Marc Maes

Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: preliminary report of 3 countries participating in the EU SAGhE study

CONTEXT The long-term mortality in adults treated with recombinant GH during childhood has been poorly investigated. Recently released data from the French part of the European Union Safety and Appropriateness of GH treatments in Europe (EU SAGhE) study have raised concerns on the long-term safety of GH treatment. OBJECTIVE To report preliminary data on long-term vital status and causes of death in patients with isolated GH deficiency or idiopathic short stature or born small for gestational age treated with GH during childhood, in Belgium, The Netherlands, and Sweden. DESIGN Data were retrieved from national registries of GH-treated patients and vital status from National Population Registries. Causes of death were retrieved from a National Cause of Death Register (Sweden), Federal and Regional Death Registries (Belgium), or individual patient records (The Netherlands). PATIENTS All patients diagnosed with isolated GH deficiency or idiopathic short stature or born small for gestational age started on recombinant GH during childhood from 1985-1997 and who had attained 18 yr of age by the end of 2010 were included. Vital status was available for approximately 98% of these 2,543 patients, corresponding to 46,556 person-years of observation. MAIN OUTCOME MEASURE Vital status, causes of death, age at death, year of death, duration of GH treatment, and mean GH dose during treatment were assessed. RESULTS Among 21 deaths identified, 12 were due to accidents, four were suicides, and one patient each died from pneumonia, endocrine dysfunction, primary cardiomyopathy, deficiency of humoral immunity, and coagulation defect. CONCLUSIONS In these cohorts, the majority of deaths (76%) were caused by accidents or suicides. Importantly, none of the patients died from cancer or from a cardiovascular disease.

Nutritional Regulation of the Growth Hormone and Insulin-Like Growth Factor-Binding Proteins

Both growth hormone (GH) and insulin-like growth factors (IGFs) associate with specific binding proteins. Besides control by hormones, these binding proteins are nutritionally regulated. The GH-binding protein (GHBP) is the extracellular portion of the GH receptor. Its concentrations in circulation are decreased in severe malnutrition, reflecting a decrease in tissue GH receptor abundance. IGFs are bound to 6 different binding proteins (IGFBPs). IGFBP-3 is relatively stable and is only depressed after prolonged periods of severe malnutrition. In contrast, IGFBP-1 is regulated acutely by nutrient intake, showing major elevations after overnight fasting and rapid postprandial decreases. IGFBP-2 is highly dependent on dietary protein intake. Nutritional factors may regulate the tissue availability and the biological actions of IGFs by their actions on IGFBPs.

Low plasma somatomedin-C in streptozotocin-induced diabetes mellitus. Correlation with changes in somatogenic and lactogenic liver binding sites.

To determine the mechanism for the decrease of somatomedin levels in insulin-dependent diabetes, the relationships among plasma immunoreactive somatomedin-C (Sm-C), plasma growth hormone (GH) and prolactin (PRL), and the somatogenic and lactogenic binding sites in liver were assessed in rats with nonketotic diabetes mellitus of different duration (1 wk or 1 mo) and severity (50 or 60 mg streptozotocin/kg BW). One week after administration of 60 mg streptozotocin (STZ)/kg, plasma Sm-C concentrations were significantly decreased (0.23 ± 0.03 versus 0.43 ± 0.03 U/ml in controls; mean ± SEM, P < 0.01). In contrast, plasma GH concentrations, bovine GH (bGH) binding, and human GH (hGH) binding were not significantly changed. After 1 mo of diabetes, no further decrease in plasma Sm-C content was observed despite a reduction in plasma GH and PRL concentrations and reduced hepatic bGH binding capacity (5 ± 2 versus 38 ± 4 fmol/mg protein; P < 0.01). In the group of rats injected with 50 mg STZ/kg, the Sm-C was reduced at 1 mo but hepatic GH binding was not. In a second study, diabetic rats (75 mg STZ/kg) were treated after 3 wk with insulin (10 U lente per day for 7 days). This treatment normalized Sm-C levels and partially restored the GH binding capacity (treated: 49 ± 4 fmol/mg protein versus untreated diabetics: 28 ± 6 fmol/mg protein; P < 0.01 and versus controls: 68 ± 4 fmol/mg protein; P < 0.05). In contrast, prolactin binding capacity remained low (treated: 23 ± 3 fmol/mg protein versus untreated diabetics: 13 ± 2 fmol/mg protein; P > 0.05) and mean plasma GH and PRL were unchanged. The findings suggest that in an early phase of nonketotic diabetes, the low plasma Sm-C is not due primarily to reduced GH receptor number. Rather, it may reflect diminished Sm-C synthesis at a site distal to the binding of growth hormone to its tissue receptor.

Reduction of serum insulin-like growth factor-I by dietary protein restriction is age dependent.

ABSTRACT: We have determined if dietary protein restriction for 1 wk has differential effects on growth, serum IGF-I, and liver growth hormone receptors at various stages of development. Female Wistar rats were fed a low (5%) protein diet for 7 d at 3, 4, 6, 8, and 12 wk of age, whereas controls were maintained on a normal (15%) protein diet. Body wt gain was impaired in the groups fed the low protein diet, despite normal energy intake, and the effect was attenuated with age. Liver cell number (DNA content) was reduced by low protein feeding in the 3-, 4-, and 6-wk age groups (p < 0.01), but not in the older animals. Protein restriction caused a dramatic decrease in serum IGF-I in the younger animals (90 and 82% reduction versus normal fed age-matched controls, at 3 and 4 wk, respectively; p < 0.001), and this effect was progressively attenuated with increasing age (49,40, and 25% reductions of serum IGF-I at 6, 8, and 12 wk, respectively). Changes in serum IGF-I correlated with those of liver cell number (r = 0.80; p < 0.001). Total and free liver growth hormone receptors were slightly decreased in the low protein diet groups at 4 (p < 0.05) and 6 wk (total: p < 0.001; free: p < 0.01) but not in the other age groups. The occurrence of profound diet induced reductions in IGF-I without proportional reductions in liver GH receptors suggest that the apparent GH resistance occurs at a postreceptor level. Because the degree of IGF-I reduction correlates with the severity of retardation of liver growth during dietary protein restriction at different ages, we conclude that the effect of protein restriction on liver growth could be mediated through IGF-I.

Low serum somatomedin-C in protein deficiency: relationship with changes in liver somatogenic and lactogenic binding sites.

We have investigated whether the low serum levels of somatomedin-C (SM-C) observed in protein malnutrition could be related to changes in liver growth hormone and prolactin binding. Growing female rats were fasted for 3 days and subsequently refed for 14 days with isocaloric diets containing 5% (low) or 25% (normal) protein. Control rats were fed a normal protein diet during the entire study. The numbers and affinity constants of somatogenic (GH) and lactogenic (PRL) binding sites were determined by analysis of saturation curves using liver homogenates incubated with 125I-labelled bovine growth hormone and 125I-labelled ovine prolactin. Serum SM-C and growth hormone concentrations were measured by radioimmunoassay. After fasting for 3 days body weight dropped by 21% (P less than 0.01 vs. controls) and serum SM-C by 53% (P less than 0.01), while GH and PRL binding capacities decreased respectively by 63% (P less than 0.01) and 62% (P less than 0.01). On refeeding with a normal protein diet, body weight, serum SM-C, GH and PRL binding capacities returned to control values. In contrast, with low protein intake, body weight, SM-C, GH and PRL binding capacities remained respectively 16%, 55%, 49% and 81% lower than controls (P less than 0.01). No significant changes in serum growth hormone concentrations occurred with fasting or refeeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and biological phenotype of a patient with familial glucocorticoid deficiency type 2 caused by a mutation of melanocortin 2 receptor accessory protein

Familial glucocorticoid deficiency (FGD) is a rare inherited disorder which may be caused by mutations in the ACTH receptor (melanocortin 2 receptor, MC2R) named FGD type 1 or by mutations in the MC2R accessory protein (MRAP) named FGD type 2. We report the case history of a male patient from birth until adulthood with FGD type 2, confirmed by a mutation of the MRAP gene.

Contributions of growth hormone receptor and postreceptor defects to growth hormone resistance in malnutrition.

Malnutrition results in poor growth and is associated with resistance to growth hormone (GH) action. The mechanisms involved in the GH resistance depend on the severity and the timing of the nutritional insult. Stringent dietary restrictions such as fasting may produce GH resistance by reducing the number of GH receptors. Less severe nutritional deprivation such a short-term protein restriction may cause GH insensitivity mainly through postreceptor mechanisms.

Description of the SAGhE Cohort: A Large European Study of Mortality and Cancer Incidence Risks after Childhood Treatment with Recombinant Growth Hormone

Background: The long-term safety of growth hormone treatment is uncertain. Raised risks of death and certain cancers have been reported inconsistently, based on limited data or short-term follow-up by pharmaceutical companies. Patients and Methods: The SAGhE (Safety and Appropriateness of Growth Hormone Treatments in Europe) study assembled cohorts of patients treated in childhood with recombinant human growth hormone (r-hGH) in 8 European countries since the first use of this treatment in 1984 and followed them for cause-specific mortality and cancer incidence. Expected rates were obtained from national and local general population data. The cohort consisted of 24,232 patients, most commonly treated for isolated growth failure (53%), Turner syndrome (13%) and growth hormone deficiency linked to neoplasia (12%). This paper describes in detail the study design, methods and data collection and discusses the strengths, biases and weaknesses consequent on this. Conclusion: The SAGhE cohort is the largest and longest follow-up cohort study of growth hormone-treated patients with follow-up and analysis independent of industry. It forms a major resource for investigating cancer and mortality risks in r-hGH patients. The interpretation of SAGhE results, however, will need to take account of the methods of cohort assembly and follow-up in each country.

Growth hormone treatment and fat redistribution in children born small for gestational age.

OBJECTIVE To determine whether in children born small for gestational age (SGA) high-dose growth hormone (GH) treatment is not only associated with catch-up of growth and with gain of lean mass, but also with a more central fat distribution. STUDY DESIGN Short children who were SGA (n = 25; age [mean +/- SD], 5.3 +/- 1.5 years) were randomly assigned to remain untreated (n = 14) or to receive GH (n = 11; sc 66 mug/Kg/d). Growth status and body composition were assessed at the studys start, after 1 year, and after 2 years with anthropometry and absorptiometry. RESULTS Children who were treated with GH gained more height and weight than children who were untreated and developed a less adipose body composition (all P < .0001), as expected. However, these changes were also accompanied by a relatively more centripetal distribution of fat mass (0-2 year change in ratio of trunk fat to limb fat; 0.26 +/- 0.23 versus 0.02 +/- 0.15; P < .0001). CONCLUSION In children who are SGA, catch-up growth induced by exogenous GH in high doses is accompanied by a less adipose body composition and a more central fat distribution.

A Novel Homozygous Mutation of the IGFALS Gene in a Female Adolescent: Indirect Evidence for a Contributing Role of the Circulating IGF-I Pool in the Pubertal Growth Spurt

Background: Mutations of the IGFALS gene have been reported since 2004 in 24 patients, but only 5 of these are females. Case Report: We describe a 14.7-year-old female of a consanguineous Moroccan family with growth retardation and normal-onset but slow progression of puberty without manifest pubertal height gain. Results: At age 3.2 years, the patients height was 85.5 cm (-2.9 SDS) and her weight 9.9 kg (-2.9 SDS) with a head circumference of 44.5 cm (-3.3 SDS). Serum IGF-I and IGFBP-3 concentrations were low with normal basal and stimulated growth hormone (GH) levels. An IGF-I generation test confirmed a lack of response to GH administration. While onset of puberty occurred at a normal age, no significant pubertal growth acceleration was observed despite progression of breast development. Sequencing of the IGFALS gene revealed a novel homozygous frameshift mutation (c.1291delT) with a stop codon (p.W431GfsX10) leading to undetectable serum levels of acid-labile subunit. Conclusion: We report the phenotype of an adolescent girl with primary IGF-I deficiency due to a novel homozygous mutation of the IGFALS gene, who presented with growth delay, normal pubertal onset with slow progression and no pubertal growth acceleration indirectly suggesting a contributing role of the circulating IGF-I pool in the pubertal growth spurt.