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1
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García‐Campos C, Modesto‐Mata M, Martinón‐Torres M, Martín‐Francés L, Martínez de Pinillos M, Arsuaga JL, Bermúdez de Castro JM. Similarities and differences in the dental tissue proportions of the deciduous and permanent canines of Early and Middle Pleistocene human populations. J Anat 2022; 240:339-356. [PMID: 34611899 PMCID: PMC8742968 DOI: 10.1111/joa.13558] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 11/28/2022] Open
Abstract
The two- and three-dimensional assessment of dental tissues has become routine in human taxonomic studies throughout the years. Nonetheless, most of our knowledge of the variability of the enamel and dentine dimensions of the human evolutionary lineage comes from the study of permanent dentition, and particularly from molars. This leads to a biased view of the variability of these features. Due to their early formation and rapid development, the deciduous teeth allow more simplified inferences regarding the processes involved in the dental tissue development of each group. Therefore, their study could be very valuable in dental palaeohistology. In this research, we have explored the dental tissue proportions of the deciduous canines belonging to some human samples of the Early and Middle Pleistocene. The purpose of this was to discuss the meaning of the similarities and differences observed in their histological pattern, as well as to evaluate the degree of covariance with that observed in the permanent dentition of these populations. Our results show that, although there are some similarities in the dental tissue proportions between the deciduous and permanent canines of the study samples, the two dental classes do not provide a similar or comparable pictures of the dental tissue pattern present in the dentition of fossil hominins. Future works on the dental tissue patterns of the anterior and posterior dentition, including deciduous teeth, of fossil samples, may help to shed light on this hypothesis.
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Affiliation(s)
| | | | - María Martinón‐Torres
- Centro Nacional de Investigación sobre la Evolución HumanaBurgosSpain
- Anthropology DepartmentUniversity College LondonLondonUK
| | - Laura Martín‐Francés
- Centro Nacional de Investigación sobre la Evolución HumanaBurgosSpain
- Anthropology DepartmentUniversity College LondonLondonUK
- Institut Català de Paleoecologia Humana i Evolució Social (IPHES)TarragonaSpain
| | | | - Juan Luis Arsuaga
- Centro MixtoUCM‐ISCIII de Evolución y Comportamiento HumanosMadridSpain
| | - José María Bermúdez de Castro
- Centro Nacional de Investigación sobre la Evolución HumanaBurgosSpain
- Anthropology DepartmentUniversity College LondonLondonUK
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2
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Johannsson G, Ragnarsson O. Growth hormone deficiency in adults with hypopituitarism-What are the risks and can they be eliminated by therapy? J Intern Med 2021; 290:1180-1193. [PMID: 34605087 DOI: 10.1111/joim.13382] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Growth hormone (GH) deficiency develops early in patients with hypothalamic-pituitary disorders and is therefore common among these patients. GH deficiency in adults is associated with increased morbidity, increased body fat mass, abdominal obesity, dyslipidaemia, reduced exercise capacity, impaired cardiac function as well as reduced self-reported well-being and impaired quality of life. Since recombinant human GH became available as replacement therapy more than 25 years ago, randomised controlled trials and long-term studies, together with meta-analyses, have shown improved outcomes in adult patients with hypopituitarism receiving GH. Many of the features associated with GH deficiency in adults improve, or even normalize, and the safety profile is reassuring. The increased interest in GH deficiency in adults with hypothalamic-pituitary disorders has also contributed to the identification of other factors of importance for an outcome such as the replacement of other pituitary hormone deficiencies, and the management of the underlying hypothalamic-pituitary disease, most commonly a pituitary tumour. In this narrative review, we summarize the burden of GH deficiency in adults with hypopituitarism, the impact of GH replacement on the outcome, as well as safety. Based on currently available data, GH replacement should be considered routine management of adults with hypopituitarism.
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Affiliation(s)
- Gudmundur Johannsson
- Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Oskar Ragnarsson
- Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden
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3
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Wang W, Duan X, Huang Z, Pan Q, Chen C, Guo L. The GH-IGF-1 Axis in Circadian Rhythm. Front Mol Neurosci 2021; 14:742294. [PMID: 34566581 PMCID: PMC8458700 DOI: 10.3389/fnmol.2021.742294] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 08/23/2021] [Indexed: 11/13/2022] Open
Abstract
Organisms have developed common behavioral and physiological adaptations to the influence of the day/night cycle. The CLOCK system forms an internal circadian rhythm in the suprachiasmatic nucleus (SCN) during light/dark input. The SCN may synchronize the growth hormone (GH) secretion rhythm with the dimming cycle through somatostatin neurons, and the change of the clock system may be related to the pulsatile release of GH. The GH-insulin-like growth factor 1 (IGF-1) axis and clock system may interact further on the metabolism through regulatory pathways in peripheral organs. We have summarized the current clinical and animal evidence on the interaction of clock systems with the GH-IGF-1 axis and discussed their effects on metabolism.
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Affiliation(s)
- Weihao Wang
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaoye Duan
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhengxiang Huang
- School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia
| | - Qi Pan
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Chen Chen
- School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia
| | - Lixin Guo
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
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4
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Towards Understanding the Direct and Indirect Actions of Growth Hormone in Controlling Hepatocyte Carbohydrate and Lipid Metabolism. Cells 2021; 10:cells10102532. [PMID: 34685512 PMCID: PMC8533955 DOI: 10.3390/cells10102532] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 09/20/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
Growth hormone (GH) is critical for achieving normal structural growth. In addition, GH plays an important role in regulating metabolic function. GH acts through its GH receptor (GHR) to modulate the production and function of insulin-like growth factor 1 (IGF1) and insulin. GH, IGF1, and insulin act on multiple tissues to coordinate metabolic control in a context-specific manner. This review will specifically focus on our current understanding of the direct and indirect actions of GH to control liver (hepatocyte) carbohydrate and lipid metabolism in the context of normal fasting (sleep) and feeding (wake) cycles and in response to prolonged nutrient deprivation and excess. Caveats and challenges related to the model systems used and areas that require further investigation towards a clearer understanding of the role GH plays in metabolic health and disease are discussed.
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5
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Kojima M, Degawa M. Androgen-Dependent Differences in the Amounts of CYP mRNAs in the Pig Kidney. Biol Pharm Bull 2021; 44:1120-1128. [PMID: 34334497 DOI: 10.1248/bpb.b21-00333] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We previously reported androgen-dependent sex and breed differences in the amounts of mRNAs of CYP isoforms in the pig liver. To clarify whether there are such sex and breed differences in the kidney, we examined the amounts of several CYP mRNAs in the kidney using both sexes of 5-month-old Landrace, Meishan and/or their crossbred F1 (LM and ML) pigs. Significant sex differences in the amounts of several CYP mRNAs were found: male < female for CYP2A19 and CYP3A29; and male > female for CYP4A24/25 in all the breeds. Sex differences in the amount of CYP2B22 mRNA (male < female) and in CYP2C33 and CYP2C49 mRNAs (male > female) were also observed in all the breeds except Landrace pigs. Furthermore, a significant sex difference (male < female) in CYP3A46 mRNA was only found in LM and ML pigs. No significant sex differences were found in either Landrace or Meishan pigs for CYP1A1, CYP1A2 and CYP4B1 mRNAs. The amounts of CYP2C33 and CYP4A24/25 mRNAs in males were higher in Meishan pigs than in Landrace pigs. Additional experiments using pigs treated by castration and/or testosterone propionate indicated that sex and breed differences in the amounts of those CYP mRNAs were, at least in part, dependent on the levels of serum testosterone. Furthermore, the effects of androgen on the amounts of CYP mRNAs in the kidney did not necessarily correlate with those in the liver, suggesting that there is a tissue-selective factor responsible for the androgen-related expression of CYP genes.
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Affiliation(s)
- Misaki Kojima
- Animal Genome Unit, Institute of Livestock and Grassland Science, National Agriculture and Food Research Organization (NARO)
| | - Masakuni Degawa
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka
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6
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Strength training and growth hormone: effects on bone of Wistar rats. SPORT SCIENCES FOR HEALTH 2021. [DOI: 10.1007/s11332-021-00784-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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7
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Caputo M, Pigni S, Agosti E, Daffara T, Ferrero A, Filigheddu N, Prodam F. Regulation of GH and GH Signaling by Nutrients. Cells 2021; 10:1376. [PMID: 34199514 PMCID: PMC8227158 DOI: 10.3390/cells10061376] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 02/06/2023] Open
Abstract
Growth hormone (GH) and insulin-like growth factor-1 (IGF-I) are pleiotropic hormones with important roles in lifespan. They promote growth, anabolic actions, and body maintenance, and in conditions of energy deprivation, favor catabolic feedback mechanisms switching from carbohydrate oxidation to lipolysis, with the aim to preserve protein storages and survival. IGF-I/insulin signaling was also the first one identified in the regulation of lifespan in relation to the nutrient-sensing. Indeed, nutrients are crucial modifiers of the GH/IGF-I axis, and these hormones also regulate the complex orchestration of utilization of nutrients in cell and tissues. The aim of this review is to summarize current knowledge on the reciprocal feedback among the GH/IGF-I axis, macro and micronutrients, and dietary regimens, including caloric restriction. Expanding the depth of information on this topic could open perspectives in nutrition management, prevention, and treatment of GH/IGF-I deficiency or excess during life.
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Affiliation(s)
- Marina Caputo
- SCDU of Endocrinology, University Hospital Maggiore della Carità, 28100 Novara, Italy; (M.C.); (S.P.); (T.D.); (A.F.)
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy;
| | - Stella Pigni
- SCDU of Endocrinology, University Hospital Maggiore della Carità, 28100 Novara, Italy; (M.C.); (S.P.); (T.D.); (A.F.)
| | - Emanuela Agosti
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy;
| | - Tommaso Daffara
- SCDU of Endocrinology, University Hospital Maggiore della Carità, 28100 Novara, Italy; (M.C.); (S.P.); (T.D.); (A.F.)
| | - Alice Ferrero
- SCDU of Endocrinology, University Hospital Maggiore della Carità, 28100 Novara, Italy; (M.C.); (S.P.); (T.D.); (A.F.)
| | - Nicoletta Filigheddu
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy;
| | - Flavia Prodam
- SCDU of Endocrinology, University Hospital Maggiore della Carità, 28100 Novara, Italy; (M.C.); (S.P.); (T.D.); (A.F.)
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy;
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8
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Minhoto GB, Khoury RD, Orozco EIF, Prado RF, Valera MC. Effect of chronic unpredictable stress on the progression of experimental apical periodontitis in rats. Int Endod J 2021; 54:1342-1352. [PMID: 33724486 DOI: 10.1111/iej.13515] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 03/08/2021] [Accepted: 03/12/2021] [Indexed: 11/29/2022]
Abstract
AIM To establish an experimental model combining chronic stress and apical periodontitis by assessing the development of periapical lesions in rats in three different time points. METHODOLOGY Forty-eight male Wistar rats were randomly assigned into two equal groups: Apical periodontitis (AP) and AP + Stress (AP + S). The animals of the AP group were not exposed to stressful conditions whereas the AP + S group were exposed to a variety of stressors on a daily basis until the end of the experiment. After three weeks of chronic unpredictable stress, apical periodontitis was induced in both groups by exposing the pulpal tissue of the mandibular first molar to the oral environment. Each group was further subdivided into three subgroups according to the euthanasia period: 14, 21 and 28 days after pulp exposure. The animals were weighed, and the blood was collected for corticosterone serum dosage by radioimmunoassay. The mandibles were removed and submitted to histopathological and microtomography analyses to assess the inflammatory response and the progression of periapical lesions. Comparisons between the AP and AP + S groups were performed using Student's t-test and Mann-Whitney U-test for parametric and nonparametric data, respectively. The one-way anova test followed by Tukey's test (parametric data) and Kruskal-Wallis followed by Dunn's test (nonparametric data) were used for comparisons between the three time points within the same group (P < 0.05). RESULTS The AP + S group had a significantly lower average percentage of weight gain at 14 days and 21 days after AP induction (P < 0.05). Significantly higher levels of corticosterone were found in the AP + S group at 21 days (P < 0.05). The AP + S group had a significantly greater intensity and extension of inflammatory infiltrate with larger areas of bone loss compared to the AP groups at 21 days (P < 0.05). The volume of the periapical lesions in the AP + S group was significantly larger than that of the AP group 21 days following pulp exposure (P < 0.05). CONCLUSIONS The chronic unpredictable stress model applied for 6 weeks exacerbated the inflammatory response and increased bone loss associated with AP, especially 21 days after its induction. This model appears to be suitable for investigating the bidirectional relationship between apical periodontitis and chronic stress.
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Affiliation(s)
- G B Minhoto
- Endodontic Division, Department of Restorative Dentistry, Institute of Science and Technology, São Paulo State University - UNESP, São José dos Campos, São Paulo, Brazil
| | - R D Khoury
- Endodontic Division, Department of Restorative Dentistry, Institute of Science and Technology, São Paulo State University - UNESP, São José dos Campos, São Paulo, Brazil
| | - E I F Orozco
- Endodontic Division, Department of Restorative Dentistry, Institute of Science and Technology, São Paulo State University - UNESP, São José dos Campos, São Paulo, Brazil
| | - R F Prado
- Endodontic Division, Department of Restorative Dentistry, Institute of Science and Technology, São Paulo State University - UNESP, São José dos Campos, São Paulo, Brazil
| | - M C Valera
- Endodontic Division, Department of Restorative Dentistry, Institute of Science and Technology, São Paulo State University - UNESP, São José dos Campos, São Paulo, Brazil
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9
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Sorkina EL, Chichkova VV, Sklyanik IA, Shestakova MV, Mel'nichenko GA, Barkan A. [The role of glucose and insulin in the metabolic regulation of growth hormone secretion]. ACTA ACUST UNITED AC 2021; 67:52-59. [PMID: 33586392 PMCID: PMC8926113 DOI: 10.14341/probl12660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 01/12/2021] [Accepted: 01/21/2021] [Indexed: 11/17/2022]
Abstract
The exact physiological basis for the suppression of growth hormone secretion by oral glucose intake remains unknown, despite the widespread use of the oral glucose tolerance test in endocrinology. Lack of growth hormone suppression by glucose occurs in about a third of patients with acromegaly, as well as in other disorders. It is currently known that the secretion of growth hormone is affected by various factors, such as age, gender, body mass index, and the redistribution of adipose tissue. There is also evidence of the impact of overeating as well as being overweight on the secretion of growth hormone. It is known that both of these conditions are associated with hyperinsulinemia, which determines the possibility of its predominant role in suppressing the secretion of growth hormone. The purpose of this review is to discuss the accumulated data on the isolated effects of hyperglycemia and hyperinsulinemia on growth hormone secretion, as well as other metabolic regulators and conditions affecting its signaling. Understanding of the pathophysiological basis of these mechanisms is essential for further research of the role of glucose and insulin in the metabolic regulation of growth hormone secretion. However, the studies in animal models are complicated by interspecific differences in the response of growth hormone to glucose loading, and the only possible available model in healthy people may be the hyperinsulinemic euglycemic clamp.
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Affiliation(s)
| | | | | | | | | | - A Barkan
- University of Michigan, Ann Arbor
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10
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Heaton AL, Kelly C, Rood J, Tam CS, Greenway FL. Mechanism for the Increase in Human Growth Hormone with Administration of a Novel Test Supplement and Results Indicating Improved Physical Fitness and Sleep Efficiency. J Med Food 2020; 24:653-659. [PMID: 33030391 DOI: 10.1089/jmf.2020.0109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
An oral test supplement increases serum human growth hormone (hGH) levels after acute administration in healthy adults. We investigated the mechanism for the increase in hGH and the effect of continued daily administration of the test supplement on measures of physical fitness and sleep efficiency. In Study 1, serum triiodothyronine (T3) was measured in samples from a prior placebo-controlled, double-blind study in which 16 healthy participants received both placebo and the test supplement in a crossover design; treatment order was randomized, and treatments were separated by a 1-week washout. In Study 2, physical fitness (VO2 max) was measured at baseline and after 2 weeks of daily administration of the test supplement (N = 12 healthy participants). Study 3 assessed daily sleep onset latency and time awake during 3 weeks of daily administration of the test supplement (N = 15 healthy participants). A fall from baseline in T3 was observed with placebo (-6.1 ± 8.5 ng/dL, P = .01). Of note, the change in T3 was smaller with the test supplement (-3.3 ± 10.7 ng/dL, P = not significant) but was not statistically different from placebo. Mean VO2 max increased by 6% from baseline after 2 weeks (P = .02). Sleep-onset latency and time awake during the night were reduced from baseline to week 3 by 22% and 65%, respectively (P = .01 and P = .02). The conservation of T3 levels suggests that the mechanism for increased hGH secretion by the test supplement is through somatostatin inhibition. Furthermore, pilot studies indicated that daily administration of the supplement improved physical fitness and sleep efficiency from baseline, effects consistent with increased endogenous hGH release. Clinical Trial Registration No. NCT02987868.
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Affiliation(s)
- Amy L Heaton
- Pennington Biomedical Research Center, LSU System, Baton Rouge, Louisiana, USA.,Sierra Research Group, LLC, Salt Lake City, Utah, USA
| | - Colleen Kelly
- Kelly Statistical Consulting, Carlsbad, California, USA
| | - Jennifer Rood
- Pennington Biomedical Research Center, LSU System, Baton Rouge, Louisiana, USA
| | - Charmaine S Tam
- Pennington Biomedical Research Center, LSU System, Baton Rouge, Louisiana, USA
| | - Frank L Greenway
- Pennington Biomedical Research Center, LSU System, Baton Rouge, Louisiana, USA
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11
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Præstholm SM, Correia CM, Grøntved L. Multifaceted Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks and Metabolism. Front Endocrinol (Lausanne) 2020; 11:572981. [PMID: 33133019 PMCID: PMC7578419 DOI: 10.3389/fendo.2020.572981] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 09/03/2020] [Indexed: 12/14/2022] Open
Abstract
Glucocorticoids (GCs) and the glucocorticoid receptor (GR) are important regulators of development, inflammation, stress response and metabolism, demonstrated in various diseases including Addison's disease, Cushing's syndrome and by the many side effects of prolonged clinical administration of GCs. These conditions include severe metabolic challenges in key metabolic organs like the liver. In the liver, GR is known to regulate the transcription of key enzymes in glucose and lipid metabolism and contribute to the regulation of circadian-expressed genes. Insights to the modes of GR regulation and the underlying functional mechanisms are key for understanding diseases and for the development of improved clinical uses of GCs. The activity and function of GR is regulated at numerous levels including ligand availability, interaction with heat shock protein (HSP) complexes, expression of GR isoforms and posttranslational modifications. Moreover, recent genomics studies show functional interaction with multiple transcription factors (TF) and coregulators in complex transcriptional networks controlling cell type-specific gene expression by GCs. In this review we describe the different regulatory steps important for GR activity and discuss how different TF interaction partners of GR selectively control hepatic gene transcription and metabolism.
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Affiliation(s)
| | | | - Lars Grøntved
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
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12
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Qian Y, Shao Q, Xu Q, Qiao H. Pharmacokinetics of Recombinant Human Growth Hormone (rhGH) in Beagles by ELISA. CURR PHARM ANAL 2020. [DOI: 10.2174/1573412915666190709094740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background::
Somatropin is recombinant human growth (GH) used for the treatment of
growth failure in children and GH deficiency in adults. At present, rhGH marketed in China is mostly
freeze-dried powder injection. As the lyophilization process is unstable, time-consuming and costly,
rhGH has been prepared into an aqueous solution for administering directly.
Introduction::
In this study, the pharmacokinetics of two dosage forms of rhGH in beagle dogs after
single subcutaneous administration was determined by enzyme-linked immunosorbent assay (ELISA).
Methods:
Twelve healthy beagles (male, 6:female, 6) were used for the pharmacokinetic study and
were equally divided into two groups. Subcutaneous injection of 0.2 IU/kg with rhGH in the two formulations.
The blood samples were taken from forearms, 0, 0.033, 0.083, 0.25, 0.5, 1, 2, 3, 4, 7, 10, 24 h
and collected the beagle plasma on time. The pharmacokinetic parameters of rhGH after subcutaneous
(s.c.) injection were determined experimentally on beagles. Primary PK endpoints were area under the
serum concentration-time curve (AUC0-t) and maximum serum concentration (Cmax). Serum rhGH level
was determined by enzyme-linked immunosorbent assay.
Results::
The calibration curves obtained were linear over the concentration range of 25 to 1600 ng/ml
for recombinant human growth. The results of the intra- and inter-day precision and accuracy studies
were well within the acceptable limits. The analysis samples were stable under different storage conditions
and temperature.
Conclusions::
The developed ELISA method has been successfully applied to the studies of pharmacokinetic
of recombinant human growth hormone in beagles.
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Affiliation(s)
- Yueyue Qian
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China
| | - Qing Shao
- Jiangsu Provincial Institute of Materia Medica, Nanjing 211816, China
| | - Quanyu Xu
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China
| | - Hongqun Qiao
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China
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13
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Adamis D, Coada I, Eikelenboom P, Chu CS, Finn K, Melvin V, Williams J, Meagher DJ, McCarthy G. Delirium, insulin-like growth factor I, growth hormone in older inpatients. World J Psychiatry 2020; 10:212-222. [PMID: 33014722 PMCID: PMC7515747 DOI: 10.5498/wjp.v10.i9.212] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 06/16/2020] [Accepted: 08/25/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Delirium is a common disorder in elderly medical inpatients with serious adverse outcomes and is characterized by sudden onset, disturbance in attention, awareness, consciousness and cognition, and often with behavioural disturbances. Central to understanding delirium, is understanding mechanisms by which body and brain wellbeing are linked and in particular how brain responses to bodily homeostatic stress is mediated. A number of studies have investigated the relationship between insulin-like growth factor I (IGF-I) and delirium in medically ill hospitalised patients with conflicting results. However, none have investigated growth hormone (GH) which is related to IGF-I via negative feedback.
AIM To investigate the relationship between serum levels of IGF-I and GH, and the occurrence of delirium.
METHODS Prospective, longitudinal, observational study. Consecutive elderly inpatients (aged 70+), were assessed twice weekly with Montreal cognitive assessment (MoCA), Confusion assessment method (CAM), Acute Physiology and Chronic Health Evaluation II. Delirium was defined using CAM. Previous history of dementia was evaluated with the Informant Questionnaire on Cognitive Decline in the Elderly. IGF-I and GH levels were estimated with the ELISA method. Generalized estimating equations (GEE) model was applied for the first five assessments to analyze those longitudinal data.
RESULTS The sample consisted of 198 participants (mean age 80.63 ± 6.81; range 70-97). Of these 92 (46.5%) were females. Eighty six (43.4%) were identified with a history of dementia. Incident or prevalent delirium during hospitalisation was identified with CAM in 40 participants (20.2%). Evaluation of missing values with Little's MCAR test indicated that they were missing completely at random (MCAR χ2 = 12.24, u: 9, P = 0.20). Using GEE for the analysis we found that low MoCA scores, low levels of IGF-I and high levels of GH were significantly associated with any delirium (prevalence, incident, or fluctuating , during the study period (Wald χ2 = 12.231; u: 1, P < 0.001, Wald χ2 = 7.196, u: 1, P = 0.007, Wald χ2 = 6.210; : u: 1, P = 0.013 respectively).
CONCLUSION The results show that low levels of IGF-I, high levels of GH and low scores in cognition are independently associated with the occurrence of any delirium during the hospitalisation of medically ill older people. The results of the study supports the hypothesis that deficits in the immunoreactivity of the brain (low cerebral reserve) may be associated with delirium.
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Affiliation(s)
- Dimitrios Adamis
- Department of Psychiatry, Sligo/Leitrim Mental Health Services, Sligo F91 CD34, Ireland
- Department of Psychiatry, Research and Academic Institute of Athens, Athens 11742, Greece
- Department of Psychiatry, University Hospital Limerick, Limerick V94 F858, Ireland
| | - Iulian Coada
- Department of Psychiatry, Sligo/Leitrim Mental Health Services, Sligo F91 CD34, Ireland
| | - Piet Eikelenboom
- Department of Psychiatry, GGZinGeest and VuMC, Amsterdam 1081 HV, the Netherlands
| | - Che-Sheng Chu
- Department of Psychiatry and Center for Geriatric and Gerontology, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
| | - Karen Finn
- Department of Biopharmaceutical and Medical Science, School of Science and Computing, Galway-Mayo Institute of Technology, Galway H91 T8NW, Ireland
| | - Vincent Melvin
- Department of Psychiatry, Sligo/Leitrim Mental Health Services, Sligo F91 CD34, Ireland
| | - John Williams
- Department of Pathology, Sligo University Hospital, Sligo F91 H684, Ireland
| | - David James Meagher
- Department of Psychiatry, University Hospital Limerick, Limerick V94 F858, Ireland
| | - Geraldine McCarthy
- Department of Psychiatry, Sligo/Leitrim Mental Health Services, Sligo F91 CD34, Ireland
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14
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Störmann S, Schopohl J. Drug treatment strategies for secondary diabetes in patients with acromegaly. Expert Opin Pharmacother 2020; 21:1883-1895. [PMID: 32633582 DOI: 10.1080/14656566.2020.1789098] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
INTRODUCTION Acromegaly is a rare disease due to oversecretion of growth hormone (GH). Even though the disease is often portrayed by its most apparent clinical features, given the abundance of GH receptors throughout the body, it truly is a systemic disease leading to numerous complications and comorbidities. A distinct medical issue in the context of acromegaly is diabetes: It can be a complication as a consequence of GH excess and its mediators, but it can also result from treatment of acromegaly. AREAS COVERED This review provides an overview of the effects of acromegaly pathophysiology on glucose homeostasis. Furthermore, it devotes an extensive section on the influence that acromegaly treatment has on glucose metabolism, including approved as well as currently investigated drugs. It also summarizes observations from the use of anti-diabetic medication in patients with acromegaly. EXPERT OPINION Glucose imbalance is an important aspect of acromegaly comorbidity and deserves more attention. Even though numerous studies have investigated glucose homeostasis in acromegaly, there is still a clear need for more basic, translational, and also clinical research to advance the understanding of the underlying mechanisms and how to best address them.
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Affiliation(s)
- Sylvère Störmann
- Klinikum der Universität München, Medizinische Klinik und Poliklinik IV , München, Germany
| | - Jochen Schopohl
- Klinikum der Universität München, Medizinische Klinik und Poliklinik IV , München, Germany
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15
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van Esdonk MJ, Burggraaf J, van der Graaf PH, Stevens J. Model informed quantification of the feed-forward stimulation of growth hormone by growth hormone-releasing hormone. Br J Clin Pharmacol 2020; 86:1575-1584. [PMID: 32087619 PMCID: PMC7373696 DOI: 10.1111/bcp.14265] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 09/27/2019] [Accepted: 11/05/2019] [Indexed: 12/21/2022] Open
Abstract
Aims Growth hormone (GH) secretion is pulsatile and secretion varies highly between individuals. To understand and ultimately predict GH secretion, it is important to first delineate and quantify the interaction and variability in the biological processes underlying stimulated GH secretion. This study reports on the development of a population nonlinear mixed effects model for GH stimulation, incorporating individual GH kinetics and the stimulation of GH by GH‐releasing hormone (GHRH). Methods Literature data on the systemic circulation, the median eminence, and the anterior pituitary were included as system parameters in the model. Population parameters were estimated on data from 8 healthy normal weight and 16 obese women who received a 33 μg recombinant human GH dose. The next day, a bolus injection of 100 μg GHRH was given to stimulate GH secretion. Results The GH kinetics were best described with the addition of 2 distribution compartments with a bodyweight dependent clearance (increasing linearly from 24.7 L/h for a 60‐kg subject to 32.1 L/h for a 100‐kg subject). The model described the data adequately with high parameter precision and significant interindividual variability on the GH clearance and distribution volume. Additionally, high variability in the amount of secreted GH, driven by GHRH receptor activation, was identified (coefficient of variation = 90%). Conclusion The stimulation of GH by GHRH was quantified and significant interindividual variability was identified on multiple parameters. This model sets the stage for further development of by inclusion of additional physiological components to quantify GH secretion in humans.
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Affiliation(s)
- Michiel J van Esdonk
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.,Centre for Human Drug Research, Leiden, The Netherlands
| | - Jacobus Burggraaf
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.,Centre for Human Drug Research, Leiden, The Netherlands
| | - Piet H van der Graaf
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.,Certara QSP, Canterbury, UK
| | - Jasper Stevens
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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16
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Keenan DM, Pichler Hefti J, Veldhuis JD, Von Wolff M. Regulation and adaptation of endocrine axes at high altitude. Am J Physiol Endocrinol Metab 2020; 318:E297-E309. [PMID: 31770013 DOI: 10.1152/ajpendo.00243.2019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
As a model of extreme conditions, eight healthy women, part of a 40-member Nepal mountain-climbing expedition, were monitored for dynamic endocrine adaptations. Endocrine measurements were made at frequent intervals over a 6-10-h period at four altitudes: 450 m, 4,800 m (base camp), 6,050 m, and again at 4,800 m (on descent) after an acclimatization (A) period (4,800 mA). Quantified hormones were growth hormone (GH), prolactin (PROL), cortisol (Cort), thyroid-stimulating hormone (TSH), and free thyroxine. These hormones are important to the anabolic/catabolic balance of the body, and are vital to growth, homeostasis, hypothalamic inhibition, regulation of stress, and metabolism. A key secondary question was the degree to which acclimatization can stabilize hormonal disruption. On the basis of statistical false discovery rates, the present analyses unveil marked adaptive changes in the thyroid axis at the level of pulsatile secretion of the pituitary hormone TSH and its downstream product, free thyroxine; strong effects on the mass of GH, TSH, Cort, and PROL secretion per burst; and prominent pulsatile frequency disruption and recovery for PROL and Cort. Because pulsatility changes reflect de facto perturbations in hypothalamo-pituitary control mechanisms, the present data introduce the concept of both frequency- and amplitude-dependent adaptive control of brain-pituitary neuroendocrine signals under conditions of extreme altitude exertion and exposure.
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Affiliation(s)
- Daniel M Keenan
- Department of Statistics, University of Virginia, Charlottesville, Virginia
| | - Jacqueline Pichler Hefti
- Department of Pulmonary Medicine, University Hospital and University of Berne, Inselspital, Berne, Switzerland
| | - Johannes D Veldhuis
- Department of Medicine, Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota
| | - Michael Von Wolff
- Women's University Hospital, Department of Gynecological endocrinology and Reproductive Medicine, Berne, Switzerland
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17
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Yuan T, Ying J, Jin L, Li C, Gui S, Li Z, Wang R, Zuo Z, Zhang Y. The role of serum growth hormone and insulin-like growth factor-1 in adult humans brain morphology. Aging (Albany NY) 2020; 12:1377-1396. [PMID: 31967977 PMCID: PMC7053622 DOI: 10.18632/aging.102688] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 12/25/2019] [Indexed: 04/11/2023]
Abstract
Growth hormone (GH) and its anabolic mediator, insulin-like growth factor-1 (IGF-1), have a critical role in the central nervous system. However, their detailed roles in the adult human brain are not clear. In this study, structural MRIs of 48 patients with GH-secreting pituitary adenoma (GH-PA), 48 sex- and age-matched clinical Non-Functional pituitary adenoma patients (NonFun-PA) and healthy controls (HCs) were assessed using voxel-based morphometry (VBM) and region-based morphometry (RBM). Correlation analyses helped determine the relationships between serum hormone levels and brain structure. The whole-brain gray matter volume (GMV) and white matter volume (WMV) significantly increased at the expense of cerebrospinal fluid volume (CSFV) in GH-PA (Bonferroni corrected, p<0.01). The increase in GMV and reduction in CSFV were significantly correlated with serum GH/IGF-1 levels (p<0.05). VBM showed significant correlations of the GMV/WMV alteration pattern between GH-PA vs HCs and GH-PA vs NonFun-PA and widespread bilateral clusters of significantly increased GMV and WMV in GH-PA (pFDR<0.05). RBM showed obviously increased GMV/WMV in 54 of 68 brain regions (p<0.05) in GH-PA compared to HCs. Our results provide imaging evidence that serum GH/IGF-1 contributes to brain growth, which may be a potential treatment option for neurodegenerative disorders and brain injury in humans.
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Affiliation(s)
- Taoyang Yuan
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Jianyou Ying
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Lu Jin
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Chuzhong Li
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Songbai Gui
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Zhenye Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Rui Wang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Zhentao Zuo
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Beijing, China
- Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China
| | - Yazhuo Zhang
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Institute for Brain Disorders, Brain Tumour Center, China National Clinical Research Center for Neurological Diseases, Key Laboratory of Central Nervous System Injury Research, Beijing, China
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18
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Pierce JR, Martin BJ, Rarick KR, Alemany JA, Staab JS, Kraemer WJ, Hymer WC, Nindl BC. Growth Hormone and Insulin-like Growth Factor-I Molecular Weight Isoform Responses to Resistance Exercise Are Sex-Dependent. Front Endocrinol (Lausanne) 2020; 11:571. [PMID: 32973684 PMCID: PMC7472848 DOI: 10.3389/fendo.2020.00571] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 07/13/2020] [Indexed: 11/25/2022] Open
Abstract
Purpose: To determine if acute resistance exercise-induced increases in growth hormone (GH) and insulin-like growth factor-I (IGF-I) were differentially responsive for one or more molecular weight (MW) isoforms and if these responses were sex-dependent. Methods: College-aged men (n = 10) and women (n = 10) performed an acute resistance exercise test (ARET; 6 sets, 10 repetition maximum (10-RM) squat, 2-min inter-set rest). Serum aliquots from blood drawn Pre-, Mid-, and Post-ARET (0, +15, and +30-min post) were processed using High Performance Liquid Chromatography (HPLC) fractionation and pooled into 3 MW fractions (Fr.A: >60; Fr.B: 30-60; Fr.C: <30 kDa). Results: We observed a hierarchy of serum protein collected among GH fractions across all time points independent of sex (Fr.C > Fr.A > Fr.B, p ≤ 0.03). Sex × time interactions indicated that women experienced earlier and augmented increases in all serum GH MW isoform fraction pools (p < 0.05); however, men demonstrated delayed and sustained GH elevations (p < 0.01) in all fractions through +30-min of recovery. Similarly, we observed a sex-independent hierarchy among IGF-I MW fraction pools (Fr.A > Fr.B > Fr.C, p ≤ 0.01). Furthermore, we observed increases in IGF-I Fr. A (ternary complexes) in men only (p ≤ 0.05), and increases in Fr.C (free/unbound IGF-I) in women only (p ≤ 0.05) vs. baseline, respectively. Conclusions: These data indicate that the processing of GH and IGF-I isoforms from the somatotrophs and hepatocytes are differential in their response to strenuous resistance exercise and reflect both temporal and sex-related differences.
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Affiliation(s)
- Joseph R. Pierce
- Military Performance Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, United States
- *Correspondence: Joseph R. Pierce
| | - Brian J. Martin
- Neuromuscular Research Laboratory/Warrior Human Performance Research Center, Department of Sports Medicine and Nutrition, University of Pittsburgh, Pittsburgh, PA, United States
| | - Kevin R. Rarick
- Military Performance Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, United States
| | - Joseph A. Alemany
- Military Performance Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, United States
| | - Jeffery S. Staab
- Military Performance Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, United States
| | - William J. Kraemer
- Department of Kinesiology, University of Connecticut, Mansfield, CT, United States
| | - Wesley C. Hymer
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, United States
| | - Bradley C. Nindl
- Military Performance Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA, United States
- Neuromuscular Research Laboratory/Warrior Human Performance Research Center, Department of Sports Medicine and Nutrition, University of Pittsburgh, Pittsburgh, PA, United States
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19
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Bolamperti S, Guidobono F, Rubinacci A, Villa I. The Role of Growth Hormone in Mesenchymal Stem Cell Commitment. Int J Mol Sci 2019; 20:ijms20215264. [PMID: 31652811 PMCID: PMC6862273 DOI: 10.3390/ijms20215264] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 10/18/2019] [Accepted: 10/21/2019] [Indexed: 12/16/2022] Open
Abstract
Growth hormone (GH) is best known for its prominent role in promoting prepubertal growth and in regulating body composition and metabolism during adulthood. In recent years, the possible role of GH in the modulation of mesenchymal stem cell (MSC) commitment has gained interest. MSCs, characterized by active self-renewal and differentiation potential, express GH receptors. In MSCs derived from different adult tissues, GH induces an inhibition of adipogenic differentiation and favors MSC differentiation towards osteogenesis. This activity of GH indicates that regulation of body composition by GH has already started in the tissue progenitor cells. These findings have fostered research on possible uses of MSCs treated with GH in those pathologies, where a lack of or delays in bone repair occur. After an overview of GH activities, this review will focus on the research that has characterized GH’s effects on MSCs and on preliminary studies on the possible application of GH in bone regenerative medicine.
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Affiliation(s)
- Simona Bolamperti
- Bone Metabolism Unit, Division of Genetics & Cell Biology, IRCCS Ospedale San Raffaele, 20132 Milan, Italy.
| | - Francesca Guidobono
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy.
| | - Alessandro Rubinacci
- Bone Metabolism Unit, Division of Genetics & Cell Biology, IRCCS Ospedale San Raffaele, 20132 Milan, Italy.
| | - Isabella Villa
- Bone Metabolism Unit, Division of Genetics & Cell Biology, IRCCS Ospedale San Raffaele, 20132 Milan, Italy.
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20
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Affiliation(s)
- Shlomo Melmed
- From the Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles
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21
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Dosouto C, Calaf J, Polo A, Haahr T, Humaidan P. Growth Hormone and Reproduction: Lessons Learned From Animal Models and Clinical Trials. Front Endocrinol (Lausanne) 2019; 10:404. [PMID: 31297089 PMCID: PMC6607366 DOI: 10.3389/fendo.2019.00404] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 06/06/2019] [Indexed: 01/13/2023] Open
Abstract
Growth Hormone (GH) has been considered as a therapeutic option to increase the number of growing follicles during Assisted Reproductive Technology (ART) for more than 30 years. In this review the biological rationale for therapeutic GH usage is explained through evidence in animal models, aiming to put this into a clinical context. First, we explain the GH-Insulin like Growth Factor (IGF)-1-gonadal axis and its role in reproduction. Evidence suggests that GH can stimulate the secretion of IGF1 not only in the liver but also in the peripheral target structures, including the ovary. Moreover, IGF-1 can be secreted locally under the influence of stimuli other than GH. In the case of the ovary, steroid hormones, gonadotropins or the combination of both seems to be involved. Even more interesting, the ovary itself can secret GH locally and exert a paracrine action modulating the intracellular signaling pathway of GH, i.e., not by the systemic pathway where GH binds to the extracellular domain of the GH receptor. Finally, these aspects from animal models are put into clinical perspective by discussing results and shortcomings of studies and meta-analyses in order to put forth the state-of-the-art rationale for therapeutic GH usage in modern ART.
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Affiliation(s)
- Carlos Dosouto
- Obstetrics, Gynecology and Reproductive Medicine, Hospital de la Santa Creu I Sant Pau- Fundació Puigvert, Barcelona, Spain
- Faculty of Medicine, Autonomous University of Barcelona, Barcelona, Spain
- *Correspondence: Carlos Dosouto
| | - Joaquim Calaf
- Obstetrics, Gynecology and Reproductive Medicine, Hospital de la Santa Creu I Sant Pau- Fundació Puigvert, Barcelona, Spain
- Faculty of Medicine, Autonomous University of Barcelona, Barcelona, Spain
| | - Ana Polo
- Obstetrics, Gynecology and Reproductive Medicine, Hospital de la Santa Creu I Sant Pau- Fundació Puigvert, Barcelona, Spain
- Faculty of Medicine, Autonomous University of Barcelona, Barcelona, Spain
| | - Thor Haahr
- The Fertility Clinic Skive Regional Hospital, Skive, Denmark
- Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Peter Humaidan
- The Fertility Clinic Skive Regional Hospital, Skive, Denmark
- Faculty of Health, Aarhus University, Aarhus, Denmark
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22
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Pamphlett R, Kum Jew S, Doble PA, Bishop DP. Elemental Analysis of Aging Human Pituitary Glands Implicates Mercury as a Contributor to the Somatopause. Front Endocrinol (Lausanne) 2019; 10:419. [PMID: 31297094 PMCID: PMC6607410 DOI: 10.3389/fendo.2019.00419] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 06/12/2019] [Indexed: 12/22/2022] Open
Abstract
Background: Growth hormone levels often decline on aging, and this "somatopause" is associated with muscle and bone loss, visceral adiposity and impaired cardiovascular function. Mercury has been detected in human pituitary glands, so to see if mercury could play a part in the somatopause we measured the proportion of people at different ages who had mercury in their anterior pituitary cells. Materials and methods: Paraffin sections of pituitary glands taken at autopsy from 94 people between the ages of 2 and 99 years were stained for inorganic mercury using autometallography. Pituitary mercury content was classified as none, low (<30% of cells) or high (>30% of cells) in increasing two-decade age groups. Autometallography combined with immunohistochemistry determined which hormone-producing cells contained mercury. Laser ablation-inductively coupled plasma-mass spectrometry was used to confirm the presence of mercury. Results: The proportion of people with low-content pituitary mercury remained between 33 and 42% at all ages. The proportion of people with high-content mercury increased with increasing age, from 0% of people in the 2-20 year group to a peak of 50% of people in the 61-80 years group, followed by a fall to 35% of people in the 81-99 years group. Mercury, when present, was found always in somatotrophs, occasionally in corticotrophs, rarely in thyrotrophs and gonadotrophs, and never in lactotrophs. Laser ablation-inductively coupled plasma-mass spectrometry detected mercury in regions of pituitaries that stained with autometallography. Conclusions: The proportion of people with mercury in their anterior pituitary cells, mostly somatotrophs, increases with aging, suggesting that mercury toxicity could be one factor contributing to the decline in growth hormone levels found in advancing age.
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Affiliation(s)
- Roger Pamphlett
- Discipline of Pathology, Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
- Department of Neuropathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
- *Correspondence: Roger Pamphlett
| | - Stephen Kum Jew
- Discipline of Pathology, Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Philip A. Doble
- The Atomic Medicine Initiative, University of Technology, Sydney, NSW, Australia
| | - David P. Bishop
- The Atomic Medicine Initiative, University of Technology, Sydney, NSW, Australia
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23
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Hage M, Kamenický P, Chanson P. Growth Hormone Response to Oral Glucose Load: From Normal to Pathological Conditions. Neuroendocrinology 2019; 108:244-255. [PMID: 30685760 DOI: 10.1159/000497214] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 01/24/2019] [Indexed: 11/19/2022]
Abstract
The exact physiological basis of acute growth hormone (GH) suppression by oral glucose is not fully understood. Glucose-mediated increase in hypothalamic somatostatin seems to be the most plausible explanation. Attempts to better understand its underlying mechanisms are compromised by species disparities in the response of GH to glucose load. While in humans, glucose inhibits GH release, the acute elevation of circulating glucose levels in rats has either no effect on GH secretion or may be stimulatory. Likewise, chronic hyperglycemia alters GH release in both humans and rats nonetheless in opposite directions. Several factors influence nadir GH concentrations including, age, gender, body mass index, pubertal age, and the type of assay used. Besides the classical suppressive effects of glucose on GH release, a paradoxical GH increase to oral glucose may be observed in around one third of patients with acromegaly as well as in various other disorders. Though its pathophysiology is poorly characterized, an altered interplay between somatostatin and GH-releasing hormone has been suggested and a link with pituitary ectopic expression of glucose-dependent insulinotropic polypeptide receptor has been recently demonstrated. A better understanding of the dynamics mediating GH response to glucose may allow a more optimal use of the OGTT as a diagnostic tool in various conditions, especially acromegaly.
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Affiliation(s)
- Mirella Hage
- Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, Institut National de la Santé et de la Recherche Médicale (Inserm) U1185, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Peter Kamenický
- Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, Institut National de la Santé et de la Recherche Médicale (Inserm) U1185, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Philippe Chanson
- Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, Institut National de la Santé et de la Recherche Médicale (Inserm) U1185, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France,
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24
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Zhang X, Yang JK, Chen C. Enhanced Pulsatile Growth Hormone Secretion and Altered Metabolic Hormones by in Vivo Hexarelin Treatment in Streptozotocin-Induced Diabetic Rats. Int J Mol Sci 2018; 19:ijms19103067. [PMID: 30297647 PMCID: PMC6213236 DOI: 10.3390/ijms19103067] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 09/21/2018] [Accepted: 10/03/2018] [Indexed: 12/30/2022] Open
Abstract
Significant growth hormone (GH) reductions have been reported in diabetic animal models with disturbed metabolic balance coinciding with GH deficiency. Therefore, enhanced GH secretion may have beneficial effects in controlling diabetes. Thus, we aim to investigate the effect of hexarelin, a synthetic GH secretagogue (GHS), on GH secretion in streptozotocin (STZ, 65 mg/kg)-induced diabetic rats. Daily hexarelin (100 μg/kg) treatment was performed for two weeks in four-week-long STZ-diabetic and vehicle control rats. Pulsatile GH secretion in STZ-rats was significantly reduced in total, pulsatile, basal, and mass of GH secretion per burst. In addition, impaired GH secretion was followed by an increase in fasting-level free fatty acids (FFAs) and a decrease in insulin-like growth factor 1 (IGF-1) compared to control rats. After hexarelin treatment, pulsatile GH secretion in STZ-rats was significantly increased in total, pulsatile, and basal, but not in the mass GH secretion per burst, compared to STZ-rats without hexarelin treatment. However, there was no significant elevation in GH secretion in the hexarelin-treated control group. In addition, hexarelin-treated STZ-rats showed a significant decrease in fasting level FFAs, whereas suppression of fasting level for IGF-1 was maintained. These results suggest that STZ-induced diabetic rats have impaired pulsatile GH secretion, causing increased FFAs and decreased IGF-1 levels in circulation. Hexarelin injections for two weeks is able to normalize impaired pulsatile GH secretion with normal fasting levels of FFAs, but fails to recover IGF-1 levels.
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Affiliation(s)
- Xinli Zhang
- School of Biomedical Sciences, University of Queensland, St Lucia, Brisbane, QLD 4072, Australia.
| | - Jin-Kui Yang
- School of Medicine, Faculty of Medicine, Capital Medical University, Beijing 100730, China.
| | - Chen Chen
- School of Biomedical Sciences, University of Queensland, St Lucia, Brisbane, QLD 4072, Australia.
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25
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Dong A, Liu S, Li Y. Gap Junctions in the Nervous System: Probing Functional Connections Using New Imaging Approaches. Front Cell Neurosci 2018; 12:320. [PMID: 30283305 PMCID: PMC6156252 DOI: 10.3389/fncel.2018.00320] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 09/03/2018] [Indexed: 11/13/2022] Open
Abstract
Gap junctions are channels that physically connect adjacent cells, mediating the rapid exchange of small molecules, and playing an essential role in a wide range of physiological processes in nearly every system in the body, including the nervous system. Thus, altered function of gap junctions has been linked with a plethora of diseases and pathological conditions. Being able to measure and characterize the distribution, function, and regulation of gap junctions in intact tissue is therefore essential for understanding the physiological and pathophysiological roles that gap junctions play. In recent decades, several robust in vitro and in vivo methods have been developed for detecting and characterizing gap junctions. Here, we review the currently available methods with respect to invasiveness, signal-to-noise ratio, temporal resolution and others, highlighting the recently developed chemical tracers and hybrid imaging systems that use novel chemical compounds and/or genetically encoded enzymes, transporters, channels, and fluorescent proteins in order to map gap junctions. Finally, we discuss possible avenues for further improving existing techniques in order to achieve highly sensitive, cell type-specific, non-invasive measures of in vivo gap junction function with high throughput and high spatiotemporal resolution.
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Affiliation(s)
- Ao Dong
- State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China.,PKU-IDG/McGovern Institute for Brain Research, Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Simin Liu
- State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China.,PKU-IDG/McGovern Institute for Brain Research, Beijing, China
| | - Yulong Li
- State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China.,PKU-IDG/McGovern Institute for Brain Research, Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
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García‐Campos C, Martinón‐Torres M, Martín‐Francés L, Martínez de Pinillos M, Modesto‐Mata M, Perea‐Pérez B, Zanolli C, Labajo González E, Sánchez Sánchez JA, Ruiz Mediavilla E, Tuniz C, Bermúdez de Castro JM. Contribution of dental tissues to sex determination in modern human populations. AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY 2018; 166:459-472. [DOI: 10.1002/ajpa.23447] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 02/05/2018] [Accepted: 02/06/2018] [Indexed: 11/10/2022]
Affiliation(s)
- Cecilia García‐Campos
- Departamento de Paleobiología de Homínidos, Centro Nacional de Investigación sobre la Evolución HumanaPaseo de la Sierra de Atapuerca 3, Burgos09002 Spain
- Anthropology DepartmentUniversity College LondonLondonWC1H 0BW United Kingdom
| | - María Martinón‐Torres
- Departamento de Paleobiología de Homínidos, Centro Nacional de Investigación sobre la Evolución HumanaPaseo de la Sierra de Atapuerca 3, Burgos09002 Spain
- Anthropology DepartmentUniversity College LondonLondonWC1H 0BW United Kingdom
| | - Laura Martín‐Francés
- Departamento de Paleobiología de Homínidos, Centro Nacional de Investigación sobre la Evolución HumanaPaseo de la Sierra de Atapuerca 3, Burgos09002 Spain
- De la Préhistoire à l'Actuel : Culture, Environnement et Anthropologie, University of Bordeaux, CNRS, MCC, PACEA, UMR 5199 F_33615Pessac Cedex France
| | - Marina Martínez de Pinillos
- Departamento de Paleobiología de Homínidos, Centro Nacional de Investigación sobre la Evolución HumanaPaseo de la Sierra de Atapuerca 3, Burgos09002 Spain
- Anthropology DepartmentUniversity College LondonLondonWC1H 0BW United Kingdom
| | - Mario Modesto‐Mata
- Departamento de Paleobiología de Homínidos, Centro Nacional de Investigación sobre la Evolución HumanaPaseo de la Sierra de Atapuerca 3, Burgos09002 Spain
- Anthropology DepartmentUniversity College LondonLondonWC1H 0BW United Kingdom
- Equipo Primeros Pobladores de Extremadura, Casa de la Cultura Rodríguez MoñinoCáceres Spain
| | - Bernardo Perea‐Pérez
- Laboratorio de Antropología Forense, Escuela de Medicina Legal y ForenseUniversidad Complutense de Madrid Spain
| | - Clément Zanolli
- Laboratoire d'Anthropobiologie Moléculaire et d'Imagerie de Synthèse, UMR 5288 CNRS, University Toulouse III—Paul Sabatier France
| | - Elena Labajo González
- Laboratorio de Antropología Forense, Escuela de Medicina Legal y ForenseUniversidad Complutense de Madrid Spain
| | | | - Elena Ruiz Mediavilla
- Laboratorio de Antropología Forense, Escuela de Medicina Legal y ForenseUniversidad Complutense de Madrid Spain
| | - Claudio Tuniz
- Multidisciplinary Laboratory, International Centre for Theoretical Physics (ICTP) of TriesteTrieste Italy
| | - José María Bermúdez de Castro
- Departamento de Paleobiología de Homínidos, Centro Nacional de Investigación sobre la Evolución HumanaPaseo de la Sierra de Atapuerca 3, Burgos09002 Spain
- Anthropology DepartmentUniversity College LondonLondonWC1H 0BW United Kingdom
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Bianchi VE, Locatelli V, Rizzi L. Neurotrophic and Neuroregenerative Effects of GH/IGF1. Int J Mol Sci 2017; 18:ijms18112441. [PMID: 29149058 PMCID: PMC5713408 DOI: 10.3390/ijms18112441] [Citation(s) in RCA: 148] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 11/06/2017] [Accepted: 11/09/2017] [Indexed: 12/12/2022] Open
Abstract
Introduction. Human neurodegenerative diseases increase progressively with age and present a high social and economic burden. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are both growth factors exerting trophic effects on neuronal regeneration in the central nervous system (CNS) and peripheral nervous system (PNS). GH and IGF-1 stimulate protein synthesis in neurons, glia, oligodendrocytes, and Schwann cells, and favor neuronal survival, inhibiting apoptosis. This study aims to evaluate the effect of GH and IGF-1 on neurons, and their possible therapeutic clinical applications on neuron regeneration in human subjects. Methods. In the literature, we searched the clinical trials and followed up studies in humans, which have evaluated the effect of GH/IGF-1 on CNS and PNS. The following keywords have been used: “GH/IGF-1” associated with “neuroregeneration”, “amyotrophic lateral sclerosis”, “Alzheimer disease”, “Parkinson’s disease”, “brain”, and “neuron”. Results. Of the retrieved articles, we found nine articles about the effect of GH in healthy patients who suffered from traumatic brain injury (TBI), and six studies (four using IGF-1 and two GH therapy) in patients with amyotrophic lateral sclerosis (ALS). The administration of GH in patients after TBI showed a significantly positive recovery of brain and mental function. Treatment with GH and IGF-1 therapy in ALS produced contradictory results. Conclusions. Although strong findings have shown the positive effects of GH/IGF-1 administration on neuroregeneration in animal models, a very limited number of clinical studies have been conducted in humans. GH/IGF-1 therapy had different effects in patients with TBI, evidencing a high recovery of neurons and clinical outcome, while in ALS patients, the results are contradictory. More complex clinical protocols are necessary to evaluate the effect of GH/IGF-1 efficacy in neurodegenerative diseases. It seems evident that GH and IGF-1 therapy favors the optimal recovery of neurons when a consistent residual activity is still present. Furthermore, the effect of GH/IGF-1 could be mediated by, or be overlapped with that of other hormones, such as estradiol and testosterone.
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Affiliation(s)
- Vittorio Emanuele Bianchi
- Endocrinology and Metabolism, Clinical Center Stella Maris, Strada Rovereta, 42-47891 Falciano, San Marino.
| | - Vittorio Locatelli
- School of Medicine and Surgery, University of Milano-Bicocca via Cadore, 48-20900 Monza Brianza, Italy.
| | - Laura Rizzi
- Molecular Biology, School of Medicine and Surgery, University of Milano-Bicocca, via Cadore, 48-20900 Monza Brianza, Italy.
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Assessing the Impact of Insulin Glargine and Detemir Treatment to Serum Total IGF1 Levels in the Insulin-Naive Type 2 Diabetic Patients. Metab Syndr Relat Disord 2017; 15:220-225. [DOI: 10.1089/met.2017.0005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
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Lecoq AL, Zizzari P, Hage M, Decourtye L, Adam C, Viengchareun S, Veldhuis JD, Geoffroy V, Lombès M, Tolle V, Guillou A, Karhu A, Kappeler L, Chanson P, Kamenický P. Mild pituitary phenotype in 3- and 12-month-old Aip-deficient male mice. J Endocrinol 2016; 231:59-69. [PMID: 27621108 DOI: 10.1530/joe-16-0190] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 08/08/2016] [Indexed: 12/30/2022]
Abstract
Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene predispose humans to pituitary adenomas, particularly of the somatotroph lineage. Mice with global heterozygous inactivation of Aip (Aip(+/-)) also develop pituitary adenomas but differ from AIP-mutated patients by the high penetrance of pituitary disease. The endocrine phenotype of these mice is unknown. The aim of this study was to determine the endocrine phenotype of Aip(+/-) mice by assessing the somatic growth, ultradian pattern of GH secretion and IGF1 concentrations of longitudinally followed male mice at 3 and 12 months of age. As the early stages of pituitary tumorigenesis are controversial, we also studied the pituitary histology and somatotroph cell proliferation in these mice. Aip(+/-) mice did not develop gigantism but exhibited a leaner phenotype than wild-type mice. Analysis of GH pulsatility by deconvolution in 12-month-old Aip(+/-) mice showed a mild increase in total GH secretion, a conserved GH pulsatility pattern, but a normal IGF1 concentration. No pituitary adenomas were detected up to 12 months of age. An increased ex vivo response to GHRH of pituitary explants from 3-month-old Aip(+/-) mice, together with areas of enlarged acini identified on reticulin staining in the pituitary of some Aip(+/-) mice, was suggestive of somatotroph hyperplasia. Global heterozygous Aip deficiency in mice is accompanied by subtle increase in GH secretion, which does not result in gigantism. The absence of pituitary adenomas in 12-month-old Aip(+/-) mice in our experimental conditions demonstrates the important phenotypic variability of this congenic mouse model.
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Affiliation(s)
- Anne-Lise Lecoq
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France
| | - Philippe Zizzari
- Inserm U894Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Mirella Hage
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France
| | - Lyvianne Decourtye
- Sorbonne UniversitésUniv Paris 06 UMRS 938, Inserm U938, CDR Saint-Antoine, Paris, France
| | - Clovis Adam
- Assistance Publique-Hôpitaux de ParisService d'Anatomie et Cytologie Pathologiques, Hôpital Bicêtre, Le Kremlin Bicêtre, France
| | - Say Viengchareun
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France
| | - Johannes D Veldhuis
- Department of MedicineEndocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Valérie Geoffroy
- Inserm U1132Hôpital Lariboisière, Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Marc Lombès
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France
| | - Virginie Tolle
- Inserm U894Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Anne Guillou
- Unité Mixte de Recherche-5203Centre National de la Recherche Scientifique, Institut de Génomique Fonctionnelle, Montpellier, France
| | - Auli Karhu
- Department of Medical GeneticsGenome-Scale Biology Research Program Biomedicum, University of Helsinki, Helsinki, Finland
| | - Laurent Kappeler
- Sorbonne UniversitésUniv Paris 06 UMRS 938, Inserm U938, CDR Saint-Antoine, Paris, France
| | - Philippe Chanson
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France Assistance Publique-Hôpitaux de ParisService d'Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre, Le Kremlin Bicêtre, France
| | - Peter Kamenický
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France Assistance Publique-Hôpitaux de ParisService d'Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre, Le Kremlin Bicêtre, France
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Steyn FJ, Tolle V, Chen C, Epelbaum J. Neuroendocrine Regulation of Growth Hormone Secretion. Compr Physiol 2016; 6:687-735. [PMID: 27065166 DOI: 10.1002/cphy.c150002] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This article reviews the main findings that emerged in the intervening years since the previous volume on hormonal control of growth in the section on the endocrine system of the Handbook of Physiology concerning the intra- and extrahypothalamic neuronal networks connecting growth hormone releasing hormone (GHRH) and somatostatin hypophysiotropic neurons and the integration between regulators of food intake/metabolism and GH release. Among these findings, the discovery of ghrelin still raises many unanswered questions. One important event was the application of deconvolution analysis to the pulsatile patterns of GH secretion in different mammalian species, including Man, according to gender, hormonal environment and ageing. Concerning this last phenomenon, a great body of evidence now supports the role of an attenuation of the GHRH/GH/Insulin-like growth factor-1 (IGF-1) axis in the control of mammalian aging.
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Affiliation(s)
- Frederik J Steyn
- University of Queensland Centre for Clinical Research and the School of Biomedical Sciences, University of Queensland, St. Lucia, Brisbane, Queensland, Australia
| | - Virginie Tolle
- Unité Mixte de Recherche en Santé 894 INSERM, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Chen Chen
- School of Biomedical Sciences, University of Queensland, St. Lucia, Brisbane, Queensland, Australia
| | - Jacques Epelbaum
- University of Queensland Centre for Clinical Research and the School of Biomedical Sciences, University of Queensland, St. Lucia, Brisbane, Queensland, Australia
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Mirza F, Canalis E. Management of endocrine disease: Secondary osteoporosis: pathophysiology and management. Eur J Endocrinol 2015; 173:R131-51. [PMID: 25971649 PMCID: PMC4534332 DOI: 10.1530/eje-15-0118] [Citation(s) in RCA: 202] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 05/12/2015] [Indexed: 12/14/2022]
Abstract
Osteoporosis is a skeletal disorder characterized by decreased mass and compromised bone strength predisposing to an increased risk of fractures. Although idiopathic osteoporosis is the most common form of osteoporosis, secondary factors may contribute to the bone loss and increased fracture risk in patients presenting with fragility fractures or osteoporosis. Several medical conditions and medications significantly increase the risk for bone loss and skeletal fragility. This review focuses on some of the common causes of osteoporosis, addressing the underlying mechanisms, diagnostic approach and treatment of low bone mass in the presence of these conditions.
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Affiliation(s)
- Faryal Mirza
- Division of Endocrinology and MetabolismDepartments of MedicineOrthopaedic SurgeryUConn Musculoskeletal Institute, UConn Health, 263 Farmington Avenue, Farmington, Connecticut 06030-5456, USA
| | - Ernesto Canalis
- Division of Endocrinology and MetabolismDepartments of MedicineOrthopaedic SurgeryUConn Musculoskeletal Institute, UConn Health, 263 Farmington Avenue, Farmington, Connecticut 06030-5456, USA Division of Endocrinology and MetabolismDepartments of MedicineOrthopaedic SurgeryUConn Musculoskeletal Institute, UConn Health, 263 Farmington Avenue, Farmington, Connecticut 06030-5456, USA
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32
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Murray PG, Higham CE, Clayton PE. 60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-GH axis: the past 60 years. J Endocrinol 2015; 226:T123-40. [PMID: 26040485 DOI: 10.1530/joe-15-0120] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/03/2015] [Indexed: 12/19/2022]
Abstract
At the time of the publication of Geoffrey Harris's monograph on 'Neural control of the pituitary gland' 60 years ago, the pituitary was recognised to produce a growth factor, and extracts administered to children with hypopituitarism could accelerate growth. Since then our understanding of the neuroendocrinology of the GH axis has included identification of the key central components of the GH axis: GH-releasing hormone and somatostatin (SST) in the 1970s and 1980s and ghrelin in the 1990s. Characterisation of the physiological control of the axis was significantly advanced by frequent blood sampling studies in the 1980s and 1990s; the pulsatile pattern of GH secretion and the factors that influenced the frequency and amplitude of the pulses have been defined. Over the same time, spontaneously occurring and targeted mutations in the GH axis in rodents combined with the recognition of genetic causes of familial hypopituitarism demonstrated the key factors controlling pituitary development. As the understanding of the control of GH secretion advanced, developments of treatments for GH axis disorders have evolved. Administration of pituitary-derived human GH was followed by the introduction of recombinant human GH in the 1980s, and, more recently, by long-acting GH preparations. For GH excess disorders, dopamine agonists were used first followed by SST analogues, and in 2005 the GH receptor blocker pegvisomant was introduced. This review will cover the evolution of these discoveries and build a picture of our current understanding of the hypothalamo-GH axis.
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Affiliation(s)
- P G Murray
- Centre for Paediatrics and Child HealthInstitute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, M13 9WL, UKDepartment of Paediatric EndocrinologyRoyal Manchester Children's Hospital, Central Manchester Foundation Hospitals NHS Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UKDepartment of EndocrinologyThe Christie Hospital NHS Foundation Trust, Manchester, M20 4BX, UKCentre for Endocrinology and DiabetesInstitute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, M13 9WL, UK Centre for Paediatrics and Child HealthInstitute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, M13 9WL, UKDepartment of Paediatric EndocrinologyRoyal Manchester Children's Hospital, Central Manchester Foundation Hospitals NHS Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UKDepartment of EndocrinologyThe Christie Hospital NHS Foundation Trust, Manchester, M20 4BX, UKCentre for Endocrinology and DiabetesInstitute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, M13 9WL, UK
| | - C E Higham
- Centre for Paediatrics and Child HealthInstitute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, M13 9WL, UKDepartment of Paediatric EndocrinologyRoyal Manchester Children's Hospital, Central Manchester Foundation Hospitals NHS Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UKDepartment of EndocrinologyThe Christie Hospital NHS Foundation Trust, Manchester, M20 4BX, UKCentre for Endocrinology and DiabetesInstitute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, M13 9WL, UK Centre for Paediatrics and Child HealthInstitute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, M13 9WL, UKDepartment of Paediatric EndocrinologyRoyal Manchester Children's Hospital, Central Manchester Foundation Hospitals NHS Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UKDepartment of EndocrinologyThe Christie Hospital NHS Foundation Trust, Manchester, M20 4BX, UKCentre for Endocrinology and DiabetesInstitute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, M13 9WL, UK
| | - P E Clayton
- Centre for Paediatrics and Child HealthInstitute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, M13 9WL, UKDepartment of Paediatric EndocrinologyRoyal Manchester Children's Hospital, Central Manchester Foundation Hospitals NHS Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UKDepartment of EndocrinologyThe Christie Hospital NHS Foundation Trust, Manchester, M20 4BX, UKCentre for Endocrinology and DiabetesInstitute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, M13 9WL, UK Centre for Paediatrics and Child HealthInstitute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, M13 9WL, UKDepartment of Paediatric EndocrinologyRoyal Manchester Children's Hospital, Central Manchester Foundation Hospitals NHS Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UKDepartment of EndocrinologyThe Christie Hospital NHS Foundation Trust, Manchester, M20 4BX, UKCentre for Endocrinology and DiabetesInstitute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, M13 9WL, UK
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Glad CAM, Carlsson LMS, Melander O, Almgren P, Sjöström L, Nilsson S, Larsson I, Svensson PA, Johannsson G. The GH receptor exon 3 deleted/full-length polymorphism is associated with central adiposity in the general population. Eur J Endocrinol 2015; 172:123-8. [PMID: 25391539 DOI: 10.1530/eje-14-0723] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE To test the hypothesis that the GH receptor (GHR) exon 3 deleted (d3)/full-length (fl) polymorphism influences anthropometry and body composition in the general population. DESIGN AND SETTING The Swedish Obese Subjects (SOS) reference study is a cross-sectional population-based study, randomly selected from a population registry. A subgroup of the population-based Malmö Diet and Cancer study (MDC-CC) was used as a replication cohort. METHODS The SOS reference study comprises 1135 subjects (46.2% men), with an average age of 49.5 years. The MDC-CC includes 5451 successfully genotyped subjects (41.5% men), with an average age of 57.5 years. GHR d3/fl genotypes were determined using TagSNP rs6873545. Linear regression analyses were used to test for genotype-phenotype associations. RESULTS In the SOS reference study, subjects homozygous for the d3-GHR weighed ∼4 kg more (P=0.011), and had larger waist-to-hip ratio (WHR, P=0.036), larger waist circumference (P=0.016), and more fat-free mass estimated from total body potassium (P=0.026) than grouped fl/d3 and fl/fl subjects (d3-recessive genetic model). The association with WHR was replicated in the MDC-CC (P=0.002), but not those with other anthropometric traits. CONCLUSIONS In this population-based study, the GHR d3/fl polymorphism was found to be of functional relevance and associated with central adiposity, such that subjects homozygous for the d3-GHR showed an increased abdominal obesity.
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Affiliation(s)
- Camilla A M Glad
- Departments of EndocrinologyMolecular and Clinical MedicineInstitute of Medicine, The Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Vita Stråket 15, SE-413 45 Gothenburg, SwedenDepartment of Clinical SciencesLund University, Malmö, SwedenDepartment of Mathematical StatisticsChalmers University of Technology, Gothenburg, SwedenDepartment of EndocrinologyDiabetology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Lena M S Carlsson
- Departments of EndocrinologyMolecular and Clinical MedicineInstitute of Medicine, The Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Vita Stråket 15, SE-413 45 Gothenburg, SwedenDepartment of Clinical SciencesLund University, Malmö, SwedenDepartment of Mathematical StatisticsChalmers University of Technology, Gothenburg, SwedenDepartment of EndocrinologyDiabetology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Olle Melander
- Departments of EndocrinologyMolecular and Clinical MedicineInstitute of Medicine, The Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Vita Stråket 15, SE-413 45 Gothenburg, SwedenDepartment of Clinical SciencesLund University, Malmö, SwedenDepartment of Mathematical StatisticsChalmers University of Technology, Gothenburg, SwedenDepartment of EndocrinologyDiabetology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Peter Almgren
- Departments of EndocrinologyMolecular and Clinical MedicineInstitute of Medicine, The Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Vita Stråket 15, SE-413 45 Gothenburg, SwedenDepartment of Clinical SciencesLund University, Malmö, SwedenDepartment of Mathematical StatisticsChalmers University of Technology, Gothenburg, SwedenDepartment of EndocrinologyDiabetology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Lars Sjöström
- Departments of EndocrinologyMolecular and Clinical MedicineInstitute of Medicine, The Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Vita Stråket 15, SE-413 45 Gothenburg, SwedenDepartment of Clinical SciencesLund University, Malmö, SwedenDepartment of Mathematical StatisticsChalmers University of Technology, Gothenburg, SwedenDepartment of EndocrinologyDiabetology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Staffan Nilsson
- Departments of EndocrinologyMolecular and Clinical MedicineInstitute of Medicine, The Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Vita Stråket 15, SE-413 45 Gothenburg, SwedenDepartment of Clinical SciencesLund University, Malmö, SwedenDepartment of Mathematical StatisticsChalmers University of Technology, Gothenburg, SwedenDepartment of EndocrinologyDiabetology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Ingrid Larsson
- Departments of EndocrinologyMolecular and Clinical MedicineInstitute of Medicine, The Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Vita Stråket 15, SE-413 45 Gothenburg, SwedenDepartment of Clinical SciencesLund University, Malmö, SwedenDepartment of Mathematical StatisticsChalmers University of Technology, Gothenburg, SwedenDepartment of EndocrinologyDiabetology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Per-Arne Svensson
- Departments of EndocrinologyMolecular and Clinical MedicineInstitute of Medicine, The Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Vita Stråket 15, SE-413 45 Gothenburg, SwedenDepartment of Clinical SciencesLund University, Malmö, SwedenDepartment of Mathematical StatisticsChalmers University of Technology, Gothenburg, SwedenDepartment of EndocrinologyDiabetology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Gudmundur Johannsson
- Departments of EndocrinologyMolecular and Clinical MedicineInstitute of Medicine, The Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Vita Stråket 15, SE-413 45 Gothenburg, SwedenDepartment of Clinical SciencesLund University, Malmö, SwedenDepartment of Mathematical StatisticsChalmers University of Technology, Gothenburg, SwedenDepartment of EndocrinologyDiabetology and Metabolism, Sahlgrenska University Hospital, Gothenburg, Sweden
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Trifunović S, Manojlović-Stojanoski M, Ristić N, Nestorović N, Medigović I, Živanović J, Milošević V. Changes of growth hormone-releasing hormone and somatostatin neurons in the rat hypothalamus induced by genistein: a stereological study. Nutr Neurosci 2014; 19:467-474. [PMID: 25087680 DOI: 10.1179/1476830514y.0000000143] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
OBJECTIVES Genistein is a plant-derived estrogenic isoflavone commonly found in dietary and therapeutic supplements, due to its potential health benefits. Growth hormone-releasing hormone (GHRH) and somatostatin (SS) are neurosecretory peptides synthesized in neurons of the hypothalamus and regulate the growth hormone secretion. Early reports indicate that estrogens have highly involved in the regulation of GHRH and SS secretions. Since little is known about the potential effects of genistein on GHRH and SS neurons, we exposed rats to genistein. METHODS Genistein were administered to adult rats in dose of 30 mg/kg, for 3 weeks. The estradiol-dipropionate treatment was used as the adequate controls to genistein. Using applied stereology on histological sections of hypothalamus, we obtained the quantitative information on arcuate (Arc) and periventricular (Pe) nucleus volume and volume density of GHRH neurons and SS neurons. Image analyses were used to obtain GHRH and SS contents in the median eminence (ME). RESULTS Administration of estradiol-dipropionate caused the increase of Arc and Pe nucleus volume, SS neuron volume density, GHRH and SS staining intensity in the ME, when compared with control. Genistein treatment increased: Arc nucleus volume and the volume density of GHRH neurons (by 26%) and SS neurons (1.5 fold), accompanied by higher GHRH and SS staining intensity in the ME, when compared to the orhidectomized group. DISCUSSION These results suggest that genistein has a significant effect on hypothalamic region, involved in the regulation of somatotropic system function, and could contribute to the understanding of genistein as substance that alter the hormonal balance.
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Affiliation(s)
- Svetlana Trifunović
- a Department of Cytology , Institute for Biological Research 'Siniša Stanković', University of Belgrade , Belgrade , Serbia
| | - Milica Manojlović-Stojanoski
- a Department of Cytology , Institute for Biological Research 'Siniša Stanković', University of Belgrade , Belgrade , Serbia
| | - Nataša Ristić
- a Department of Cytology , Institute for Biological Research 'Siniša Stanković', University of Belgrade , Belgrade , Serbia
| | - Nataša Nestorović
- a Department of Cytology , Institute for Biological Research 'Siniša Stanković', University of Belgrade , Belgrade , Serbia
| | - Ivana Medigović
- a Department of Cytology , Institute for Biological Research 'Siniša Stanković', University of Belgrade , Belgrade , Serbia
| | - Jasmina Živanović
- a Department of Cytology , Institute for Biological Research 'Siniša Stanković', University of Belgrade , Belgrade , Serbia
| | - Verica Milošević
- a Department of Cytology , Institute for Biological Research 'Siniša Stanković', University of Belgrade , Belgrade , Serbia
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Abstract
The somatostatin (SRIF) system, which includes the SRIF ligand and receptors, regulates anterior pituitary gland function, mainly inhibiting hormone secretion and to some extent pituitary tumor cell growth. SRIF-14 via its cognate G-protein-coupled receptors (subtypes 1-5) activates multiple cellular signaling pathways including adenylate cyclase/cAMP, MAPK, ion channel-dependent pathways, and others. In addition, recent data have suggested SRIF-independent constitutive SRIF receptor activity responsible for GH and ACTH inhibition in vitro. This review summarizes current knowledge on ligand-dependent and independent SRIF receptor molecular and functional effects on hormone-secreting cells in the anterior pituitary gland.
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Affiliation(s)
- Tamar Eigler
- Division of EndocrinologyDiabetes and Metabolism, Department of Medicine, Pituitary Center, Cedars Sinai Medical Center, Davis Building, Room 3066, 8700 Beverly Boulevard, Los Angeles, California 90048, USA
| | - Anat Ben-Shlomo
- Division of EndocrinologyDiabetes and Metabolism, Department of Medicine, Pituitary Center, Cedars Sinai Medical Center, Davis Building, Room 3066, 8700 Beverly Boulevard, Los Angeles, California 90048, USA
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36
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Giustina A, Mazziotti G, Maffezzoni F, Amoroso V, Berruti A. Investigational drugs targeting somatostatin receptors for treatment of acromegaly and neuroendocrine tumors. Expert Opin Investig Drugs 2014; 23:1619-35. [DOI: 10.1517/13543784.2014.942728] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Thomas GA, Kraemer WJ, Comstock BA, Dunn-Lewis C, Maresh CM, Volek JS. Obesity, growth hormone and exercise. Sports Med 2014; 43:839-49. [PMID: 23812873 DOI: 10.1007/s40279-013-0064-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Growth hormone (GH) is regulated, suppressed and stimulated by numerous physiological stimuli. However, it is believed that obesity disrupts the physiological and pathological factors that regulate, suppress or stimulate GH release. Pulsatile GH has been potently stimulated in healthy subjects by both aerobic and resistance exercise of the right intensity and duration. GH modulates fuel metabolism, reduces total fat mass and abdominal fat mass, and could be a potent stimulus of lipolysis when administered to obese individuals exogenously. Only pulsatile GH has been shown to augment adipose tissue lipolysis and, therefore, increasing pulsatile GH response may be a therapeutic target. This review discusses the factors that cause secretion of GH, how obesity may alter GH secretion and how both aerobic and resistance exercise stimulates GH, as well as how exercise of a specific intensity may be used as a stimulus for GH release in individuals who are obese. Only five prior studies have investigated exercise as a stimulus of endogenous GH in individuals who are obese. Based on prior literature, resistance exercise may provide a therapeutic target for releasing endogenous GH in individuals who are obese if specific exercise programme variables are utilized. Biological activity of GH indicates that this may be an important precursor to beneficial changes in body fat and lean tissue mass in obese individuals. However, additional research is needed including what molecular GH variants are acutely released and involved at target tissues as a result of different exercise stimuli and what specific exercise programme variables may serve to stimulate GH in individuals who are obese.
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38
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Norman C, Rollene NL, Erickson D, Miles JM, Bowers CY, Veldhuis JD. Estradiol regulates GH-releasing peptide's interactions with GH-releasing hormone and somatostatin in postmenopausal women. Eur J Endocrinol 2014; 170:121-9. [PMID: 24114435 PMCID: PMC3892701 DOI: 10.1530/eje-13-0733] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
OBJECTIVE Estrogen stimulates pulsatile secretion of GH, via mechanisms that are largely unknown. An untested hypothesis is that estradiol (E₂) drives GH secretion by amplifying interactions among GH-releasing hormone (GHRH), somatostatin (SS), and GH-releasing peptide (GHRP). DESIGN The design comprised double-blind randomized prospective administration of transdermal E₂ vs placebo to healthy postmenopausal women (n=24) followed by pulsatile GHRH or SS infusions for 13 h overnight with or without continuous GHRP2 stimulation. METHODS End points were mean concentrations, deconvolved secretion, and approximate entropy (ApEn; a regularity measure) of GH. RESULTS By generalized ANOVA models, it was observed that E₂ vs placebo supplementation: i) augmented mean (13-h) GH concentrations (P=0.023), GHRH-induced pulsatile GH secretion over the first 3 h (P=0.0085) and pulsatile GH secretion over the next 10 h (P=0.054); ii) increased GHRP-modulated (P=0.022) and SS-modulated (P<0.001) GH ApEn; and iii) did not amplify GHRH/GHRP synergy during pulsatile GH secretion. By linear regression, E₂ concentrations were found to be positively correlated with GH secretion during GHRP2 infusion (P=0.022), whereas BMI was found to be negatively correlated with GH secretion during GHRH (P=0.006) and combined GHRH/GHRP (P=0.015) stimulation. E₂ and BMI jointly determined triple (combined l-arginine, GHRH, and GHRP2) stimulation of GH secretion after saline (R²=0.44 and P=0.003) and pulsatile GHRH (R²=0.39 and P=0.013) infusions. CONCLUSION In summary, in postmenopausal women, E₂ supplementation augments the amount (mass) and alters the pattern (regularity) of GH secretion via interactions among GHRH, SS, GHRP, and BMI. These outcomes introduce a more complex model of E₂ supplementation in coordinating GH secretion in aging women.
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Affiliation(s)
- Charlotte Höybye
- Department of Endocrinology, Metabolism and Diabetology, Karolinska University Hospital, Stockholm, Sweden
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40
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Rojanathammanee L, Rakoczy S, Brown-Borg HM. Growth hormone alters the glutathione S-transferase and mitochondrial thioredoxin systems in long-living Ames dwarf mice. J Gerontol A Biol Sci Med Sci 2013; 69:1199-211. [PMID: 24285747 DOI: 10.1093/gerona/glt178] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Ames dwarf mice are deficient in growth hormone (GH), prolactin, and thyroid-stimulating hormone and live significantly longer than their wild-type (WT) siblings. The lack of GH is associated with stress resistance and increased longevity. However, the mechanism underlying GH's actions on cellular stress defense have yet to be elucidated. In this study, WT or Ames dwarf mice were treated with saline or GH (WT saline, Dwarf saline, and Dwarf GH) two times daily for 7 days. The body and liver weights of Ames dwarf mice were significantly increased after 7 days of GH administration. Mitochondrial protein levels of the glutathione S-transferase (GST) isozymes, K1 and M4 (GSTK1 and GSTM4), were significantly higher in dwarf mice (Dwarf saline) when compared with WT mice (WT saline). GH administration downregulated the expression of GSTK1 proteins in dwarf mice. We further investigated GST activity from liver lysates using different substrates. Substrate-specific GST activity (bromosulfophthalein, dichloronitrobenzene, and 4-hydrox-ynonenal) was significantly reduced in GH-treated dwarf mice. In addition, GH treatment attenuated the activity of thioredoxin and glutaredoxin in liver mitochondria of Ames mice. Importantly, GH treatment suppressed Trx2 and TrxR2 mRNA expression. These data indicate that GH has a role in stress resistance by altering the functional capacity of the GST system through the regulation of specific GST family members in long-living Ames dwarf mice. It also affects the regulation of thioredoxin and glutaredoxin, factors that regulate posttranslational modification of proteins and redox balance, thereby further influencing stress resistance.
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Affiliation(s)
- Lalida Rojanathammanee
- Department of Pharmacology, Physiology, and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks. School of Sports Science, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima, Thailand
| | - Sharlene Rakoczy
- Department of Pharmacology, Physiology, and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks
| | - Holly M Brown-Borg
- Department of Pharmacology, Physiology, and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks.
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41
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Preoperative prediction of growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis modification and postoperative changes in candidates for bariatric surgery. Obes Surg 2013. [PMID: 23179244 DOI: 10.1007/s11695-012-0820-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
BACKGROUND Several factors alter the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in obese patients, but GH/IGF-1 correlation with anthropometric parameters and lipid metabolism is still unclear. We evaluated this relationship and the postoperative axis modifications in candidates for bariatric surgery. METHODS Eighty-eight patients (males/females (M/F), 34/54) scheduled for bariatric surgery (biliopancreatic diversion or laparoscopic-adjustable gastric banding) between 2008 and 2010 were included in this observational, open, prospective study. RESULTS Preoperative serum GH concentrations were found near the lowest limit of normal range in both sexes, with males showing the lowest values (130 vs. 1,405 pg/ml; p < 0.01). Serum concentrations of IGF-1 were within the normal range (M/F, 179/168.5 ng/ml), whereas IGF-binding protein (BP)1 and 3 values were at the lowest limits of normal range in both sexes (M/F 1.8/3.1 μg/ml and M/F 4.1/4.2 μg/ml, respectively). A statistically significant inverse correlation was found between GH, IGF-1, and IGF-BP1-3 values and total cholesterol, LDL-cholesterol, and triglycerides values in both sexes. GH and IGF-BP1-3 values were also inversely related to waist circumference and waist/hip ratio (WHR). GH, IGF-1, and IGF-BP1 and 3 values (35 cases) increased 1 year postoperatively in both sexes, mainly after malabsorptive procedures. CONCLUSIONS Our results support the hypothesis that GH deficiency associated with low levels of binding proteins in obese patients may be an endocrine response to visceral fat and high levels of non-esterified fatty acids, assessable in daily clinical practice by WHR, total and LDL-cholesterol, and triglycerides. In these patients, malabsorptive procedures might be the treatment of choice due to the metabolic adaptations induced.
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43
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Chaves VE, Júnior FM, Bertolini GL. The metabolic effects of growth hormone in adipose tissue. Endocrine 2013; 44:293-302. [PMID: 23430368 DOI: 10.1007/s12020-013-9904-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Accepted: 02/09/2013] [Indexed: 11/27/2022]
Abstract
There is a general consensus that a reduction in growth hormone (GH) secretion results in obesity. However, the pathophysiologic role of GH in the metabolism of lipids is yet to be fully understood. The major somatic targets of GH are bones and muscles, but GH stimulates lipolysis and seems to regulate lipid deposition in adipose tissue. Patients with isolated GH deficiency (GHD) have enlarged fat depots due to higher fat cell volume, but their fat cell numbers are lower than those of matched controls. The treatment of patients with GH results in a relative loss of body fat and shifts both fat cell number and fat cell volume toward normal, indicating an adipogenic effect of GH. Adults with GHD are characterized by perturbations in body composition, lipid metabolism, cardiovascular risk profile, and bone mineral density. It is well established that GHD is usually accompanied by an increase in fat accumulation; GH replacement in GHD results in the reduction of fat mass, particularly abdominal fat mass. In addition, abdominal obesity results in a secondary reduction in GH secretion that is reversible with weight loss. However, whereas GH replacement in patients with GHD leads to specific depletion of intra-abdominal fat, administering GH to obese individuals does not seem to result in a consistent reduction or redistribution of body fat. Although administering GH to obese non-GHD subjects has only led to equivocal results, more recent studies indicate that GH still remains a plausible metabolic candidate.
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Affiliation(s)
- Valéria Ernestânia Chaves
- Laboratory of Physiology and Pharmacology, Federal University of São João del-Rei, Divinópolis, Minas Gerais, Brazil
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44
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Abstract
Secretion of growth hormone (GH) and IGF-1 levels decline during advancing years-of-life. These changes (somatopause) are associated with loss of vitality, muscle mass, physical function, together with the occurrence of frailty, central adiposity, cardiovascular complications, and deterioration of mental function. For GH treatment to be considered for anti-aging, improved longevity, organ-specific function, or quality of life should be demonstrable. A limited number of controlled studies suggest that GH supplementation in older men increases lean mass by ∼2 kg with similar reductions in fat mass. There is little evidence that GH treatment improves muscle strength and performance (e.g. walking speed or ability to climb stairs) or quality of life. The GHRH agonist (tesamorelin) restores normal GH pulsatility and amplitude, selectively reduces visceral fat, intima media thickness and triglycerides, and improves cognitive function in older persons. This report critically reviews the potential for GH augmentation during aging with emphasis on men since women appear more resistant to treatment.
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Affiliation(s)
- Fred R Sattler
- Keck School of Medicine, University of Southern California, 2020 Zonal Avenue, IRD Building, Room 434, Los Angeles, CA 90033, USA.
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Almeida M, O'Brien CA. Basic biology of skeletal aging: role of stress response pathways. J Gerontol A Biol Sci Med Sci 2013; 68:1197-208. [PMID: 23825036 DOI: 10.1093/gerona/glt079] [Citation(s) in RCA: 138] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Although a decline in bone formation and loss of bone mass are common features of human aging, the molecular mechanisms mediating these effects have remained unclear. Evidence from pharmacological and genetic studies in mice has provided support for a deleterious effect of oxidative stress in bone and has strengthened the idea that an increase in reactive oxygen species (ROS) with advancing age represents a pathophysiological mechanism underlying age-related bone loss. Mesenchymal stem cells and osteocytes are long-lived cells and, therefore, are more susceptible than other types of bone cells to the molecular changes caused by aging, including increased levels of ROS and decreased autophagy. However, short-lived cells like osteoblast progenitors and mature osteoblasts and osteoclasts are also affected by the altered aged environment characterized by lower levels of sex steroids, increased endogenous glucocorticoids, and higher oxidized lipids. This article reviews current knowledge on the effects of the aging process on bone, with particular emphasis on the role of ROS and autophagy in cells of the osteoblast lineage in mice.
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Affiliation(s)
- Maria Almeida
- Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR 72205.
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Veldhuis JD, Sharma A, Roelfsema F. Age-dependent and gender-dependent regulation of hypothalamic-adrenocorticotropic-adrenal axis. Endocrinol Metab Clin North Am 2013; 42:201-25. [PMID: 23702398 PMCID: PMC3675779 DOI: 10.1016/j.ecl.2013.02.002] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Tightly regulated output of glucocorticoids is critical to maintaining immune competence, the structure of neurons, muscle, and bone, blood pressure, glucose homeostasis, work capacity, and vitality in the human and experimental animal. Age, sex steroids, gender, stress, body composition, and disease govern glucocorticoid availability through incompletely understood mechanisms. According to an ensemble concept of neuroendocrine regulation, successful stress adaptations require repeated incremental signaling adjustments among hypothalamic corticotropin-releasing hormone and arginine vasopressin, pituitary adrenocorticotropic hormone, and adrenal corticosteroids. Signals are transduced via (positive) feedforward and (negative) feedback effects. Age and gonadal steroids strongly modulate stress-adaptive glucocorticoid secretion by such interlinked pathways.
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Affiliation(s)
- Johannes D Veldhuis
- Endocrine Research Unit, Mayo School of Graduate Medical Education, Center for Translational Science Activities, Mayo Clinic, Rochester, MN 55905, USA.
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47
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Jin J, Sawai K, Hashizume T. Effects of photoperiod on secretory patterns of growth hormone in adult male goats. Anim Sci J 2013; 84:790-7. [DOI: 10.1111/asj.12073] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 02/24/2013] [Indexed: 11/30/2022]
Affiliation(s)
- Jin Jin
- Faculty of Agriculture; Iwate University; Morioka Japan
| | - Ken Sawai
- Faculty of Agriculture; Iwate University; Morioka Japan
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Benso A, Gramaglia E, Olivetti I, Tomelini M, Gigliardi VR, Frara S, Calvi E, Belcastro S, St Pierre DH, Ghigo E, Broglio F. The GH-releasing effect of acylated ghrelin in normal subjects is refractory to GH acute auto-feedback but is inhibited after short-term GH administration inducing IGF1 increase. Eur J Endocrinol 2013; 168:509-14. [PMID: 23295542 DOI: 10.1530/eje-12-0691] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE GH secretion is regulated by an interplay between GH-releasing hormone (GHRH), somatostatin (SST), and other central and peripheral signals. Acylated ghrelin (AG) amplifies GH pulsatility acting, at least partially, independently from GHRH and SST. The GH response to GHRH is inhibited by recombinant human GH (rhGH), likely due to a SST-mediated negative GH auto-feedback. The effect of exogenous rhGH on the GH-releasing effect of AG has never been tested. DESIGN AND METHODS In six healthy volunteers, we studied the GH response to acute AG administration (1.0 μg/kg i.v.) during saline or rhGH infusion (4.0 μg/kg per h i.v.) or after 4-day rhGH (10.0 μg/kg s.c.) administration. RESULTS Compared with saline, rhGH infusion increased GH levels (P<0.01). During saline, acute i.v. AG induced a marked increase (P<0.01) in GH levels similar to those observed after AG administration during rhGH infusion. During s.c. rhGH, IGF1 levels rose from day 0 to day 5 (P<0.01). After 4-day s.c. rhGH, i.v. AG increased (P<0.01) GH levels, though significantly (P<0.05) less than on day 0. CONCLUSIONS The marked somatotroph-releasing effect of AG is refractory to a direct GH auto-feedback whereas is markedly inhibited after 4-day rhGH administration, suggesting the possibility of a selective IGF1-mediated inhibitory feedback.
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Affiliation(s)
- A Benso
- Division of Endocrinology, Diabetology and Metabolism, Department of Internal Medicine, San Giovanni Battista, Molinette Hospital, University of Turin, Turin, Italy
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Kamycheva E, Berg V, Jorde R. Insulin-like growth factor I, growth hormone, and insulin sensitivity: the effects of a one-year cholecalciferol supplementation in middle-aged overweight and obese subjects. Endocrine 2013; 43:412-8. [PMID: 23109222 DOI: 10.1007/s12020-012-9825-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Accepted: 10/19/2012] [Indexed: 12/24/2022]
Abstract
Both altered GH-IGF-I axis and low serum levels of 25-hydroxyvitamin D (25(OH)D) are linked to measures of metabolic syndrome. Our hypothesis was that there is a relation between GH, IGF-I, and 25(OH)D; and that vitamin D supplementation may have an effect on the levels of GH, IGF-I, and IGF-I/IGFBP-3 ratio. 318 overweight and obese subjects completed a one-year randomized intervention with either 40,000 or 20,000 IU cholecalciferol per week or placebo. GH, IGF-I, IGFBP-3 and measures of insulin resistance were evaluated at baseline and at the end of study. There was a significant relation between entities of GH-IGF-I axis and insulin resistance. Subjects with severe obesity had significantly lower serum 25(OH)D and had a significant linear decline in IGF-I/IGFBP-3 ratio with increasing serum 25(OH)D quartiles. Vitamin D status was an independent predictor of GH-IGF-I axis and supplementation with vitamin D decreased IGF-I/IGFBP-3 ratio in subjects without severe obesity. No corresponding effect of vitamin D supplementation on BMI or insulin resistance was observed. Adverse effects of GH-IGF-I axis on glucose metabolism and the development of metabolic syndrome may be in part associated with the changes in vitamin D status.
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Affiliation(s)
- Elena Kamycheva
- Department of Medicine, University Hospital of North Norway, 9038, Tromsø, Norway.
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50
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Abstract
A minimal-model framework is that growth hormone (GH) secretion is controlled by an ensemble of interlinked peptides, namely, GH-releasing hormone (GHRH), somatostatin (SS), and ghrelin. Clinical studies, laboratory experiments, rare sporadic mutations, targeted gene silencing, and biomathematical models establish that at least three signals regulate GH secretion. A clarion implication of the concept of integrative control is that no one peptidic effector operates alone or can be adequately studied alone. A major unanswered question is how pathophysiology disrupts the core regulatory ensemble, thereby forcing relative GH and IGF-1 deficiency or excess. However, salient technical hurdles exist, namely, the lack of reliable experimental strategies and the paucity of validated analytical tools to distinguish the interlinked roles of GHRH, SS, and ghrelin. To address these significant obstacles requires administering peptide secretagogues in distinct combinations akin to the classical insulin/glucose clamp and implementing an analytical formalism to parse the interactive roles of GHRH, SS, and ghrelin objectively.
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