokinetic profiles demonstrated a t_1/2 of 10–12 h. Adverse events with HQK‐1001 treatment were not significantly different from placebo treatment. The 20 mg/kg treatment doses increased median HbF above baseline levels by 6·6% and 4·4 g/l (P < 0·01) in 8/9 subjects; total haemoglobin (Hb) increased by a mean of 11 g/l in 4/9 subjects. These findings identified a safe oral therapeutic which induces fetal globin in BTI. Further investigation of HQK‐1001 with longer dosing to definitively evaluate its haematological potential appears warranted.     

Pharmacokinetic and pharmacodynamic properties of taspoglutide,a once‐weekly,human GLP‐1 analogue,after single‐dose administration in patients with Type 2 diabetes

Aims The study objectives were to evaluate the pharmacokinetic and pharmacodynamic properties, as well as safety and tolerability, of single doses of taspoglutide, a human glucagon‐like peptide‐1 (GLP‐1) analogue. Methods In a double‐blind, placebo‐controlled study, 48 patients with Type 2 diabetes [mean age 56 ± 7 years; mean body mass index (BMI) 30.4 ± 3.0 kg/m²] inadequately controlled with metformin (≤ 2 g/day) were enrolled in three sequential cohorts; 12 patients in each cohort were randomized to a single subcutaneous injection of taspoglutide (1, 8 or 30 mg) and four received placebo. Results Plasma concentrations peaked within 24 h after injection and were sustained for ≥ 14 days with all doses. In comparison with placebo, the 8‐ and 30‐mg doses of taspoglutide significantly reduced glycaemic parameters, including 24‐h blood glucose and 5‐h postprandial glucose areas under the curve (AUCs), for up to 14 days with the 30‐mg dose (P < 0.001). The most common adverse events, primarily gastrointestinal in nature, were dose‐dependent and transient. Conclusions A single dose of taspoglutide significantly improved glycaemic parameters in Type 2 diabetes patients for up to 14 days. The formulation was well tolerated and appears suitable for weekly administration.     

Circulating levels of insulin‐like growth factors and their binding proteins in patients with chronic liver disease: lack of correlation with bone mineral density

Abstract: Background/Aims: Insulin‐like growth factor‐I (IGF‐I) levels are low in patients with chronic liver disease (CLD) and have been found to correlate with measurements of bone mineral density (BMD) in men with viral cirrhosis. The aim of this study was to investigate the relationship between circulating IGF‐I levels and BMD in patients with CLD of other causes. Methods: Fifty‐eight patients with CLD were included. Age‐ and sex‐matched normal individuals served as controls. Serum levels of IGF‐I and IGF‐II and their binding proteins (IGFBP‐1–3) were measured by radioimmunoassay. BMD was measured by dual energy X‐ray absorptiometry. Results: IGF‐I levels were 57±33 and 136±48 ng/ml; p<0.0001 in patients and controls, respectively. IGF‐II and IGFBP‐3 levels were lower (p<0.0001) and IGFBP‐1 and IGFBP‐2 levels were higher in patients compared with controls (p<0.0005 and p<0.0001, respectively). All growth factors, except for IGFBP‐2, correlated with parameters of liver function. In a multiple regression analysis, adjusting for age, no correlation was found between IGF‐I, IGF‐II, IGFBP‐1–3 and BMD in either patients or controls. Conclusion: Patients with CLD have low levels of IGF‐I, IGF‐II and IGFBP‐3 that correlate with liver function. No relationship was found between low levels of growth factors and BMD.     

Could associations between breastfeeding and insulin‐like growth factors underlie associations of breastfeeding with adult chronic disease? The Avon Longitudinal Study of Parents and Children

Objective The influence of infant feeding method (breast/formula) on growth factor levels could underlie associations of breastfeeding with childhood growth and risk factors for cardiovascular disease. We investigated associations of having been breastfed with serum IGF‐I and IGFBP‐3 in childhood. Methods Prospective birth cohort study (subsample of the Avon Longitudinal Study of Parents and Children, UK) based on 871 children born in 1991/1992 who underwent clinical follow‐up and blood tests at age 7–8 years. A total of 488 (56%) children had complete data. Results In children with complete data, the age‐ and sex‐standardized IGF‐I levels of those who were partially or exclusively breastfed were 6·1 and 13·8 ng/ml higher, respectively, than those who were never breastfed (increase in IGF‐I levels per category of breastfeeding exclusivity: 7·1 ng/ml; 95% CI: 0·3–13·9; P = 0·04). In models also controlling for birthweight, gestational age, mother's age, and socioeconomic and dietary factors, the breastfeeding–IGF‐I association was attenuated (regression coefficient: 3·3 ng/ml; ?4·2–10·7; P = 0·4); further adjustment for IGFBP‐3 made little difference (regression coefficient: 4·1 ng/ml; ?2·8–10·9; P = 0·2). There was little evidence for an association between breastfeeding and IGFBP‐3 or the molar ratio IGF‐I/IGFBP‐3. Conclusions The positive association between breastfeeding and IGF‐I could be due to residual confounding or to chance. Nevertheless, the magnitude of the fully adjusted effect estimate and the novelty of the association suggest that larger studies should now be conducted to confirm or refute the hypothesis that variations in IGF‐I by infant feeding mode explain associations of breastfeeding with health in later life.     

Phase 2 study of tabalumab,a human anti‐B‐cell activating factor antibody,with bortezomib and dexamethasone in patients with previously treated multiple myeloma

In this double‐blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N  = 72), tabalumab 100 mg (N  = 74), or tabalumab 300 mg (N  = 74), each in combination with dexamethasone 20 mg and subcutaneous bortezomib 1·3 mg/m² on a 21‐day cycle. No significant intergroup differences were observed among primary (median progression‐free survival [mPFS ]) or secondary efficacy outcomes. The mPFS was 6·6, 7·5 and 7·6 months for the tabalumab 100, 300 mg and placebo groups, respectively (tabalumab 100 mg vs. placebo Hazard ratio (HR ) [95% confidence interval (CI )] = 1·13 [0·80–1·59], P  =  0·480; tabalumab 300 mg vs. placebo HR [95% CI ] = 1·03 [0·72–1·45], P  =  0·884). The most commonly‐reported treatment‐emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baseline BAFF (also termed TNFSF 13B) expression (n  = 162) had significantly longer mPFS than those with high BAFF expression (n  = 55), using the 75th percentile cut‐off point (mPFS [95% CI ] = 8·3 [7·0–9·3] months vs. 5·8 [3·7–6·6] months; HR [95% CI ] = 1·59 [1·11–2·29], P  =  0·015). Although generally well tolerated, PFS was not improved during treatment with tabalumab compared to placebo. A higher dose of 300 mg tabalumab did not improve efficacy compared to the 100 mg dose. Nonetheless, BAFF appears to have some prognostic value in patients with multiple myeloma.     

Inverse changes in fetal insulin-like growth factor (IGF)-1 and IGF binding protein-1 in association with higher birth weight in maternal diabetes

Objective The insulin like growth factor (IGF) system plays a key role in regulating fetal growth, is metabolically regulated, and may influence development of increased birth weight in offspring of mothers with diabetes. We examined IGF‐1 and IGF binding protein‐1 (IGFBP‐1) concentrations in cord blood samples from offspring of mothers with gestational and type 2 diabetes. Design and patients Case‐control study of Maori and Pacific Island mothers recruited prospectively at Middlemore Hospital, South Auckland, New Zealand. Measurements Cord blood (for insulin, IGF‐1 and IGFBP‐1) was taken from umbilical vein at birth from singleton babies born after 32 weeks of gestation from138 mothers with gestational diabetes (GDM), 39 mothers with type 2 diabetes (T2DM) and 95 control mothers. Results Babies born to mothers with both GDM and T2DM had significantly increased birth weight (Z‐score birth weight mean ± SD: GDM 0·94 ± 1·31, T2DM 0·53 ± 1·1) compared to controls (Z‐score birth weight −0·08 ± 1·10). IGFBP‐1 was significantly reduced in both diabetic groups (median interquartile range: GDM 67(31–137) ng/ml, T2DM 59(29–105) ng/ml, control 114(56–249) ng/ml). Cord IGF‐1 was significantly increased in cord blood of infants of mothers with GDM (42·2 ± 16·3 ng/ml vs. control 34·7 ± 18·5 ng/ml) but not T2DM (38·7 ± 17·4 ng/ml). In all offspring, IGF‐1 and IGFBP‐1 were positively and negatively correlated with birth weight, respectively. Conclusions Maternal diabetes results in inverse changes of circulating fetal IGF‐1 and IGFBP‐1 at birth. A decrease in circulating IGFBP‐1 and to a lesser extent an increase in circulating IGF‐1 may present an important mechanism that contributes to increased birth weight in diabetic pregnancies.     

Dose‐dependent acute effects of recombinant human TSH (rhTSH) on thyroid size and function: comparison of 0·1, 0·3 and 0·9 mg of rhTSH

Context Recombinant human TSH (rhTSH) is used to augment the effect of radioiodine therapy for nontoxic multinodular goitre. Reports of acute thyroid swelling and hyperthyroidism warrant safety studies evaluating whether these side‐effects are dose dependent. Objective To determine the effects on thyroid size and function of various doses of rhTSH. Design In nine healthy male volunteers, the effect of placebo, 0·1, 0·3 and 0·9 mg of rhTSH was examined in a paired design including four consecutive study rounds. Main outcome measures Main outcome measures were evaluated at baseline, 24 h, 48 h, 96 h, 7 days and 28 days after rhTSH and included: Thyroid volume (TV) estimation by planimetric ultrasound, and thyroid function by serum TSH, free T3, free T4 and Tg levels. Results Following placebo or 0·1 mg rhTSH, the TV did not change significantly from baseline at any time. At 24 and 48 h after administration of 0·3 mg rhTSH, the TV increased by 37·4 ± 12·3% (SEM) (P = 0·03) and 45·3 ± 16·1% (P = 0·05) respectively. After 0·9 mg rhTSH, the TV increased by 23·3 ± 5·8% (P = 0·008) and 35·5 ± 18·4% (P = 0·02) respectively. The increase in serum FT3, FT4 and thyroglobulin (Tg) was greater when administering 0·3 mg compared with 0·1 mg (P = 0·02) and when administering 0·9 mg compared with 0·3 mg (P = 0·02). After 0·1 mg rhTSH, the increase in FT3 and Tg was not significantly different from placebo whereas the FT4 increase was significantly higher (P = 0·02 compared with placebo). Conclusions In healthy individuals, rhTSH‐induced thyroid swelling and hyperthyroidism is rapid and dose dependent. If valid for patients with goitre, our results suggest that these adverse effects are unlikely to be of clinical significance, following doses of rhTSH of 0·1 mg or less.     

Phase I,multicentre, dose‐escalation trial of monotherapy with milatuzumab (humanized anti‐CD74 monoclonal antibody) in relapsed or refractory multiple myeloma

CD74, expressed in multiple myeloma (MM), was evaluated as a target for immunotherapy with milatuzumab (a humanized anti‐CD74 antibody). In a multicentre dose escalation study, 25 patients with advanced MM received milatuzumab doses of 1·5 (N = 8), 4·0 (N = 9), 8·0 (N = 4) or 16·0 mg/kg (N = 4) administered twice weekly x 4. They had a median of 5 prior treatments (17 post ≥1 stem cell transplantation) and were refractory (N = 7) or relapsed (N = 18) with generally short‐lived responses to last treatment (median 4·0 months). After increasing prophylactic medications and slowing administration, infusions were well tolerated (National Cancer Institute‐Common Terminology Criteria v3 toxicity Grades 1–2) with no dose‐limiting toxicity at higher doses. Only one patient developed borderline positive human anti‐milatuzumab antibody titres of uncertain clinical significance. Although milatuzumab was rapidly cleared from circulation with little serum accumulation and low trough levels, B‐cell levels were moderately decreased with treatment (median decrease, 34%). There were no objective responses by European Group for Blood and Marrow Transplantation criteria, but 5 of 19 patients (26%) who completed treatment in this heavily pretreated and generally refractory group had stable disease for ≥3 months post‐treatment (one continuing for 17 months). Disease stabilization and evidence of pharmacodynamic activity support further development for use in combination with other agents or as a drug conjugate. ( Clinicaltrials.gov identifier: NCT00421525)     

Sotatercept in patients with osteolytic lesions of multiple myeloma

This phase IIa study evaluated the safety and tolerability of sotatercept, and its effects on bone metabolism and haematopoiesis in newly diagnosed and relapsed multiple myeloma (MM) patients. Patients were randomized (4:1) to receive four 28‐d cycles of sotatercept (0·1, 0·3, or 0·5 mg/kg) or placebo. Patients also received six cycles of combination oral melphalan, prednisolone, and thalidomide (MPT). Thirty patients were enrolled; six received placebo and 24 received sotatercept. Overall, 25% of patients received all four sotatercept doses; 71% of sotatercept‐treated patients had ≥1 dose interruption mainly due to increases in haemoglobin levels. Grade ≥3 adverse events (AEs) were reported in 17% of patients receiving placebo and 58% receiving sotatercept. Grade 4 AEs in sotatercept‐treated patients were neutropenia, granulocytopenia, and atrial fibrillation (one patient each). In patients without bisphosphonate use, anabolic improvements in bone mineral density and in bone formation relative to placebo occurred, whereas bone resorption was minimally affected. Increases in haemoglobin levels, versus baseline, and the duration of the increases, were higher in the sotatercept‐treated patients, with a trend suggesting a dose‐related effect. Multiple doses of sotatercept plus MPT appear to be safe and generally well‐tolerated in MM patients.     

Effect of growth hormone deficiency and recombinant hGH (rhGH) replacement on the hypothalamic-pituitary-adrenal axis in children with idiopathic isolated GH deficiency

Objective Recombinant hGH (rhGH) therapy may unmask central hypoadrenalism in adults with organic GH deficiency (GHD), likely by normalizing 11β‐hydroxysteroid dehydrogenase type 1 isoenzyme (11βHSD1) activity and reducing cortisone to cortisol conversion. The aim of the present study was to evaluate the hypothalamic–pituitary–adrenal (HPA) axis in children with idiopathic isolated GHD and normal pituitary magnetic resonance imaging (MRI) both before and during rhGH therapy. Design and patients This was a single‐centre study of 10 consecutive children [five males and five females, mean age: 12·2 ± 1·0 year]. Evaluation was performed at baseline and on rhGH (mean duration: 10·9 ± 2·9 months, mean dose: 0·030 ± 0·002 mg/kg bw/day). Measurements HPA function was assessed by serum cortisol levels before and after appropriate provocative stimuli, that is, 1 µg ACTH test (N = 5 patients) or insulin tolerance test (ITT, N = 5 patients), evaluating all children with the same stimulation test both before and during rhGH therapy. Central hypoadrenalism was excluded by the presence of either a peak of > 500 nmol/l or a rise in cortisol levels of > 200 nmol/l, after both tests. Results On rhGH therapy, serum IGF‐I levels normalized, while serum cortisol and ACTH levels did not significantly differ from those recorded at baseline. The mean serum cortisol peak after both provocative tests was not significantly different on rhGH therapy and at baseline (498 ± 41 vs. 580 ± 35 nmol/l, respectively, P = 0·06), the mean cortisol rise being 280 ± 45 and 270 ± 36 nmol/l on rhGH and at baseline, respectively. Conclusions According to the diagnostic criteria, no child became hypoadrenal on rhGH, contrary to what observed in patients with organic GHD, further supporting the view that only in patients with organic multiple pituitary hormone deficiency GHD masks the presence of a hidden central hypoadrenalism.     

Preterm birth and the endocrine regulation of growth in childhood and adolescence

Objective Poor growth during childhood is a common problem associated with preterm birth, but few studies have examined the associations between linear growth, weight and body composition with the postnatal hormonal milieu in preterm children. We aimed to define the IGF‐IGFBP axis in preterm children and its association with growth. Design and patients A cohort of healthy 2‐ to 20‐year‐old subjects who were born prematurely (<37 weeks gestation) and experienced normal neurological development were recruited. In total, 54 premature and 82 control subjects were included in this study. Results Preterm subjects were relatively shorter (P < 0·001) and leaner (P < 0·05) than their parents in contrast to the term cohort. Preterm children also appeared to fail to reach their genetic height potential (prepuberty: P < 0·01; puberty: P < 0·05). Only IGFBP‐2 differed between preterm and term cohorts, with higher levels observed in prepubertal preterm subjects (P < 0·01). In the term group, height SDS was positively associated with IGF‐I (P < 0·01) and IGFBP‐3 (P < 0·001) concentrations, but no such associations were observed for preterm subjects. Conclusion Preterm children are shorter and lighter than controls throughout childhood, remaining below their genetic height potential. Preterm birth appears to alter the endocrine regulation of postnatal growth in childhood and adolescence, so growth is no longer associated with its normal endocrine regulators.     

Insulin resistance and body composition in preterm born children during prepubertal ages

Background Premature born children may show insulin resistance in childhood which may be due to intrauterine or postnatal adverse environmental factors. Objective Aim of this study was to evaluate insulin resistance and body composition in preterm born children born appropriate for gestational age (AGA) or small for gestational age (SGA) and relations with IGF‐I, IGFBP‐3 axis. Methods Ninety‐three preterm born children grouped as premature SGA (n = 30) and premature AGA (n = 63) were evaluated at age 4·6 ± 0·2 years and 4·7 ± 0·1 years with respect to their glucose, insulin, IGF‐I, IGFBP‐3, IGFBP‐1, leptin levels and body composition by dual‐energy X‐ray absorptiometry. Their data were compared to that of body mass index (BMI) matched term SGA (n = 42) and term AGA (n = 44) children of age 4·5 ± 0·2 and 3·8 ± 0·1 years. All children had height appropriate for their target height. Insulin resistance was evaluated by basal insulin and homeostasis model assessment for insulin resistance (HOMA‐IR). Results Basal insulin level was similar in preterm AGA (4·3 ± 1·4 pmol/l) and term AGA (7·9 ± 6·4 pmol/l) children at similar and normal BMI levels. Preterm SGA children had insulin levels (5·0 ± 3·6 pmol/l) similar to preterm AGA children but significantly lower than that in term SGA children (23·7 ± 20·8 pmol/l) (P = 0·001). Similar results were obtained for HOMA‐IR. Term SGA children had also significantly lower IGFBP‐1 levels. Body composition, leptin and IGFBP‐3 did not differ between the respective groups. IGF‐I was lower in preterm AGA (5·0 ± 0·6 nmol/l) than in term AGA (8·3 ± 1·2 nmol/l) (P < 0·001) children. Conclusions Premature born AGA and SGA children do not have insulin resistance when compared to term children if they have made a catch‐up growth appropriate for their target height and have normal BMI. The similar insulin levels in preterm SGA and preterm AGA children together with increased insulin levels in term SGA children points to the fact that it is the intrauterine restriction in the third trimester that has an adverse effect on future adverse metabolic outcome.