A. Di Nisio, L. De Toni, I. Šabović, M. S. Rocca, V. De Filippis, G. Opocher, B. Azzena, R. Vettor, M. Plebani, C. Foresta
Context Vitamin D accumulates in adipose tissue (AT), and vitamin D deficiency is frequent in obesity. Objective We hypothesize that trafficking of vitamin D is altered in dysfunctional AT. Design, Patients, Settings Fifty-four normal-weight and 67 obese males were recruited in a prospective study and randomly assigned to supplementation with 50 µg/wk 25-hydroxyvitamin-D3 or 150 µg/wk vitamin D3 for 1 year, raising dosage by 50% if vitamin D sufficiency [serum 25-hydroxyvitamin-D3 >50 nmol/L], was not achieved at 6 months; 97 subjects completed the study. Methods Vitamin D3 and 25-hydroxyvitamin-D3 were quantified by HPLC-MS in control and insulin-resistant (IR) 3T3-L1 cells and subcutaneous AT (SAT) from lean and obese subjects, incubated with or without adrenaline; expression of 25-hydroxylase (Cyp27a1), 1α-hydroxylase (Cyp27b1), and vitamin D receptor (Vdr) was analyzed by real-time polymerase chain reaction. Results In IR adipocytes, uptake of D3 and 25-hydroxyvitamin-D3 was higher, but, after adrenaline stimulation, the decrement in D3 and 25-hydroxyvitamin-D3 was stronger in control cells, which also showed increased expression of Cyp27a1 and Cyp27b1 and higher levels of 25-hydroxyvitamin-D3. In SAT from obese subjects, adrenaline-induced release of D3 and 25-hydroxyvitamin-D3 was blunted; in both IR cells and obese SAT, protein expression of β2-adrenergic receptor was reduced. Supplementation with 25-hydroxyvitamin-D3 was more effective in achieving vitamin D sufficiency in obese, but not in normal weight subjects. Conclusion Dysfunctional AT shows a reduced catecholamine-induced release of D3 and 25-hydroxyvitamin-D3 and altered activity of vitamin D-metabolizing enzymes; for these reasons supplementation with 25-hydroxyvitamin-D3 is more effective in obese individuals.
{"title":"Impaired Release of Vitamin D in Dysfunctional Adipose Tissue: New Cues on Vitamin D Supplementation in Obesity","authors":"A. Di Nisio, L. De Toni, I. Šabović, M. S. Rocca, V. De Filippis, G. Opocher, B. Azzena, R. Vettor, M. Plebani, C. Foresta","doi":"10.1210/jc.2016-3591","DOIUrl":"https://doi.org/10.1210/jc.2016-3591","url":null,"abstract":"Context\u0000Vitamin D accumulates in adipose tissue (AT), and vitamin D deficiency is frequent in obesity.\u0000\u0000\u0000Objective\u0000We hypothesize that trafficking of vitamin D is altered in dysfunctional AT.\u0000\u0000\u0000Design, Patients, Settings\u0000Fifty-four normal-weight and 67 obese males were recruited in a prospective study and randomly assigned to supplementation with 50 µg/wk 25-hydroxyvitamin-D3 or 150 µg/wk vitamin D3 for 1 year, raising dosage by 50% if vitamin D sufficiency [serum 25-hydroxyvitamin-D3 >50 nmol/L], was not achieved at 6 months; 97 subjects completed the study.\u0000\u0000\u0000Methods\u0000Vitamin D3 and 25-hydroxyvitamin-D3 were quantified by HPLC-MS in control and insulin-resistant (IR) 3T3-L1 cells and subcutaneous AT (SAT) from lean and obese subjects, incubated with or without adrenaline; expression of 25-hydroxylase (Cyp27a1), 1α-hydroxylase (Cyp27b1), and vitamin D receptor (Vdr) was analyzed by real-time polymerase chain reaction.\u0000\u0000\u0000Results\u0000In IR adipocytes, uptake of D3 and 25-hydroxyvitamin-D3 was higher, but, after adrenaline stimulation, the decrement in D3 and 25-hydroxyvitamin-D3 was stronger in control cells, which also showed increased expression of Cyp27a1 and Cyp27b1 and higher levels of 25-hydroxyvitamin-D3. In SAT from obese subjects, adrenaline-induced release of D3 and 25-hydroxyvitamin-D3 was blunted; in both IR cells and obese SAT, protein expression of β2-adrenergic receptor was reduced. Supplementation with 25-hydroxyvitamin-D3 was more effective in achieving vitamin D sufficiency in obese, but not in normal weight subjects.\u0000\u0000\u0000Conclusion\u0000Dysfunctional AT shows a reduced catecholamine-induced release of D3 and 25-hydroxyvitamin-D3 and altered activity of vitamin D-metabolizing enzymes; for these reasons supplementation with 25-hydroxyvitamin-D3 is more effective in obese individuals.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"26 1","pages":"2564–2574"},"PeriodicalIF":0.0,"publicationDate":"2017-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90986743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Verroken, H. Zmierczak, S. Goemaere, J. Kaufman, B. Lapauw
Context In type 2 diabetes mellitus, fracture risk is increased despite preserved areal bone mineral density. Although this apparent paradox may in part be explained by insulin resistance affecting bone structure and/or material properties, few studies have investigated the association between insulin resistance and bone geometry. Objective We aimed to explore this association in a cohort of nondiabetic men at the age of peak bone mass. Design, Setting, and Participants Nine hundred ninety-six nondiabetic men aged 25 to 45 years were recruited in a cross-sectional, population-based sibling pair study at a university research center. Main Outcome Measures Insulin resistance was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR), with insulin and glucose measured from fasting serum samples. Bone geometry was assessed using peripheral quantitative computed tomography at the distal radius and the radial and tibial shafts. Results In age-, height-, and weight-adjusted analyses, HOMA-IR was inversely associated with trabecular area at the distal radius and with cortical area, periosteal and endosteal circumference, and polar strength strain index at the radial and tibial shafts (β ≤ -0.13, P < 0.001). These associations remained essentially unchanged after additional adjustment for dual-energy X-ray absorptiometry-derived body composition, bone turnover markers, muscle size or function measurements, or adiponectin, leptin, insulin-like growth factor 1, or sex steroid levels. Conclusion In this cohort of nondiabetic men at the age of peak bone mass, insulin resistance is inversely associated with trabecular and cortical bone size. These associations persist after adjustment for body composition, muscle size or function, or sex steroid levels, suggesting an independent effect of insulin resistance on bone geometry.
{"title":"Insulin Resistance Is Associated With Smaller Cortical Bone Size in Nondiabetic Men at the Age of Peak Bone Mass","authors":"C. Verroken, H. Zmierczak, S. Goemaere, J. Kaufman, B. Lapauw","doi":"10.1210/jc.2016-3609","DOIUrl":"https://doi.org/10.1210/jc.2016-3609","url":null,"abstract":"Context\u0000In type 2 diabetes mellitus, fracture risk is increased despite preserved areal bone mineral density. Although this apparent paradox may in part be explained by insulin resistance affecting bone structure and/or material properties, few studies have investigated the association between insulin resistance and bone geometry.\u0000\u0000\u0000Objective\u0000We aimed to explore this association in a cohort of nondiabetic men at the age of peak bone mass.\u0000\u0000\u0000Design, Setting, and Participants\u0000Nine hundred ninety-six nondiabetic men aged 25 to 45 years were recruited in a cross-sectional, population-based sibling pair study at a university research center.\u0000\u0000\u0000Main Outcome Measures\u0000Insulin resistance was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR), with insulin and glucose measured from fasting serum samples. Bone geometry was assessed using peripheral quantitative computed tomography at the distal radius and the radial and tibial shafts.\u0000\u0000\u0000Results\u0000In age-, height-, and weight-adjusted analyses, HOMA-IR was inversely associated with trabecular area at the distal radius and with cortical area, periosteal and endosteal circumference, and polar strength strain index at the radial and tibial shafts (β ≤ -0.13, P < 0.001). These associations remained essentially unchanged after additional adjustment for dual-energy X-ray absorptiometry-derived body composition, bone turnover markers, muscle size or function measurements, or adiponectin, leptin, insulin-like growth factor 1, or sex steroid levels.\u0000\u0000\u0000Conclusion\u0000In this cohort of nondiabetic men at the age of peak bone mass, insulin resistance is inversely associated with trabecular and cortical bone size. These associations persist after adjustment for body composition, muscle size or function, or sex steroid levels, suggesting an independent effect of insulin resistance on bone geometry.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"2012 1","pages":"1807–1815"},"PeriodicalIF":0.0,"publicationDate":"2017-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73952953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Manouk van der Steen, R. Pfundt, S. Maas, W. B. Bakker-van Waarde, R. Odink, A. Hokken-Koelega
Background Some children born small for gestational age (SGA) show advanced bone age (BA) maturation during growth hormone (GH) treatment. ACAN gene mutations have been described in children with short stature and advanced BA. Objective To determine the presence of ACAN gene mutations in short SGA children with advanced BA and assess the response to GH treatment. Methods BA assessment in 290 GH-treated SGA children. ACAN sequencing in 29 children with advanced BA ≥0.5 years compared with calendar age. Results Four of 29 SGA children with advanced BA had an ACAN gene mutation (13.8%). Mutations were related to additional characteristics: midface hypoplasia (P = 0.003), joint problems (P = 0.010), and broad great toes (P = 0.003). Children with one or fewer additional characteristic had no mutation. Of children with two additional characteristics, 50% had a mutation. Of children with three additional characteristics, 100% had a mutation. All GH-treated children with a mutation received gonadotropin-releasing hormone analog (GnRHa) treatment for 2 years from onset of puberty. At adult height, one girl was 5 cm taller than her mother and one boy was 8 cm taller than his father with the same ACAN gene mutation. Conclusion This study expands the differential diagnosis of genetic variants in children born SGA and proposes a clinical scoring system for identifying subjects most likely to have an ACAN gene mutation. ACAN sequencing should be considered in children born SGA with persistent short stature, advanced BA, and midface hypoplasia, joint problems, or broad great toes. Our findings suggest that children with an ACAN gene mutation benefit from GH treatment with 2 years of GnRHa.
{"title":"ACAN Gene Mutations in Short Children Born SGA and Response to Growth Hormone Treatment","authors":"Manouk van der Steen, R. Pfundt, S. Maas, W. B. Bakker-van Waarde, R. Odink, A. Hokken-Koelega","doi":"10.1210/jc.2016-2941","DOIUrl":"https://doi.org/10.1210/jc.2016-2941","url":null,"abstract":"Background\u0000Some children born small for gestational age (SGA) show advanced bone age (BA) maturation during growth hormone (GH) treatment. ACAN gene mutations have been described in children with short stature and advanced BA.\u0000\u0000\u0000Objective\u0000To determine the presence of ACAN gene mutations in short SGA children with advanced BA and assess the response to GH treatment.\u0000\u0000\u0000Methods\u0000BA assessment in 290 GH-treated SGA children. ACAN sequencing in 29 children with advanced BA ≥0.5 years compared with calendar age.\u0000\u0000\u0000Results\u0000Four of 29 SGA children with advanced BA had an ACAN gene mutation (13.8%). Mutations were related to additional characteristics: midface hypoplasia (P = 0.003), joint problems (P = 0.010), and broad great toes (P = 0.003). Children with one or fewer additional characteristic had no mutation. Of children with two additional characteristics, 50% had a mutation. Of children with three additional characteristics, 100% had a mutation. All GH-treated children with a mutation received gonadotropin-releasing hormone analog (GnRHa) treatment for 2 years from onset of puberty. At adult height, one girl was 5 cm taller than her mother and one boy was 8 cm taller than his father with the same ACAN gene mutation.\u0000\u0000\u0000Conclusion\u0000This study expands the differential diagnosis of genetic variants in children born SGA and proposes a clinical scoring system for identifying subjects most likely to have an ACAN gene mutation. ACAN sequencing should be considered in children born SGA with persistent short stature, advanced BA, and midface hypoplasia, joint problems, or broad great toes. Our findings suggest that children with an ACAN gene mutation benefit from GH treatment with 2 years of GnRHa.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"1 1","pages":"1458–1467"},"PeriodicalIF":0.0,"publicationDate":"2017-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81564804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T. N. Kjær, M. J. Ornstrup, Morten Møller Poulsen, H. Stødkilde-Jørgensen, N. Jessen, J. Jørgensen, B. Richelsen, S. Pedersen
Context Low-grade inflammation is associated with obesity and the metabolic syndrome (MetS). Preclinical evidence suggests that resveratrol (RSV) has beneficial metabolic and anti-inflammatory effects that could have therapeutic implications. Objective To investigate effects of long-term RSV treatment on inflammation and MetS. Setting and Design A randomized, placebo-controlled, double-blind, parallel group clinical trial conducted at Aarhus University Hospital. Participants Middle-aged community-dwelling men (N = 74) with MetS, 66 of whom completed all visits (mean ± standard error of the mean): age, 49.5 ± 0.796 years; body mass index, 33.8 ± 0.44 kg/m2; waist circumference, 115 ± 1.14 cm. Intervention Daily oral supplementation with 1000 mg RSV (RSVhigh), 150 mg RSV, or placebo for 16 weeks. Main outcome measures Plasma levels of high-sensitivity C-reactive protein (hs-CRP), circulating lipids, and inflammatory markers in circulation and adipose/muscle tissue biopsy specimens; glucose metabolism; and body composition including visceral fat and ectopic fat deposition. Results RSV treatment did not lower circulating levels of hs-CRP, interleukin 6, or soluble urokinase plasminogen activator receptor in plasma, and inflammatory gene expression in adipose and muscle tissues also remained unchanged. RSV treatment had no effect on blood pressure, body composition, and lipid deposition in the liver or striated muscle. RSV treatment had no beneficial effect on glucose or lipid metabolism. RSVhigh treatment significantly increased total cholesterol (P < 0.002), low-density lipoprotein (LDL) cholesterol (P < 0.006), and fructosamine (P < 0.013) levels compared with placebo. Conclusion RSV treatment did not improve inflammatory status, glucose homeostasis, blood pressure, or hepatic lipid content in middle-aged men with MetS. On the contrary, RSVhigh significantly increased total cholesterol, LDL cholesterol, and fructosamine levels compared with placebo.
{"title":"No Beneficial Effects of Resveratrol on the Metabolic Syndrome: A Randomized Placebo-Controlled Clinical Trial","authors":"T. N. Kjær, M. J. Ornstrup, Morten Møller Poulsen, H. Stødkilde-Jørgensen, N. Jessen, J. Jørgensen, B. Richelsen, S. Pedersen","doi":"10.1210/jc.2016-2160","DOIUrl":"https://doi.org/10.1210/jc.2016-2160","url":null,"abstract":"Context\u0000Low-grade inflammation is associated with obesity and the metabolic syndrome (MetS). Preclinical evidence suggests that resveratrol (RSV) has beneficial metabolic and anti-inflammatory effects that could have therapeutic implications.\u0000\u0000\u0000Objective\u0000To investigate effects of long-term RSV treatment on inflammation and MetS.\u0000\u0000\u0000Setting and Design\u0000A randomized, placebo-controlled, double-blind, parallel group clinical trial conducted at Aarhus University Hospital.\u0000\u0000\u0000Participants\u0000Middle-aged community-dwelling men (N = 74) with MetS, 66 of whom completed all visits (mean ± standard error of the mean): age, 49.5 ± 0.796 years; body mass index, 33.8 ± 0.44 kg/m2; waist circumference, 115 ± 1.14 cm.\u0000\u0000\u0000Intervention\u0000Daily oral supplementation with 1000 mg RSV (RSVhigh), 150 mg RSV, or placebo for 16 weeks.\u0000\u0000\u0000Main outcome measures\u0000Plasma levels of high-sensitivity C-reactive protein (hs-CRP), circulating lipids, and inflammatory markers in circulation and adipose/muscle tissue biopsy specimens; glucose metabolism; and body composition including visceral fat and ectopic fat deposition.\u0000\u0000\u0000Results\u0000RSV treatment did not lower circulating levels of hs-CRP, interleukin 6, or soluble urokinase plasminogen activator receptor in plasma, and inflammatory gene expression in adipose and muscle tissues also remained unchanged. RSV treatment had no effect on blood pressure, body composition, and lipid deposition in the liver or striated muscle. RSV treatment had no beneficial effect on glucose or lipid metabolism. RSVhigh treatment significantly increased total cholesterol (P < 0.002), low-density lipoprotein (LDL) cholesterol (P < 0.006), and fructosamine (P < 0.013) levels compared with placebo.\u0000\u0000\u0000Conclusion\u0000RSV treatment did not improve inflammatory status, glucose homeostasis, blood pressure, or hepatic lipid content in middle-aged men with MetS. On the contrary, RSVhigh significantly increased total cholesterol, LDL cholesterol, and fructosamine levels compared with placebo.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"50 1","pages":"1642–1651"},"PeriodicalIF":0.0,"publicationDate":"2017-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83669765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Ueda, R. Dunbar, A. Wolska, Tracey U. Sikora, Maria Escobar, Naomi Seliktar, Emil M Degoma, S. Derohannessian, Linda Morrell, A. McIntyre, Frances M. Burke, D. Sviridov, M. Amar, R. Shamburek, L. Freeman, R. Hegele, A. Remaley, D. Rader
Context Familial chylomicronemia syndrome (FCS) is a rare heritable disorder associated with severe hypertriglyceridemia and recurrent pancreatitis. Lipoprotein lipase deficiency and apolipoprotein C-II deficiency are two well-characterized autosomal recessive causes of FCS, and three other genes have been described to cause FCS. Because therapeutic approaches can vary according to the underlying etiology, it is important to establish the molecular etiology of FCS. Case Description A man originally from North Africa was referred to the University of Pennsylvania Lipid Clinic for severe hypertriglyceridemia and recurrent pancreatitis, consistent with the clinical diagnosis of FCS. Molecular analyses of FCS-associated genes revealed a homozygous missense variant R72T in APOC2. Molecular modeling of the variant predicted that the apolipoprotein C-II R72T peptide has reduced lipid binding affinity. In vitro studies of the patient's plasma confirmed the lack of functional apoC-II activity. Moreover, the apoC-II protein was undetectable in the patient's plasma, quantitatively as well as qualitatively. Conclusions We identified a missense APOC2 variant causing apoC-II deficiency in a patient with severe hypertriglyceridemia and recurrent pancreatitis. Beyond dietary management and usual pharmacologic therapies, an apoC-II mimetic peptide may become an optional therapy in patients with apoC-II deficiency in the future.
{"title":"A Novel APOC2 Missense Mutation Causing Apolipoprotein C-II Deficiency With Severe Triglyceridemia and Pancreatitis","authors":"M. Ueda, R. Dunbar, A. Wolska, Tracey U. Sikora, Maria Escobar, Naomi Seliktar, Emil M Degoma, S. Derohannessian, Linda Morrell, A. McIntyre, Frances M. Burke, D. Sviridov, M. Amar, R. Shamburek, L. Freeman, R. Hegele, A. Remaley, D. Rader","doi":"10.1210/jc.2016-3903","DOIUrl":"https://doi.org/10.1210/jc.2016-3903","url":null,"abstract":"Context\u0000Familial chylomicronemia syndrome (FCS) is a rare heritable disorder associated with severe hypertriglyceridemia and recurrent pancreatitis. Lipoprotein lipase deficiency and apolipoprotein C-II deficiency are two well-characterized autosomal recessive causes of FCS, and three other genes have been described to cause FCS. Because therapeutic approaches can vary according to the underlying etiology, it is important to establish the molecular etiology of FCS.\u0000\u0000\u0000Case Description\u0000A man originally from North Africa was referred to the University of Pennsylvania Lipid Clinic for severe hypertriglyceridemia and recurrent pancreatitis, consistent with the clinical diagnosis of FCS. Molecular analyses of FCS-associated genes revealed a homozygous missense variant R72T in APOC2. Molecular modeling of the variant predicted that the apolipoprotein C-II R72T peptide has reduced lipid binding affinity. In vitro studies of the patient's plasma confirmed the lack of functional apoC-II activity. Moreover, the apoC-II protein was undetectable in the patient's plasma, quantitatively as well as qualitatively.\u0000\u0000\u0000Conclusions\u0000We identified a missense APOC2 variant causing apoC-II deficiency in a patient with severe hypertriglyceridemia and recurrent pancreatitis. Beyond dietary management and usual pharmacologic therapies, an apoC-II mimetic peptide may become an optional therapy in patients with apoC-II deficiency in the future.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"26 1","pages":"1454–1457"},"PeriodicalIF":0.0,"publicationDate":"2017-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91200875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Swerdlow, Rosie Cooke, D. Beckers, B. Borgström, G. Butler, J. Carel, S. Cianfarani, P. Clayton, J. Coste, A. Deodati, E. Ecosse, R. Gausche, C. Giacomozzi, A. Hokken-Koelega, Aysha J. Khan, W. Kiess, C. Kuehni, P. Mullis, R. Pfaffle, L. Sävendahl, G. Sommer, Muriel Thomas, Anders Tidblad, S. Tollerfield, L. van Eycken, G. Zandwijken
Context Growth hormone (GH) is prescribed for an increasing range of indications, but there has been concern that it might raise cancer risk. Published data are limited. Objective To examine cancer risks in relation to GH treatment. Design Cohort study. Setting Population-based. Patients Cohort of 23,984 patients treated with recombinant human GH (r-hGH) in eight European countries since this treatment was first used in 1984. Cancer expectations from country-specific national population statistics. Main Outcome Measures Cancer incidence and cancer mortality. Results Incidence and mortality risks in the cohort were raised for several cancer sites, largely consequent on second primary malignancies in patients given r-hGH after cancer treatment. There was no clear raised risk in patients with growth failure without other major disease. Only for bone and bladder cancers was incidence significantly raised in GH-treated patients without previous cancer. Cancer risk was unrelated to duration or cumulative dose of r-hGH treatment, but for patients treated after previous cancer, cancer mortality risk increased significantly with increasing daily r-hGH dose (P trend < 0.001). Hodgkin lymphoma (HL) incidence increased significantly with longer follow-up (P trend = 0.001 for patients overall and 0.002 for patients without previous cancer). Conclusions Our results do not generally support a carcinogenic effect of r-hGH, but the unexplained trend in cancer mortality risk in relation to GH dose in patients with previous cancer, and the indication of possible effects on bone cancer, bladder cancer, and HL risks, need further investigation.
{"title":"Cancer Risks in Patients Treated With Growth Hormone in Childhood: The SAGhE European Cohort Study","authors":"A. Swerdlow, Rosie Cooke, D. Beckers, B. Borgström, G. Butler, J. Carel, S. Cianfarani, P. Clayton, J. Coste, A. Deodati, E. Ecosse, R. Gausche, C. Giacomozzi, A. Hokken-Koelega, Aysha J. Khan, W. Kiess, C. Kuehni, P. Mullis, R. Pfaffle, L. Sävendahl, G. Sommer, Muriel Thomas, Anders Tidblad, S. Tollerfield, L. van Eycken, G. Zandwijken","doi":"10.1210/jc.2016-2046","DOIUrl":"https://doi.org/10.1210/jc.2016-2046","url":null,"abstract":"Context\u0000Growth hormone (GH) is prescribed for an increasing range of indications, but there has been concern that it might raise cancer risk. Published data are limited.\u0000\u0000\u0000Objective\u0000To examine cancer risks in relation to GH treatment.\u0000\u0000\u0000Design\u0000Cohort study.\u0000\u0000\u0000Setting\u0000Population-based.\u0000\u0000\u0000Patients\u0000Cohort of 23,984 patients treated with recombinant human GH (r-hGH) in eight European countries since this treatment was first used in 1984. Cancer expectations from country-specific national population statistics.\u0000\u0000\u0000Main Outcome Measures\u0000Cancer incidence and cancer mortality.\u0000\u0000\u0000Results\u0000Incidence and mortality risks in the cohort were raised for several cancer sites, largely consequent on second primary malignancies in patients given r-hGH after cancer treatment. There was no clear raised risk in patients with growth failure without other major disease. Only for bone and bladder cancers was incidence significantly raised in GH-treated patients without previous cancer. Cancer risk was unrelated to duration or cumulative dose of r-hGH treatment, but for patients treated after previous cancer, cancer mortality risk increased significantly with increasing daily r-hGH dose (P trend < 0.001). Hodgkin lymphoma (HL) incidence increased significantly with longer follow-up (P trend = 0.001 for patients overall and 0.002 for patients without previous cancer).\u0000\u0000\u0000Conclusions\u0000Our results do not generally support a carcinogenic effect of r-hGH, but the unexplained trend in cancer mortality risk in relation to GH dose in patients with previous cancer, and the indication of possible effects on bone cancer, bladder cancer, and HL risks, need further investigation.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"19 1","pages":"1661–1672"},"PeriodicalIF":0.0,"publicationDate":"2017-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86888976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Chatelain, O. Malievskiy, K. Radziuk, G. Senatorova, Magdy O Abdou, E. Vlachopapadopoulou, Y. Skorodok, V. Peterkova, J. Leff, M. Beckert
Context TransCon Growth Hormone (GH) (Ascendis Pharma) is a long-acting recombinant sustained-release human GH prodrug in development for children with GH deficiency (GHD). Objective To compare the pharmacokinetics, pharmacodynamics, safety, and efficacy of weekly TransCon GH to that of daily GH in prepubertal children with GHD. Design Randomized, open-label, active-controlled study of three doses of weekly TransCon GH versus daily Genotropin (Pfizer). Setting Thirty-eight centers in 14 European countries and Egypt. Patients Prepubertal male and female treatment-naïve children with GHD (n = 53). Interventions Subjects received one of three TransCon GH doses (0.14, 0.21, or 0.30 mg GH/kg/wk) or Genotropin 0.03 mg GH/kg/d for 26 weeks. Main Outcome Measures GH and insulinlike growth factor-1 (IGF-1) levels, growth, adverse events, and immunogenicity. Results Both GH maximum concentration and area under the curve were similar following TransCon GH or Genotropin administration at comparable doses. A dose response was observed, with IGF-1 standard deviation scores increasing into the normal range for all three TransCon GH doses. Annualized mean height velocity for the three TransCon GH doses ranged from 11.9 cm to 13.9 cm, which was not statistically different from 11.6 cm for Genotropin. Adverse events were mild to moderate, and most were unrelated to the study drug. Injection site tolerance was good. One TransCon GH subject developed a low-titer, nonneutralizing antibody response to GH. Conclusions The results suggest that long-acting TransCon GH is comparable to daily Genotropin for GH (pharmacokinetics) and IGF-1 (pharmacodynamics) levels, safety, and efficacy and support advancement into phase 3 development.
{"title":"A Randomized Phase 2 Study of Long-Acting TransCon GH vs Daily GH in Childhood GH Deficiency","authors":"P. Chatelain, O. Malievskiy, K. Radziuk, G. Senatorova, Magdy O Abdou, E. Vlachopapadopoulou, Y. Skorodok, V. Peterkova, J. Leff, M. Beckert","doi":"10.1210/jc.2016-3776","DOIUrl":"https://doi.org/10.1210/jc.2016-3776","url":null,"abstract":"Context\u0000TransCon Growth Hormone (GH) (Ascendis Pharma) is a long-acting recombinant sustained-release human GH prodrug in development for children with GH deficiency (GHD).\u0000\u0000\u0000Objective\u0000To compare the pharmacokinetics, pharmacodynamics, safety, and efficacy of weekly TransCon GH to that of daily GH in prepubertal children with GHD.\u0000\u0000\u0000Design\u0000Randomized, open-label, active-controlled study of three doses of weekly TransCon GH versus daily Genotropin (Pfizer).\u0000\u0000\u0000Setting\u0000Thirty-eight centers in 14 European countries and Egypt.\u0000\u0000\u0000Patients\u0000Prepubertal male and female treatment-naïve children with GHD (n = 53).\u0000\u0000\u0000Interventions\u0000Subjects received one of three TransCon GH doses (0.14, 0.21, or 0.30 mg GH/kg/wk) or Genotropin 0.03 mg GH/kg/d for 26 weeks.\u0000\u0000\u0000Main Outcome Measures\u0000GH and insulinlike growth factor-1 (IGF-1) levels, growth, adverse events, and immunogenicity.\u0000\u0000\u0000Results\u0000Both GH maximum concentration and area under the curve were similar following TransCon GH or Genotropin administration at comparable doses. A dose response was observed, with IGF-1 standard deviation scores increasing into the normal range for all three TransCon GH doses. Annualized mean height velocity for the three TransCon GH doses ranged from 11.9 cm to 13.9 cm, which was not statistically different from 11.6 cm for Genotropin. Adverse events were mild to moderate, and most were unrelated to the study drug. Injection site tolerance was good. One TransCon GH subject developed a low-titer, nonneutralizing antibody response to GH.\u0000\u0000\u0000Conclusions\u0000The results suggest that long-acting TransCon GH is comparable to daily Genotropin for GH (pharmacokinetics) and IGF-1 (pharmacodynamics) levels, safety, and efficacy and support advancement into phase 3 development.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"23 1","pages":"1673–1682"},"PeriodicalIF":0.0,"publicationDate":"2017-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84841317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Nies, Mariëlle S. Klein Hesselink, G. Huizinga, E. Sulkers, A. Brouwers, J. Burgerhof, E. van Dam, B. Havekes, M. V. D. van den Heuvel-Eibrink, E. Corssmit, L. Kremer, R. Netea-Maier, H. J. van der Pal, R. Peeters, J. Plukker, C. Ronckers, H. V. van Santen, W. Tissing, T. Links, G. Bocca
Context Little is known about long-term quality of life (QoL) of survivors of pediatric differentiated thyroid carcinoma. Therefore, this study aimed to evaluate generic health-related QoL (HRQoL), fatigue, anxiety, and depression in these survivors compared with matched controls, and to evaluate thyroid cancer-specific HRQoL in survivors only. Design Survivors diagnosed between 1970 and 2013 at age ≤18 years, were included. Exclusion criteria were a follow-up <5 years, attained age <18 years, or diagnosis of DTC as a second malignant neoplasm (SMN). Controls were matched by age, sex, and socioeconomic status. Survivors and controls were asked to complete 3 questionnaires [Short-Form 36 (HRQoL), Multidimensional Fatigue Inventory 20 (fatigue), and Hospital Anxiety and Depression Scale (anxiety/depression)]. Survivors completed a thyroid cancer-specific HRQoL questionnaire. Results Sixty-seven survivors and 56 controls. Median age of survivors at evaluation was 34.2 years (range, 18.8 to 61.7). Median follow-up was 17.8 years (range, 5.0 to 44.7). On most QoL subscales, scores of survivors and controls did not differ significantly. However, survivors had more physical problems (P = 0.031), role limitations due to physical problems (P = 0.021), and mental fatigue (P = 0.016) than controls. Some thyroid cancer-specific complaints (e.g., sensory complaints and chilliness) were present in survivors. Unemployment and more extensive disease or treatment characteristics were most frequently associated with worse QoL. Conclusions Overall, long-term QoL in survivors of pediatric DTC was normal. Survivors experienced mild impairment of QoL in some domains (physical problems, mental fatigue, and various thyroid cancer-specific complaints). Factors possibly affecting QoL need further exploration.
{"title":"Long-Term Quality of Life in Adult Survivors of Pediatric Differentiated Thyroid Carcinoma","authors":"M. Nies, Mariëlle S. Klein Hesselink, G. Huizinga, E. Sulkers, A. Brouwers, J. Burgerhof, E. van Dam, B. Havekes, M. V. D. van den Heuvel-Eibrink, E. Corssmit, L. Kremer, R. Netea-Maier, H. J. van der Pal, R. Peeters, J. Plukker, C. Ronckers, H. V. van Santen, W. Tissing, T. Links, G. Bocca","doi":"10.1210/jc.2016-2246","DOIUrl":"https://doi.org/10.1210/jc.2016-2246","url":null,"abstract":"Context\u0000Little is known about long-term quality of life (QoL) of survivors of pediatric differentiated thyroid carcinoma. Therefore, this study aimed to evaluate generic health-related QoL (HRQoL), fatigue, anxiety, and depression in these survivors compared with matched controls, and to evaluate thyroid cancer-specific HRQoL in survivors only.\u0000\u0000\u0000Design\u0000Survivors diagnosed between 1970 and 2013 at age ≤18 years, were included. Exclusion criteria were a follow-up <5 years, attained age <18 years, or diagnosis of DTC as a second malignant neoplasm (SMN). Controls were matched by age, sex, and socioeconomic status. Survivors and controls were asked to complete 3 questionnaires [Short-Form 36 (HRQoL), Multidimensional Fatigue Inventory 20 (fatigue), and Hospital Anxiety and Depression Scale (anxiety/depression)]. Survivors completed a thyroid cancer-specific HRQoL questionnaire.\u0000\u0000\u0000Results\u0000Sixty-seven survivors and 56 controls. Median age of survivors at evaluation was 34.2 years (range, 18.8 to 61.7). Median follow-up was 17.8 years (range, 5.0 to 44.7). On most QoL subscales, scores of survivors and controls did not differ significantly. However, survivors had more physical problems (P = 0.031), role limitations due to physical problems (P = 0.021), and mental fatigue (P = 0.016) than controls. Some thyroid cancer-specific complaints (e.g., sensory complaints and chilliness) were present in survivors. Unemployment and more extensive disease or treatment characteristics were most frequently associated with worse QoL.\u0000\u0000\u0000Conclusions\u0000Overall, long-term QoL in survivors of pediatric DTC was normal. Survivors experienced mild impairment of QoL in some domains (physical problems, mental fatigue, and various thyroid cancer-specific complaints). Factors possibly affecting QoL need further exploration.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"18 1","pages":"1218–1226"},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91528649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Notsu, M. Yamauchi, Masahiro Yamamoto, Kiyoko Nawata, T. Sugimoto
Context Some observational studies have revealed an association between excessive aldosterone levels and reduced bone mineral density (BMD). However, whether patients with primary aldosteronism (PA) are at higher risk of fracture than healthy individuals remains unclear. Objective This study aimed to clarify whether PA represents a risk factor for vertebral fracture (VF). Design and Patients We enrolled 56 patients with PA and 56 age- and sex-matched healthy individuals. Serum and urinary biological parameters, BMD, and presence of VFs were evaluated in both groups. We compared parameters between PA and control participants and performed multiple logistic regression analyses after adjustments for variables. Results Patients with PA showed higher systolic and diastolic blood pressure, higher hemoglobin A1c (HbA1c) and triglycerides, higher urinary calcium-to-creatinine ratio, and lower high-density lipoprotein cholesterol than controls (P < 0.05, each). Prevalence of VFs was significantly higher in patients with PA (44.6%) than in controls (23.2%, P < 0.05). Patients with PA showed severe fracture more frequently than controls. Multivariate logistic regression analyses adjusted for age, sex, and body mass index identified PA as being associated with the presence of VFs (odds ratio, 3.13; 95% confidence interval, 1.30 to 7.51; P < 0.05). This association remained statistically significant after further adjustment for systolic and diastolic blood pressure, HbA1c, triglycerides, and high-density lipoprotein cholesterol but not after adjustment for calcium-to-creatinine ratio and BMD. Conclusions We identified PA as a risk factor for VF, independent of blood pressure, HbA1c, and lipid profile. Fracture severity was significantly higher in patients with PA than in age- and sex-matched controls.
{"title":"Primary Aldosteronism as a Risk Factor for Vertebral Fracture","authors":"M. Notsu, M. Yamauchi, Masahiro Yamamoto, Kiyoko Nawata, T. Sugimoto","doi":"10.1210/jc.2016-3206","DOIUrl":"https://doi.org/10.1210/jc.2016-3206","url":null,"abstract":"Context\u0000Some observational studies have revealed an association between excessive aldosterone levels and reduced bone mineral density (BMD). However, whether patients with primary aldosteronism (PA) are at higher risk of fracture than healthy individuals remains unclear.\u0000\u0000\u0000Objective\u0000This study aimed to clarify whether PA represents a risk factor for vertebral fracture (VF).\u0000\u0000\u0000Design and Patients\u0000We enrolled 56 patients with PA and 56 age- and sex-matched healthy individuals. Serum and urinary biological parameters, BMD, and presence of VFs were evaluated in both groups. We compared parameters between PA and control participants and performed multiple logistic regression analyses after adjustments for variables.\u0000\u0000\u0000Results\u0000Patients with PA showed higher systolic and diastolic blood pressure, higher hemoglobin A1c (HbA1c) and triglycerides, higher urinary calcium-to-creatinine ratio, and lower high-density lipoprotein cholesterol than controls (P < 0.05, each). Prevalence of VFs was significantly higher in patients with PA (44.6%) than in controls (23.2%, P < 0.05). Patients with PA showed severe fracture more frequently than controls. Multivariate logistic regression analyses adjusted for age, sex, and body mass index identified PA as being associated with the presence of VFs (odds ratio, 3.13; 95% confidence interval, 1.30 to 7.51; P < 0.05). This association remained statistically significant after further adjustment for systolic and diastolic blood pressure, HbA1c, triglycerides, and high-density lipoprotein cholesterol but not after adjustment for calcium-to-creatinine ratio and BMD.\u0000\u0000\u0000Conclusions\u0000We identified PA as a risk factor for VF, independent of blood pressure, HbA1c, and lipid profile. Fracture severity was significantly higher in patients with PA than in age- and sex-matched controls.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"84 1","pages":"1237–1243"},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76792787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N. S. Hansen, K. S. Strasko, Line Hjort, L. Kelstrup, Azadeh Houshmand-Øregaard, M. Schrölkamp, Heidi S Schultz, C. Schéele, B. Pedersen, C. Ling, T. Clausen, P. Damm, A. Vaag, C. Broholm
Context Offspring of women with gestational diabetes (O-GDM) or type 1 diabetes mellitus (O-T1DM) have been exposed to hyperglycemia in utero and have an increased risk of developing metabolic disease in adulthood. Design In total, we recruited 206 adult offspring comprising the two fetal hyperglycemic groups, O-GDM and O-T1DM, and, as a control group, offspring from the background population (O-BP). Subcutaneous fat biopsies were obtained and preadipocyte cell cultures were established from adult male O-GDM (n = 18, age 30.1 ± 2.5 years), O-T1DM (n = 18, age 31.6 ± 2.2 years), and O-BP (n = 16; age, 31.5 ± 2.7 years) and cultured in vitro. Main Outcome Measures First, we studied in vivo adipocyte histology. Second, we studied in vitro preadipocyte leptin secretion, gene expression, and LEP DNA methylation. This was studied in combination with in vitro preadipocyte lipogenesis, lipolysis, and mitochondrial respiration. Results We show that subcutaneous adipocytes from O-GDM are enlarged compared with O-BP adipocytes. Preadipocytes isolated from male O-GDM and O-T1DM and cultured in vitro displayed decreased LEP promoter methylation, increased leptin gene expression, and elevated leptin secretion throughout differentiation, compared with adipocytes established from male O-BP. In addition, the preadipocytes demonstrated functional defects including decreased maximal mitochondrial capacity with increased lipolysis and decreased ability to store fatty acids when challenged with 3 days of extra fatty acid supply. Conclusions Taken together, these findings show that intrinsic epigenetic and functional changes exist in preadipocyte cultures from individuals exposed to fetal hyperglycemia who are at increased risk of developing metabolic disease.
{"title":"Fetal Hyperglycemia Changes Human Preadipocyte Function in Adult Life","authors":"N. S. Hansen, K. S. Strasko, Line Hjort, L. Kelstrup, Azadeh Houshmand-Øregaard, M. Schrölkamp, Heidi S Schultz, C. Schéele, B. Pedersen, C. Ling, T. Clausen, P. Damm, A. Vaag, C. Broholm","doi":"10.1210/jc.2016-3907","DOIUrl":"https://doi.org/10.1210/jc.2016-3907","url":null,"abstract":"Context\u0000Offspring of women with gestational diabetes (O-GDM) or type 1 diabetes mellitus (O-T1DM) have been exposed to hyperglycemia in utero and have an increased risk of developing metabolic disease in adulthood.\u0000\u0000\u0000Design\u0000In total, we recruited 206 adult offspring comprising the two fetal hyperglycemic groups, O-GDM and O-T1DM, and, as a control group, offspring from the background population (O-BP). Subcutaneous fat biopsies were obtained and preadipocyte cell cultures were established from adult male O-GDM (n = 18, age 30.1 ± 2.5 years), O-T1DM (n = 18, age 31.6 ± 2.2 years), and O-BP (n = 16; age, 31.5 ± 2.7 years) and cultured in vitro.\u0000\u0000\u0000Main Outcome Measures\u0000First, we studied in vivo adipocyte histology. Second, we studied in vitro preadipocyte leptin secretion, gene expression, and LEP DNA methylation. This was studied in combination with in vitro preadipocyte lipogenesis, lipolysis, and mitochondrial respiration.\u0000\u0000\u0000Results\u0000We show that subcutaneous adipocytes from O-GDM are enlarged compared with O-BP adipocytes. Preadipocytes isolated from male O-GDM and O-T1DM and cultured in vitro displayed decreased LEP promoter methylation, increased leptin gene expression, and elevated leptin secretion throughout differentiation, compared with adipocytes established from male O-BP. In addition, the preadipocytes demonstrated functional defects including decreased maximal mitochondrial capacity with increased lipolysis and decreased ability to store fatty acids when challenged with 3 days of extra fatty acid supply.\u0000\u0000\u0000Conclusions\u0000Taken together, these findings show that intrinsic epigenetic and functional changes exist in preadipocyte cultures from individuals exposed to fetal hyperglycemia who are at increased risk of developing metabolic disease.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"65 1","pages":"1141–1150"},"PeriodicalIF":0.0,"publicationDate":"2017-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87844926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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