International Journal of Environmental Research and Public Health, 2015
We test the hypothesis that differences in social status between groups of people within a popula... more We test the hypothesis that differences in social status between groups of people within a population may induce variation in insulin-like growth factor-1(IGF-1) levels and, by extension, growth in height. This is called the community effect in height hypothesis. The relationship between IGF-1, assessed via finger-prick dried blood spot, and elite level sport competition outcomes were analysed for a sample of 116 undergraduate men and women. There was a statistically significant difference between winners and losers of a competition. Winners, as a group, had higher average pre-game and post-game IGF-1 levels than losers. We proposed this type of difference as a proxy for social dominance. We found no evidence that winners increased in IGF-1 levels over losers or that members of the same team were more similar in IGF-1 levels than they were to players from other teams. These findings provide limited support toward the community effect in height hypothesis. The findings are discussed in relation to the action of the growth hormone/IGF-1 axis as a transducer of multiple bio-social influences into a coherent signal which allows the growing human to adjust and adapt to local ecological conditions.
of the ASF depot was not reduced with GH treatment. The interaction for BMR increased (P = 0.81) ... more of the ASF depot was not reduced with GH treatment. The interaction for BMR increased (P = 0.81) after adjusting for the fatfree mass. Conclusion: GH treatment accelerates linear growth and lean tissue accrual, including bone mineral. GH treatment reduces adiposity especially AVF. GH did not directly increase energy expenditure but rather was a result of the increase in metabolically active fat-free mass.
Experimental and Clinical Endocrinology & Diabetes, 1993
A competitive enzyme immunoassay for the determination of human insulin-like growth factor I in m... more A competitive enzyme immunoassay for the determination of human insulin-like growth factor I in microtiter plates was established. Using a polyclonal antiserum raised in rabbits against hIGF-I ovalbumin conjugate the assay system was able to detect IGF-I at a range of 12-800 pg/well with a sensitivity of 10 pg/well. It showed a low (< 0.5%) cross reactivity with hIGF-II. The serum concentrations of IGF-I found by EIA agreed well with those found in a conventional RIA (r = 0.965, p < 0.001). Effects of age and sex on IGF-I levels were studied in 260 normal adults. There was no evidence for sex differences but a steep decline of values from the third to the fourth and from the eight to the ninth decade, respectively. To asses the diagnostic capability of the IGF-I determination in liver cirrhosis, 71 sera of patients classified according to Child classes (A-C) were measured. Although significantly diminished concentrations were found in class B vs A and in class C vs B, the diagnostic sensitivity in cross-sectional examinations proved to be low (class A: 0.33, class B: 0.67). Only in the case of extensively destroyed liver parenchyma (Child C: 0.94) IGF-I was a good indicator of impaired hepatocellular capacity. In 29 patients with acromegaly serum IGF-I levels were investigated. All patients with active acromegaly showed increased IGF-I levels. In contrast, in inactive or weakly active acromegaly values were considerably lower.(ABSTRACT TRUNCATED AT 250 WORDS)
Experimental and Clinical Endocrinology & Diabetes, 1995
The aim of this study was to investigate the regulation of various proteins of the GHIGF axis dur... more The aim of this study was to investigate the regulation of various proteins of the GHIGF axis during progression of liver failure and to search for potential prognostic markers of functional hepatic reserve. Serum levels of growth hormone (GH) and high affinity growth hormone binding protein (GHBP), insulin-like growth factor I (IGF-I) and IGF binding proteins (IGFBP) -1, -2 and -3 were determined in patients with liver cirrhosis. A continuous decline in the concentrations of IGF-I, IGFBP-3 and serum GH-binding activity (GHBP) was observed during progression of cirrhosis and the data correlated significantly with choline esterase, total serum protein and the Child score. In addition, GHBP showed a significant correlation with the enzymatic activity of glutamate dehydrogenase or transaminases and seems so to be influenced by the degree of liver cell damage. In contrast, IGFBP-1 and IGFBP-2 levels were significantly elevated in preterminal disease suggesting an upregulatory mechanism is still effective in this situation. Only when liver function had markedly deteriorated, the serum levels of these two parameters decreased again, possibly due to an impaired synthesis. The excellent correlation between the serum levels of IGF-I (r = -0.64, p < 0.001) or IGFBP-3 (r = -0.67, p < 0.001) and the Child score index suggests that they reflect the hepatic functions just as conventional indicators. For an appropriate interpretation of the liver function the measurement of the growth related peptides can be a valuable tool to estimate pathological alteration in the functional hepatic reserve or in the glucose homeostasis.
Experimental and Clinical Endocrinology & Diabetes, 1998
During diagnostic lumbar punctions cerbrospinal fluid (CSF) was collected for the determination o... more During diagnostic lumbar punctions cerbrospinal fluid (CSF) was collected for the determination of GH, IGF-I, IGFBP-3 and IGFBP-2. The patients were 0.3 to 68 years od and suffered from viral infections, leukemias, M. Hodgkin or multiple sclerosis. Only CSF samples without any pathological alterations were analysed. In infants and adults CSF GH concentrations significantly declined with age, while IGF-I and the two binding proteins were unrelated to age. GH was not correlated to IGF-I, IGFBP-3 or IGFBP-2. However, IGF-I was strongly related to IGFBP-3 (r = 0.529; < 0.001) and IGFBP-2 (r = 0.796; < 0.001) as was IGFBP-3 to IGFBP-2 (r = 0.685; < 0.001), suggesting dependence of the three variables. With IGFBP-3 or IGFBP-2 as control variables (partial correlation) IGF-I was no longer related to the binding proteins, while the relation of IGFBP-3 to IGFBP-2 remained unchanged with IGF-I as the control variable (r = 0.687; < 0.001). The results suggest that the age-related decrease of CSF GH may contribute to the age-dependent decline of GH receptors in brain, which are up-regulated by GH. Furthermore, in CSF IGF-I concentrations were determined by the two binding proteins. It may be speculated that the transfer of IGF-I through the blood CSF barrier or its production in brain may be closely related to the IGF-binding proteins.
The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013
To determine whether an individualized dose titration regimen (ID) for adult GH replacement thera... more To determine whether an individualized dose titration regimen (ID) for adult GH replacement therapy would have similar efficacy and better tolerability than a fixed body weight-based dosing regimen (FD), 387 adults with GH deficiency were randomized to FD (n = 200) or ID (n = 187) for 32 wk. In FD, subjects received sequentially 4, 8, and 12 microg/kg.d GH. ID was started at 0.2 mg/d and increased by 0.2-mg/d increments, based on clinical and serum IGF-I responses, to a maximum of 0.8 mg/d. Increases (mean +/- sd) in serum IGF-I were similar in both groups (FD, 110.2 +/- 87.8 vs. ID, 99.6 +/- 77.7 microg/liter, P = 0.20) despite higher final GH doses in FD (0.70 +/- 0.32 vs. 0.54 +/- 0.22 mg/d, P < 0.001). Favorable changes in several efficacy measures were observed with no significant differences between the FD and ID groups: lean body mass increased; health-related quality of life improved; and abdominal fat mass, hip circumference, sum of skinfolds, and total and low-density lipoprotein cholesterol decreased. The decrease in fat mass was greater with FD than ID for men (-2.7 +/- 2.7 kg vs. -1.8 +/- 2.5 kg, P = 0.04) but not for women (-2.1 +/- 2.4 vs. -2.0 +/- 3.8 kg). The change in waist circumference was greater with FD than ID for women but not for men. There was a significant reduction of systolic blood pressure in ID but not in FD. The adverse event profile was similar between FD and ID except that ID had a lower occurrence of peripheral edema (9.1% vs. 16.5%, P = 0.03) and rash (1.1% vs. 5.5%, P = 0.02) than FD. In summary, the use of ID resulted in improved tolerability and similar efficacy compared with FD. We conclude that GH replacement therapy should be initiated at a low dose and titrated to a dose producing maximal benefits without adverse side effects and an IGF-I level within the age- and sex-adjusted normal range.
Objective: Leptin, the product of the ob gene, is overexpressed in human obesity and increased se... more Objective: Leptin, the product of the ob gene, is overexpressed in human obesity and increased serum leptin levels are closely correlated with adipose tissue mass, but the regulation of leptin production is not completely understood. The aim of this study was to characterize the role of tumor necrosis factor (TNF)-a and transforming growth factor (TGF)-b1 in depot-specific secretion of leptin
The regulation of leptin production in humans is poorly understood but appears to depend on total... more The regulation of leptin production in humans is poorly understood but appears to depend on total body fat, changes in energy intake and insulin levels. Since growth hormone (GH) is an important regulator of both lipid metabolism and insulin secretion and action, we tested whether GH status directly or indirectly regulates leptin secretion.
Der Nervenarzt 1·99 | 33 Abb.1 ᭡ Die Aufnahme-BMI von 272 Patientinnen mit Anorexia nervosa wurde... more Der Nervenarzt 1·99 | 33 Abb.1 ᭡ Die Aufnahme-BMI von 272 Patientinnen mit Anorexia nervosa wurden zu ganzen Zahlen jeweils abgerundet und zum Katamnese-BMI in Bezug gesetzt. Die Katamnese erfolgte im Schnitt 9,6 Jahre nach der Aufnahme.Verstorbene Patientinnen sind durch einen schwarzen Kreis dargestellt. Die Box-Plots umfassen jeweils die Patientinnen, die das zweite und dritte Quartil bilden. Die waagrechten Linien in den Box-Plots kennzeichnen den Median
The Journal of Clinical Endocrinology and Metabolism, Apr 19, 2012
Context:The prevalence of SHOX deficiency in children with short stature (SS) is variable in the ... more Context:The prevalence of SHOX deficiency in children with short stature (SS) is variable in the literature and various genotypes have been identified.Objectives:The aim of our study was to determine the frequency and distribution of SHOX genotypes in a large sample of children with SS in France.Design, Setting, and Patients:Children were enrolled in 38 French pediatric endocrinology centers and were either diagnosed with Leri-Weill syndrome (LWS), idiopathic short stature (ISS), or disproportionate short stature (DSS).Intervention and Main Outcome Measure:SHOX analysis was performed centrally as part of the Genetics and Neuroendocrinology of Short Stature International Study observational study. We compared patients with (SHOX-D) and without SHOX deficiency (non-SHOX-D).Results:Among the 537 patients tested [58.3% females, mean age 11.0 (4.2) yr], 27.7% had SHOX deficiency (LWS, 48.9%; ISS, 16.9%; DSS, 18.8%). Mean height [-2.3 (0.9) sd score] was similar in SHOX-D and non-SHOX-D patients. The majority of SHOX-D patients with LWS had either a deletion encompassing SHOX or a point mutation (69%), whereas 59% of those with ISS had a deletion downstream of SHOX in the enhancer region. The height of the parents carrying a deletion downstream of SHOX was higher than the height of the parents carrying the other gene anomalies.Conclusions:SHOX deletions and point mutations as well as downstream SHOX enhancer deletions were identified in almost one third of the patients tested. An anomaly in this latter region seemed to be linked to a milder phenotype. Although further confirmation is needed, we suggest that the enhancer region should be systematically analyzed in patients suspected of SHOX deficiency.
Background: GH therapy in adult patients with GH deficiency (GHD) was approved over 10 yr ago, an... more Background: GH therapy in adult patients with GH deficiency (GHD) was approved over 10 yr ago, and the indication has subsequently gained broad acceptance. The HypoCCS surveillance database is a suitable means to examine the evolution of diagnostic patterns since 1996.
The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013
Lean body mass (LBM), fat mass (FM), and total bone mineral content are significantly reduced in ... more Lean body mass (LBM), fat mass (FM), and total bone mineral content are significantly reduced in adult GHD subjects who had received pediatric GH. To test the hypothesis that continued GH therapy after final height is necessary to attain adult body composition, we performed a prospective, multinational, randomized, controlled, 2-yr study in patients who completed pediatric GH treatment at final height. Patients were randomized to GH at 25.0 g/kg⅐d (pediatric dose; n ؍ 58) or 12.5 g/kg⅐d (adult dose; n ؍ 59) or no GH treatment (control; n ؍ 32). LBM and FM were measured by dual energy x-ray absorptiometry and were centrally evaluated. IGF-I, IGFbinding protein-3, and lipid concentrations were also measured centrally. During the 2 yr, GH-treated patients gained a significant amount of LBM compared with controls (P < 0.001), but the change with the higher pediatric dose (14.2 ؎ 11.7%) was not different from that seen with the lower adult dose (12.7 ؎ 9.4%; P ؍ 0.970). Similarly, the decrease in FM was significantly (P ؍ 0.029) influenced by treatment, but with no dose effect (adult dose, ؊7.1 ؎ 22.8%; pediatric dose, ؊6.0 ؎ 26.6%; P ؍ 0.950). When the GH treatment effect was analyzed by gender, males gained 15.6 ؎ 9.8% and 14.3 ؎ 11.7% LBM (P ؍ 0.711) and lost 12.4 ؎ 22.2% and 11.0 ؎ 27.1% FM (P ؍ 0.921) with the low and high doses, respectively. Females gained 8.3 ؎ 7.3% and 12.5 ؎ 12.8% LBM with the two doses (P ؍ 0.630), but increased their FM by 3.5 ؎ 16.2% with the lower dose and lost only 1.2 ؎ 23.2% FM with the higher dose (P ؍ 0.325). A similar pattern was seen in IGF-I SD score; the 2-yr GH dose response was significantly higher with the pediatric than with the adult dose in females (P ؍ 0.008), but not males (P ؍ 0.790). The divergent pattern of change in LBM and FM in males and females is consistent with normal developmental sexual dimorphism and indicates that GH-dependent progress to target body composition continues after the age at which GH treatment is usually terminated. Dose requirements may have to be adjusted by gender, with females requiring a higher dose than males. (J Clin Endocrinol Metab 89: [4857][4858][4859][4860][4861][4862] 2004)
There is increasing evidence that in the fetal and postnatal development of the adrenal gland, tr... more There is increasing evidence that in the fetal and postnatal development of the adrenal gland, trophic and differentiating effects of ACTH are locally modulated by a species-specific pattern of growth factors. As we have shown previously in human adult adrenocortical cells (HAC) in culture, IGF-I and, even more, IGF-II enhance the steroidogenesis and ACTH responsiveness. We now examined the secretion of IGFs and their binding proteins (IGFBP) in the medium of 12 serum free primary cultures of HAC by specific RIAs and [125I]IGF ligand blot or by immunoblot, and their long-term regulation by ACTH. HAC secrete 0.41 and 0.91 ng IGF-I and IGF-II/5×105 cells per day, respectively, and their secretion is significantly stimulated 2- and 1.6-fold, respectively, by ACTH. HAC secrete at least three IGFBPs. The 43–46 kDa and the 29 kDa proteins correspond to glycosylated and fragmented forms of IGFBP-3, and the 36 kDa protein to IGFBP-2. The most abundant protein is the 24 kDa IGFBP, with identical electrophoretic mobility to IGFBP-4. IGFBP-3, as measured by RIA, is in the range of 1 ng/day. None of the IGFBPs is significantly changed by ACTH. Thus, we have evidence for a local IGF system, and the IGF-levels are in a range compatible with a physiological auto or paracrine action on steroidogenesis.
Bailliere S Clinical Endocrinology and Metabolism, 1992
Children with congenital CRF lose height potential mainly during two distinct growth periods; inf... more Children with congenital CRF lose height potential mainly during two distinct growth periods; infancy and puberty. The onset of puberty is late, the pubertal growth spurt starts from a very low rate of growth velocity, and peak height velocity is lower than normal although the absolute increment of height velocity is comparable to the increment in normal children. Furthermore, the duration of pubertal growth spurt is reduced in CRF. During infancy and early childhood, malnutrition, electrolyte disturbances and metabolic acidosis are the main contributing factors for reduced growth, whereas hormonal disturbances are responsible for growth impairment during puberty. There is evidence for resistance to growth hormone in CRF, which starts in early childhood and persists until the end of puberty. Growth hormone secretion is normal in CRF, but GH half-life is prolonged. The binding activity of the stable growth hormone binding protein is reduced, which points to a low receptor expression in the liver. Hepatic IGF-I production is diminished. However, the serum concentration of IGF binding proteins (IGFBP) is increased due to reduced renal filtration of low molecular weight subunits of IGFBP. Mainly, the accumulation of IGFBP-3 leads to increased IGF-binding capacity of the uraemic serum. Both, reduced IGF-I production and increased binding of IGF to IGFBP-3 result in decreased IGF bioactivity. During infancy, loss of growth potential can be prevented by adequate nutrition. Later in life, catch-up growth cannot be induced by nutritional intervention or dialysis. Renal transplantation allows catch-up growth in only a small percentage of patients. Treatment with one IU rhGH/kg/week improves growth velocity and growth in all stages of renal disease. The mean increment of height in prepubertal children is +1.5 SDS within two treatment years. The effect of rhGH during puberty as well as the effect on final height remain to be determined.
To study interactions between insulin-like growth factor-II (IGF-II) and growth hormone (GH) in v... more To study interactions between insulin-like growth factor-II (IGF-II) and growth hormone (GH) in vivo, we crossed hemizygous transgenic mice carrying phosphoenolpyruvate carboxykinase (PEPCK)-IGF-II fusion genes with hemizygous PEPCK-bovine GH (bGH) transgenic mice. Offspring harbouring both transgenes (IB), the IGF-II transgene (I) or the bGH transgene (B), and non-transgenic littermates (C) were obtained. Blood samples were taken before (end of week 12) and after (end of week 14) the mice had received a diet high in protein and low in carbohydrates to stimulate PEPCK promoter-controlled transgene expression. Mean serum GH concentrations of both B and IB mice corresponded to 900 ng/ml and increased more than twofold (P < 0.001) after 1 week of the high-protein diet. GH concentrations in controls and I mice were less than 20 ng/ml. Serum IGF-II concentrations in I and IB mice were three-to fourfold higher than those in C and B mice. Whereas IGF-II concentrations were not changed by the high-protein diet in the last two groups, serum IGF-II increased significantly in I (P < 0.001) and IB mice (P < 0.05). This increase was significantly (P < 0.05) less pronounced in IB than in I mice. Circulating IGF-I concentrations were about twofold (P < 0.001) higher in B and IB than in C and I mice, and showed a tendency to be lower in I than in C and in IB than in B mice when animals were maintained on the standard diet. The high-protein diet did not change circulating IGF-I concentrations in controls and B mice, but resulted in a significant reduction of serum IGF-I concentrations in I (P < 0.05) and IB mice (P < 0.001). Consequently, after PEPCK-IGF-II transgene expression was stimulated, serum IGF-I concentrations were significantly (P < 0.05) lower in I than in C and in IB than in B mice. Serum IGF-binding protein (IGFBP)-2 concentrations were significantly (P < 0:05) higher in I mice than in all other groups when mice were maintained on the standard diet, with a tendency to reduced IGFBP-2 concentrations in B mice. After the high-protein diet, serum IGFBP-2 concentrations did not change in C and I mice, but increased by two-to threefold in B and IB mice (P < 0:001). Serum IGFBP-3 concentrations tended to be greater in B and IB than in C and I mice, but these differences were mostly not significant. IGFBP-4 concentrations were significantly (P < 0:001) increased by GH overproduction in B and IB mice. Our data suggest that the reduction in circulating IGF-I concentrations by increased IGF-II is most probably due to the limited serum IGF binding capacity and the short half-life of free IGFs, rather than to a reduction in GH-dependent IGF-I production. Effects of GH overproduction on serum IGFBP-2 concentrations depend on dietary factors and may be both inhibitory and stimulatory.
International Journal of Environmental Research and Public Health, 2015
We test the hypothesis that differences in social status between groups of people within a popula... more We test the hypothesis that differences in social status between groups of people within a population may induce variation in insulin-like growth factor-1(IGF-1) levels and, by extension, growth in height. This is called the community effect in height hypothesis. The relationship between IGF-1, assessed via finger-prick dried blood spot, and elite level sport competition outcomes were analysed for a sample of 116 undergraduate men and women. There was a statistically significant difference between winners and losers of a competition. Winners, as a group, had higher average pre-game and post-game IGF-1 levels than losers. We proposed this type of difference as a proxy for social dominance. We found no evidence that winners increased in IGF-1 levels over losers or that members of the same team were more similar in IGF-1 levels than they were to players from other teams. These findings provide limited support toward the community effect in height hypothesis. The findings are discussed in relation to the action of the growth hormone/IGF-1 axis as a transducer of multiple bio-social influences into a coherent signal which allows the growing human to adjust and adapt to local ecological conditions.
of the ASF depot was not reduced with GH treatment. The interaction for BMR increased (P = 0.81) ... more of the ASF depot was not reduced with GH treatment. The interaction for BMR increased (P = 0.81) after adjusting for the fatfree mass. Conclusion: GH treatment accelerates linear growth and lean tissue accrual, including bone mineral. GH treatment reduces adiposity especially AVF. GH did not directly increase energy expenditure but rather was a result of the increase in metabolically active fat-free mass.
Experimental and Clinical Endocrinology & Diabetes, 1993
A competitive enzyme immunoassay for the determination of human insulin-like growth factor I in m... more A competitive enzyme immunoassay for the determination of human insulin-like growth factor I in microtiter plates was established. Using a polyclonal antiserum raised in rabbits against hIGF-I ovalbumin conjugate the assay system was able to detect IGF-I at a range of 12-800 pg/well with a sensitivity of 10 pg/well. It showed a low (&lt; 0.5%) cross reactivity with hIGF-II. The serum concentrations of IGF-I found by EIA agreed well with those found in a conventional RIA (r = 0.965, p &lt; 0.001). Effects of age and sex on IGF-I levels were studied in 260 normal adults. There was no evidence for sex differences but a steep decline of values from the third to the fourth and from the eight to the ninth decade, respectively. To asses the diagnostic capability of the IGF-I determination in liver cirrhosis, 71 sera of patients classified according to Child classes (A-C) were measured. Although significantly diminished concentrations were found in class B vs A and in class C vs B, the diagnostic sensitivity in cross-sectional examinations proved to be low (class A: 0.33, class B: 0.67). Only in the case of extensively destroyed liver parenchyma (Child C: 0.94) IGF-I was a good indicator of impaired hepatocellular capacity. In 29 patients with acromegaly serum IGF-I levels were investigated. All patients with active acromegaly showed increased IGF-I levels. In contrast, in inactive or weakly active acromegaly values were considerably lower.(ABSTRACT TRUNCATED AT 250 WORDS)
Experimental and Clinical Endocrinology & Diabetes, 1995
The aim of this study was to investigate the regulation of various proteins of the GHIGF axis dur... more The aim of this study was to investigate the regulation of various proteins of the GHIGF axis during progression of liver failure and to search for potential prognostic markers of functional hepatic reserve. Serum levels of growth hormone (GH) and high affinity growth hormone binding protein (GHBP), insulin-like growth factor I (IGF-I) and IGF binding proteins (IGFBP) -1, -2 and -3 were determined in patients with liver cirrhosis. A continuous decline in the concentrations of IGF-I, IGFBP-3 and serum GH-binding activity (GHBP) was observed during progression of cirrhosis and the data correlated significantly with choline esterase, total serum protein and the Child score. In addition, GHBP showed a significant correlation with the enzymatic activity of glutamate dehydrogenase or transaminases and seems so to be influenced by the degree of liver cell damage. In contrast, IGFBP-1 and IGFBP-2 levels were significantly elevated in preterminal disease suggesting an upregulatory mechanism is still effective in this situation. Only when liver function had markedly deteriorated, the serum levels of these two parameters decreased again, possibly due to an impaired synthesis. The excellent correlation between the serum levels of IGF-I (r = -0.64, p &lt; 0.001) or IGFBP-3 (r = -0.67, p &lt; 0.001) and the Child score index suggests that they reflect the hepatic functions just as conventional indicators. For an appropriate interpretation of the liver function the measurement of the growth related peptides can be a valuable tool to estimate pathological alteration in the functional hepatic reserve or in the glucose homeostasis.
Experimental and Clinical Endocrinology & Diabetes, 1998
During diagnostic lumbar punctions cerbrospinal fluid (CSF) was collected for the determination o... more During diagnostic lumbar punctions cerbrospinal fluid (CSF) was collected for the determination of GH, IGF-I, IGFBP-3 and IGFBP-2. The patients were 0.3 to 68 years od and suffered from viral infections, leukemias, M. Hodgkin or multiple sclerosis. Only CSF samples without any pathological alterations were analysed. In infants and adults CSF GH concentrations significantly declined with age, while IGF-I and the two binding proteins were unrelated to age. GH was not correlated to IGF-I, IGFBP-3 or IGFBP-2. However, IGF-I was strongly related to IGFBP-3 (r = 0.529; &lt; 0.001) and IGFBP-2 (r = 0.796; &lt; 0.001) as was IGFBP-3 to IGFBP-2 (r = 0.685; &lt; 0.001), suggesting dependence of the three variables. With IGFBP-3 or IGFBP-2 as control variables (partial correlation) IGF-I was no longer related to the binding proteins, while the relation of IGFBP-3 to IGFBP-2 remained unchanged with IGF-I as the control variable (r = 0.687; &lt; 0.001). The results suggest that the age-related decrease of CSF GH may contribute to the age-dependent decline of GH receptors in brain, which are up-regulated by GH. Furthermore, in CSF IGF-I concentrations were determined by the two binding proteins. It may be speculated that the transfer of IGF-I through the blood CSF barrier or its production in brain may be closely related to the IGF-binding proteins.
The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013
To determine whether an individualized dose titration regimen (ID) for adult GH replacement thera... more To determine whether an individualized dose titration regimen (ID) for adult GH replacement therapy would have similar efficacy and better tolerability than a fixed body weight-based dosing regimen (FD), 387 adults with GH deficiency were randomized to FD (n = 200) or ID (n = 187) for 32 wk. In FD, subjects received sequentially 4, 8, and 12 microg/kg.d GH. ID was started at 0.2 mg/d and increased by 0.2-mg/d increments, based on clinical and serum IGF-I responses, to a maximum of 0.8 mg/d. Increases (mean +/- sd) in serum IGF-I were similar in both groups (FD, 110.2 +/- 87.8 vs. ID, 99.6 +/- 77.7 microg/liter, P = 0.20) despite higher final GH doses in FD (0.70 +/- 0.32 vs. 0.54 +/- 0.22 mg/d, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Favorable changes in several efficacy measures were observed with no significant differences between the FD and ID groups: lean body mass increased; health-related quality of life improved; and abdominal fat mass, hip circumference, sum of skinfolds, and total and low-density lipoprotein cholesterol decreased. The decrease in fat mass was greater with FD than ID for men (-2.7 +/- 2.7 kg vs. -1.8 +/- 2.5 kg, P = 0.04) but not for women (-2.1 +/- 2.4 vs. -2.0 +/- 3.8 kg). The change in waist circumference was greater with FD than ID for women but not for men. There was a significant reduction of systolic blood pressure in ID but not in FD. The adverse event profile was similar between FD and ID except that ID had a lower occurrence of peripheral edema (9.1% vs. 16.5%, P = 0.03) and rash (1.1% vs. 5.5%, P = 0.02) than FD. In summary, the use of ID resulted in improved tolerability and similar efficacy compared with FD. We conclude that GH replacement therapy should be initiated at a low dose and titrated to a dose producing maximal benefits without adverse side effects and an IGF-I level within the age- and sex-adjusted normal range.
Objective: Leptin, the product of the ob gene, is overexpressed in human obesity and increased se... more Objective: Leptin, the product of the ob gene, is overexpressed in human obesity and increased serum leptin levels are closely correlated with adipose tissue mass, but the regulation of leptin production is not completely understood. The aim of this study was to characterize the role of tumor necrosis factor (TNF)-a and transforming growth factor (TGF)-b1 in depot-specific secretion of leptin
The regulation of leptin production in humans is poorly understood but appears to depend on total... more The regulation of leptin production in humans is poorly understood but appears to depend on total body fat, changes in energy intake and insulin levels. Since growth hormone (GH) is an important regulator of both lipid metabolism and insulin secretion and action, we tested whether GH status directly or indirectly regulates leptin secretion.
Der Nervenarzt 1·99 | 33 Abb.1 ᭡ Die Aufnahme-BMI von 272 Patientinnen mit Anorexia nervosa wurde... more Der Nervenarzt 1·99 | 33 Abb.1 ᭡ Die Aufnahme-BMI von 272 Patientinnen mit Anorexia nervosa wurden zu ganzen Zahlen jeweils abgerundet und zum Katamnese-BMI in Bezug gesetzt. Die Katamnese erfolgte im Schnitt 9,6 Jahre nach der Aufnahme.Verstorbene Patientinnen sind durch einen schwarzen Kreis dargestellt. Die Box-Plots umfassen jeweils die Patientinnen, die das zweite und dritte Quartil bilden. Die waagrechten Linien in den Box-Plots kennzeichnen den Median
The Journal of Clinical Endocrinology and Metabolism, Apr 19, 2012
Context:The prevalence of SHOX deficiency in children with short stature (SS) is variable in the ... more Context:The prevalence of SHOX deficiency in children with short stature (SS) is variable in the literature and various genotypes have been identified.Objectives:The aim of our study was to determine the frequency and distribution of SHOX genotypes in a large sample of children with SS in France.Design, Setting, and Patients:Children were enrolled in 38 French pediatric endocrinology centers and were either diagnosed with Leri-Weill syndrome (LWS), idiopathic short stature (ISS), or disproportionate short stature (DSS).Intervention and Main Outcome Measure:SHOX analysis was performed centrally as part of the Genetics and Neuroendocrinology of Short Stature International Study observational study. We compared patients with (SHOX-D) and without SHOX deficiency (non-SHOX-D).Results:Among the 537 patients tested [58.3% females, mean age 11.0 (4.2) yr], 27.7% had SHOX deficiency (LWS, 48.9%; ISS, 16.9%; DSS, 18.8%). Mean height [-2.3 (0.9) sd score] was similar in SHOX-D and non-SHOX-D patients. The majority of SHOX-D patients with LWS had either a deletion encompassing SHOX or a point mutation (69%), whereas 59% of those with ISS had a deletion downstream of SHOX in the enhancer region. The height of the parents carrying a deletion downstream of SHOX was higher than the height of the parents carrying the other gene anomalies.Conclusions:SHOX deletions and point mutations as well as downstream SHOX enhancer deletions were identified in almost one third of the patients tested. An anomaly in this latter region seemed to be linked to a milder phenotype. Although further confirmation is needed, we suggest that the enhancer region should be systematically analyzed in patients suspected of SHOX deficiency.
Background: GH therapy in adult patients with GH deficiency (GHD) was approved over 10 yr ago, an... more Background: GH therapy in adult patients with GH deficiency (GHD) was approved over 10 yr ago, and the indication has subsequently gained broad acceptance. The HypoCCS surveillance database is a suitable means to examine the evolution of diagnostic patterns since 1996.
The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013
Lean body mass (LBM), fat mass (FM), and total bone mineral content are significantly reduced in ... more Lean body mass (LBM), fat mass (FM), and total bone mineral content are significantly reduced in adult GHD subjects who had received pediatric GH. To test the hypothesis that continued GH therapy after final height is necessary to attain adult body composition, we performed a prospective, multinational, randomized, controlled, 2-yr study in patients who completed pediatric GH treatment at final height. Patients were randomized to GH at 25.0 g/kg⅐d (pediatric dose; n ؍ 58) or 12.5 g/kg⅐d (adult dose; n ؍ 59) or no GH treatment (control; n ؍ 32). LBM and FM were measured by dual energy x-ray absorptiometry and were centrally evaluated. IGF-I, IGFbinding protein-3, and lipid concentrations were also measured centrally. During the 2 yr, GH-treated patients gained a significant amount of LBM compared with controls (P < 0.001), but the change with the higher pediatric dose (14.2 ؎ 11.7%) was not different from that seen with the lower adult dose (12.7 ؎ 9.4%; P ؍ 0.970). Similarly, the decrease in FM was significantly (P ؍ 0.029) influenced by treatment, but with no dose effect (adult dose, ؊7.1 ؎ 22.8%; pediatric dose, ؊6.0 ؎ 26.6%; P ؍ 0.950). When the GH treatment effect was analyzed by gender, males gained 15.6 ؎ 9.8% and 14.3 ؎ 11.7% LBM (P ؍ 0.711) and lost 12.4 ؎ 22.2% and 11.0 ؎ 27.1% FM (P ؍ 0.921) with the low and high doses, respectively. Females gained 8.3 ؎ 7.3% and 12.5 ؎ 12.8% LBM with the two doses (P ؍ 0.630), but increased their FM by 3.5 ؎ 16.2% with the lower dose and lost only 1.2 ؎ 23.2% FM with the higher dose (P ؍ 0.325). A similar pattern was seen in IGF-I SD score; the 2-yr GH dose response was significantly higher with the pediatric than with the adult dose in females (P ؍ 0.008), but not males (P ؍ 0.790). The divergent pattern of change in LBM and FM in males and females is consistent with normal developmental sexual dimorphism and indicates that GH-dependent progress to target body composition continues after the age at which GH treatment is usually terminated. Dose requirements may have to be adjusted by gender, with females requiring a higher dose than males. (J Clin Endocrinol Metab 89: [4857][4858][4859][4860][4861][4862] 2004)
There is increasing evidence that in the fetal and postnatal development of the adrenal gland, tr... more There is increasing evidence that in the fetal and postnatal development of the adrenal gland, trophic and differentiating effects of ACTH are locally modulated by a species-specific pattern of growth factors. As we have shown previously in human adult adrenocortical cells (HAC) in culture, IGF-I and, even more, IGF-II enhance the steroidogenesis and ACTH responsiveness. We now examined the secretion of IGFs and their binding proteins (IGFBP) in the medium of 12 serum free primary cultures of HAC by specific RIAs and [125I]IGF ligand blot or by immunoblot, and their long-term regulation by ACTH. HAC secrete 0.41 and 0.91 ng IGF-I and IGF-II/5×105 cells per day, respectively, and their secretion is significantly stimulated 2- and 1.6-fold, respectively, by ACTH. HAC secrete at least three IGFBPs. The 43–46 kDa and the 29 kDa proteins correspond to glycosylated and fragmented forms of IGFBP-3, and the 36 kDa protein to IGFBP-2. The most abundant protein is the 24 kDa IGFBP, with identical electrophoretic mobility to IGFBP-4. IGFBP-3, as measured by RIA, is in the range of 1 ng/day. None of the IGFBPs is significantly changed by ACTH. Thus, we have evidence for a local IGF system, and the IGF-levels are in a range compatible with a physiological auto or paracrine action on steroidogenesis.
Bailliere S Clinical Endocrinology and Metabolism, 1992
Children with congenital CRF lose height potential mainly during two distinct growth periods; inf... more Children with congenital CRF lose height potential mainly during two distinct growth periods; infancy and puberty. The onset of puberty is late, the pubertal growth spurt starts from a very low rate of growth velocity, and peak height velocity is lower than normal although the absolute increment of height velocity is comparable to the increment in normal children. Furthermore, the duration of pubertal growth spurt is reduced in CRF. During infancy and early childhood, malnutrition, electrolyte disturbances and metabolic acidosis are the main contributing factors for reduced growth, whereas hormonal disturbances are responsible for growth impairment during puberty. There is evidence for resistance to growth hormone in CRF, which starts in early childhood and persists until the end of puberty. Growth hormone secretion is normal in CRF, but GH half-life is prolonged. The binding activity of the stable growth hormone binding protein is reduced, which points to a low receptor expression in the liver. Hepatic IGF-I production is diminished. However, the serum concentration of IGF binding proteins (IGFBP) is increased due to reduced renal filtration of low molecular weight subunits of IGFBP. Mainly, the accumulation of IGFBP-3 leads to increased IGF-binding capacity of the uraemic serum. Both, reduced IGF-I production and increased binding of IGF to IGFBP-3 result in decreased IGF bioactivity. During infancy, loss of growth potential can be prevented by adequate nutrition. Later in life, catch-up growth cannot be induced by nutritional intervention or dialysis. Renal transplantation allows catch-up growth in only a small percentage of patients. Treatment with one IU rhGH/kg/week improves growth velocity and growth in all stages of renal disease. The mean increment of height in prepubertal children is +1.5 SDS within two treatment years. The effect of rhGH during puberty as well as the effect on final height remain to be determined.
To study interactions between insulin-like growth factor-II (IGF-II) and growth hormone (GH) in v... more To study interactions between insulin-like growth factor-II (IGF-II) and growth hormone (GH) in vivo, we crossed hemizygous transgenic mice carrying phosphoenolpyruvate carboxykinase (PEPCK)-IGF-II fusion genes with hemizygous PEPCK-bovine GH (bGH) transgenic mice. Offspring harbouring both transgenes (IB), the IGF-II transgene (I) or the bGH transgene (B), and non-transgenic littermates (C) were obtained. Blood samples were taken before (end of week 12) and after (end of week 14) the mice had received a diet high in protein and low in carbohydrates to stimulate PEPCK promoter-controlled transgene expression. Mean serum GH concentrations of both B and IB mice corresponded to 900 ng/ml and increased more than twofold (P < 0.001) after 1 week of the high-protein diet. GH concentrations in controls and I mice were less than 20 ng/ml. Serum IGF-II concentrations in I and IB mice were three-to fourfold higher than those in C and B mice. Whereas IGF-II concentrations were not changed by the high-protein diet in the last two groups, serum IGF-II increased significantly in I (P < 0.001) and IB mice (P < 0.05). This increase was significantly (P < 0.05) less pronounced in IB than in I mice. Circulating IGF-I concentrations were about twofold (P < 0.001) higher in B and IB than in C and I mice, and showed a tendency to be lower in I than in C and in IB than in B mice when animals were maintained on the standard diet. The high-protein diet did not change circulating IGF-I concentrations in controls and B mice, but resulted in a significant reduction of serum IGF-I concentrations in I (P < 0.05) and IB mice (P < 0.001). Consequently, after PEPCK-IGF-II transgene expression was stimulated, serum IGF-I concentrations were significantly (P < 0.05) lower in I than in C and in IB than in B mice. Serum IGF-binding protein (IGFBP)-2 concentrations were significantly (P < 0:05) higher in I mice than in all other groups when mice were maintained on the standard diet, with a tendency to reduced IGFBP-2 concentrations in B mice. After the high-protein diet, serum IGFBP-2 concentrations did not change in C and I mice, but increased by two-to threefold in B and IB mice (P < 0:001). Serum IGFBP-3 concentrations tended to be greater in B and IB than in C and I mice, but these differences were mostly not significant. IGFBP-4 concentrations were significantly (P < 0:001) increased by GH overproduction in B and IB mice. Our data suggest that the reduction in circulating IGF-I concentrations by increased IGF-II is most probably due to the limited serum IGF binding capacity and the short half-life of free IGFs, rather than to a reduction in GH-dependent IGF-I production. Effects of GH overproduction on serum IGFBP-2 concentrations depend on dietary factors and may be both inhibitory and stimulatory.
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Papers by Werner Blum