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Lynnette K. Nieman - One of the best experts on this subject based on the ideXlab platform.
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Growth Hormone Receptor messenger ribonucleic acid expression in leiomyoma and surrounding myometrium.
American Journal of Obstetrics and Gynecology, 1995Co-Authors: Fady I. Sharara, Lynnette K. NiemanAbstract:Abstract OBJECTIVE: Uterine leiomyomas are the most common pelvic tumors, occurring in one of four women, and they represent the single most common indication for hysterectomy. The genesis and Growth-promoting factors responsible for their development are poorly understood. We speculate that Growth Hormone may play a role in the initiation of these tumors; women with acromegaly have a higher incidence of leiomyomas and Growth Hormone promotes uterine Growth in rats, with or without the addition of estradiol. We evaluated the presence of Growth Hormone Receptor messenger ribonucleic acid in the human uterus and leiomyomas to investigate whether Growth Hormone might act directly rather than by hepatic generation of insulin-like Growth factor-I. STUDY DESIGN: Paired samples of leiomyomas and adjacent normal myometrium from nine premenopausal women (32 to 52 years old) were collected at surgery. Three patients received a gonadotropin-releasing Hormone agonist for 3 months before the surgical procedure; six did not receive any adjuvant therapy. We used a digoxigenin-labeled oligoprobe sharing no homology to the Growth Hormone-binding protein or to the prolactin Receptor, to investigate whether Growth Hormone Receptor messenger ribonucleic acid was present in tissue sections or amplified complementary deoxyribonucleic acid from leiomyoma and the surrounding myometrium. RESULTS: The ratios of Growth Hormone Receptor/reduced glyceraldehyde-phosphate dehydrogenase in leiomyomas and the surrounding myometrium as assessed by densitometry analysis of polymerase chain reaction products were similar and were not altered by gonadotropin-releasing Hormone agonist treatment. In situ hybridization localized the Growth Hormone Receptor messenger ribonucleic acid to the nuclei and cytoplasm of leiomyoma and myometrium. CONCLUSION: The presence of Growth Hormone Receptor messenger ribonucleic acid suggests that the human uterus is a target tissue for Growth Hormone action. Future investigations are needed to investigate further the role of Growth Hormone in the development of leiomyomas.
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Growth Hormone Receptor messenger ribonucleic acid expression in leiomyoma and surrounding myometrium.
American journal of obstetrics and gynecology, 1995Co-Authors: Fady I. Sharara, Lynnette K. NiemanAbstract:Uterine leiomyomas are the most common pelvic tumors, occurring in one of four women, and they represent the single most common indication for hysterectomy. The genesis and Growth-promoting factors responsible for their development are poorly understood. We speculate that Growth Hormone may play a role in the initiation of these tumors; women with acromegaly have a higher incidence of leiomyomas and Growth Hormone promotes uterine Growth in rats, with or without the addition of estradiol. We evaluated the presence of Growth Hormone Receptor messenger ribonucleic acid in the human uterus and leiomyomas to investigate whether Growth Hormone might act directly rather than by hepatic generation of insulin-like Growth factor-I. Paired samples of leiomyomas and adjacent normal myometrium from nine premenopausal women (32 to 52 years old) were collected at surgery. Three patients received a gonadotropin-releasing Hormone agonist for 3 months before the surgical procedure; six did not receive any adjuvant therapy. We used a digoxigenin-labeled oligoprobe sharing no homology to the Growth Hormone-binding protein or to the prolactin Receptor, to investigate whether Growth Hormone Receptor messenger ribonucleic acid was present in tissue sections or amplified complementary deoxyribonucleic acid from leiomyoma and the surrounding myometrium. The ratios of Growth Hormone Receptor/reduced glyceraldehyde-phosphate dehydrogenase in leiomyomas and the surrounding myometrium as assessed by densitometry analysis of polymerase chain reaction products were similar and were not altered by gonadotropin-releasing Hormone agonist treatment. In situ hybridization localized the Growth Hormone Receptor messenger ribonucleic acid to the nuclei and cytoplasm of leiomyoma and myometrium. The presence of Growth Hormone Receptor messenger ribonucleic acid suggests that the human uterus is a target tissue for Growth Hormone action. Future investigations are needed to investigate further the role of Growth Hormone in the development of leiomyomas.
Fady I. Sharara - One of the best experts on this subject based on the ideXlab platform.
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Growth Hormone Receptor messenger ribonucleic acid expression in leiomyoma and surrounding myometrium.
American Journal of Obstetrics and Gynecology, 1995Co-Authors: Fady I. Sharara, Lynnette K. NiemanAbstract:Abstract OBJECTIVE: Uterine leiomyomas are the most common pelvic tumors, occurring in one of four women, and they represent the single most common indication for hysterectomy. The genesis and Growth-promoting factors responsible for their development are poorly understood. We speculate that Growth Hormone may play a role in the initiation of these tumors; women with acromegaly have a higher incidence of leiomyomas and Growth Hormone promotes uterine Growth in rats, with or without the addition of estradiol. We evaluated the presence of Growth Hormone Receptor messenger ribonucleic acid in the human uterus and leiomyomas to investigate whether Growth Hormone might act directly rather than by hepatic generation of insulin-like Growth factor-I. STUDY DESIGN: Paired samples of leiomyomas and adjacent normal myometrium from nine premenopausal women (32 to 52 years old) were collected at surgery. Three patients received a gonadotropin-releasing Hormone agonist for 3 months before the surgical procedure; six did not receive any adjuvant therapy. We used a digoxigenin-labeled oligoprobe sharing no homology to the Growth Hormone-binding protein or to the prolactin Receptor, to investigate whether Growth Hormone Receptor messenger ribonucleic acid was present in tissue sections or amplified complementary deoxyribonucleic acid from leiomyoma and the surrounding myometrium. RESULTS: The ratios of Growth Hormone Receptor/reduced glyceraldehyde-phosphate dehydrogenase in leiomyomas and the surrounding myometrium as assessed by densitometry analysis of polymerase chain reaction products were similar and were not altered by gonadotropin-releasing Hormone agonist treatment. In situ hybridization localized the Growth Hormone Receptor messenger ribonucleic acid to the nuclei and cytoplasm of leiomyoma and myometrium. CONCLUSION: The presence of Growth Hormone Receptor messenger ribonucleic acid suggests that the human uterus is a target tissue for Growth Hormone action. Future investigations are needed to investigate further the role of Growth Hormone in the development of leiomyomas.
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Growth Hormone Receptor messenger ribonucleic acid expression in leiomyoma and surrounding myometrium.
American journal of obstetrics and gynecology, 1995Co-Authors: Fady I. Sharara, Lynnette K. NiemanAbstract:Uterine leiomyomas are the most common pelvic tumors, occurring in one of four women, and they represent the single most common indication for hysterectomy. The genesis and Growth-promoting factors responsible for their development are poorly understood. We speculate that Growth Hormone may play a role in the initiation of these tumors; women with acromegaly have a higher incidence of leiomyomas and Growth Hormone promotes uterine Growth in rats, with or without the addition of estradiol. We evaluated the presence of Growth Hormone Receptor messenger ribonucleic acid in the human uterus and leiomyomas to investigate whether Growth Hormone might act directly rather than by hepatic generation of insulin-like Growth factor-I. Paired samples of leiomyomas and adjacent normal myometrium from nine premenopausal women (32 to 52 years old) were collected at surgery. Three patients received a gonadotropin-releasing Hormone agonist for 3 months before the surgical procedure; six did not receive any adjuvant therapy. We used a digoxigenin-labeled oligoprobe sharing no homology to the Growth Hormone-binding protein or to the prolactin Receptor, to investigate whether Growth Hormone Receptor messenger ribonucleic acid was present in tissue sections or amplified complementary deoxyribonucleic acid from leiomyoma and the surrounding myometrium. The ratios of Growth Hormone Receptor/reduced glyceraldehyde-phosphate dehydrogenase in leiomyomas and the surrounding myometrium as assessed by densitometry analysis of polymerase chain reaction products were similar and were not altered by gonadotropin-releasing Hormone agonist treatment. In situ hybridization localized the Growth Hormone Receptor messenger ribonucleic acid to the nuclei and cytoplasm of leiomyoma and myometrium. The presence of Growth Hormone Receptor messenger ribonucleic acid suggests that the human uterus is a target tissue for Growth Hormone action. Future investigations are needed to investigate further the role of Growth Hormone in the development of leiomyomas.
Michael J. Waters - One of the best experts on this subject based on the ideXlab platform.
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The Growth Hormone Receptor
Comprehensive Physiology, 2011Co-Authors: Michael J. WatersAbstract:The sections in this article are: 1 Cloning of the Receptor 2 The Hematopoietic Cytokine Receptor Family 3 The Crystal Structure of the Growth Hormone Receptor and its Complex with the Hormone 3.1 Stoichiometry 3.2 Domain Structure 3.3 Binding to the Hormone 3.4 Comparison with the Prolactin Receptor 4 Structure of Growth Hormone and its Variants 4.1 Structural and Functional Studies on Human Growth Hormone 4.2 Nature of the Binding Specificity: Recruitment of Other Hormones 4.3 Improving the Binding Affinity 4.4 Binding to the Rabbit Growth Hormone Receptor 4.5 Determinants of Primate Specificity 5 Mechanisms for Generating the Biological Signals 5.1 Requirement for Dimerization 5.2 Apparent Exceptions to the Dimerization Requirement 5.3 Is Dimerization Sufficient? The Question of Conformational Change 6 The Growth Hormone Receptor Gene and the Syndrome of Growth Hormone Insensitivity 6.1 Structure of the Gene: Alternate Splicing 6.2 Primary Growth Hormone Insensitivity in Humans: Laron Dwarfism 7 The Growth Hormone-Binding Protein 7.1 Early Studies 7.2 The Modern Era 7.3 Identity of the Growth Hormone–Binding Protein 7.4 Mode of Release of the Growth Hormone–Binding Protein 7.5 Functional Aspects of Growth Hormone–Binding Proteins 7.6 Utility of Serum Growth Hormone–Binding Protein as a Measure of Growth Hormone Receptor Expression 7.7 Physiological Considerations: Relation to Growth Potential 7.8 Methods of Measuring Growth Hormone–Binding Protein Status 7.9 Regulation of Growth Hormone–Binding Protein 8 Receptor Regulation 8.1 The Receptor Life Cycle 8.2 Short-Term Processes: Downregulation 8.3 Long-Term Regulation: Induction of Receptor Message 8.4 Ontogeny 8.5 Sex and Pregnancy 8.6 Growth Hormone 8.7 Steroids 8.8 Other Factors 9 Receptor Localization 10 Conclusion
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The Growth Hormone Receptor: mechanism of activation and clinical implications
Nature Reviews Endocrinology, 2010Co-Authors: Andrew J. Brooks, Michael J. WatersAbstract:The Growth Hormone Receptor mediates a wide range of Growth-related and metabolic actions, both directly and via insulin-like Growth factor 1 (IGF-1) Receptor loss-of-function, predominantly owing to mutations in the extracellular domain, results in Growth Hormone insensitivity or Laron syndrome Receptor gain-of-function mutations are not known, but excessive Receptor stimulation by Growth Hormone leads to gigantism, adult acromegaly and cancer (if autocrine Growth Hormone signaling is involved) The Hormone–Receptor complex is well-defined at a molecular level for the extracellular domain The Growth Hormone Receptor exists as a constitutive dimer, and activation involves rearrangement of the Receptor subunits to align the tyrosine-protein kinases JAK2 and Src bound below the cell membrane for activation JAK2 and the Src family of proto-oncogene tyrosine-protein kinases initiate signaling, the former involving the key transcription factor signal transducer and activator of transcription 5b Growth Hormone is widely used clinically to promote Growth and anabolism and for other purposes. Its actions are mediated via the Growth Hormone Receptor, both directly by tyrosine kinase activation and indirectly by induction of insulin-like Growth factor 1 (IGF-1). Insensitivity to Growth Hormone (Laron syndrome) can result from mutations in the Growth Hormone Receptor and can be treated with IGF-1. This treatment is, however, not fully effective owing to the loss of the direct actions of Growth Hormone and altered availability of exogenous IGF-1. Excessive activation of the Growth Hormone Receptor by circulating Growth Hormone results in gigantism and acromegaly, whereas cell transformation and cancer can occur in response to autocrine activation of the Receptor. Advances in understanding the mechanism of Receptor activation have led to a model in which the Growth Hormone Receptor exists as a constitutive dimer. Binding of the Hormone realigns the subunits by rotation and closer apposition, resulting in juxtaposition of the catalytic domains of the associated tyrosine-protein kinase JAK2 below the cell membrane. This change results in activation of JAK2 by transphosphorylation, then phosphorylation of Receptor tyrosines in the cytoplasmic domain, which enables binding of adaptor proteins, as well as direct phosphorylation of target proteins. This model is discussed in the light of salient information from closely related class 1 cytokine Receptors, such as the erythropoietin, prolactin and thrombopoietin Receptors. This Review addresses the relative roles of Growth Hormone and IGF 1 in mediating their biological effects, as well as the clinical outcome of inappropriate Growth Hormone signaling. Furthermore, it summarizes novel information provided by transgenic mouse models and mutagenesis studies on the roles and mechanisms of activation of the Growth Hormone Receptor in the context of related class 1 cytokine Receptors.
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the Growth Hormone Receptor mechanism of activation and clinical implications
Nature Reviews Endocrinology, 2010Co-Authors: Andrew J. Brooks, Michael J. WatersAbstract:Growth Hormone is widely used clinically to promote Growth and anabolism and for other purposes. Its actions are mediated via the Growth Hormone Receptor, both directly by tyrosine kinase activation and indirectly by induction of insulin-like Growth factor 1 (IGF-1). Insensitivity to Growth Hormone (Laron syndrome) can result from mutations in the Growth Hormone Receptor and can be treated with IGF-1. This treatment is, however, not fully effective owing to the loss of the direct actions of Growth Hormone and altered availability of exogenous IGF-1. Excessive activation of the Growth Hormone Receptor by circulating Growth Hormone results in gigantism and acromegaly, whereas cell transformation and cancer can occur in response to autocrine activation of the Receptor. Advances in understanding the mechanism of Receptor activation have led to a model in which the Growth Hormone Receptor exists as a constitutive dimer. Binding of the Hormone realigns the subunits by rotation and closer apposition, resulting in juxtaposition of the catalytic domains of the associated tyrosine-protein kinase JAK2 below the cell membrane. This change results in activation of JAK2 by transphosphorylation, then phosphorylation of Receptor tyrosines in the cytoplasmic domain, which enables binding of adaptor proteins, as well as direct phosphorylation of target proteins. This model is discussed in the light of salient information from closely related class 1 cytokine Receptors, such as the erythropoietin, prolactin and thrombopoietin Receptors.
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Growth Hormone Receptor; mechanism of action.
The international journal of biochemistry & cell biology, 2007Co-Authors: Andrew J. Brooks, Jong Wei Wooh, Kathryn A. Tunny, Michael J. WatersAbstract:The Growth Hormone Receptor has been an archetype for ligand-induced Receptor dimerisation in cytokine Receptor signalling. However, we now know that it exists as a constitutive dimer and is activated by a reorganisation of Receptor subunits as a result of asymmetric placement of two Receptor binding sites on the Hormone monomer. This review highlights several topics including: current models of Receptor activation; recent advances in the understanding of GH signalling demonstrating that ligand-induced signalling activates Src/ERK pathway in parallel to the classical JAK2-STAT5 signalling; and the nuclear localised Growth Hormone Receptor correlates with high proliferation status and carcinogenesis.
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Crystallization and preliminary X-ray diffraction analysis of the unliganded human Growth Hormone Receptor.
Acta Crystallographica Section D Biological Crystallography, 2004Co-Authors: William J. Mckinstry, Michael J. Waters, Yu Wan, Julian J. Adams, Richard J. Brown, Michael W. ParkerAbstract:The crystal structure of the extracellular domain of Growth Hormone Receptor complexed to its ligand, Growth Hormone, has been known since 1992. However, no information exists for the unliganded form of the Receptor. The human Growth Hormone Receptor's extracellular ligand-binding domain, encompassing amino-acid residues 1–238, has been expressed in Escherichia coli, purified by anion ion-exchange chromatography and crystallized in its unliganded state by the hanging-drop vapour-diffusion method in 100 mM HEPES pH 7.0 containing 27.5%(w/v) PEG 5000 monomethyl ether and 200 mM ammonium sulfate as the co-precipitants. The crystals belong to the othorhombic space group C2221, have unit-cell parameters a = 99.7, b = 112.2, c = 93.2 A and diffract to 2.5 A resolution using synchrotron radiation. The crystal structure will shed light on the nature of any conformation changes that occur upon ligand binding and will provide information to develop potential low-molecular-weight agonists/antagonists to treat clinical diseases in which the Growth Hormone Receptor is implicated.
Peter J Trainer - One of the best experts on this subject based on the ideXlab platform.
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long term treatment of acromegaly with pegvisomant a Growth Hormone Receptor antagonist
The Lancet, 2001Co-Authors: Aart Jan Van Der Lely, Peter J Trainer, Laurence Katznelson, Kent R Hutson, Michael G Besser, Ariel L Barkan, Anne Klibanski, Vivien Hermanbonert, Shlomo Melmed, Mary Lee VanceAbstract:Summary Background Pegvisomant is a new Growth Hormone Receptor antagonist that improves symptoms and normalises insulin-like Growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days. Methods Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum Growth Hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis. Findings Mean serum IGF-1 concentrations fell by at least 50%: 467 μg/L (SE 24), 526 μg/L (29), and 523 μg/L (40) in patients treated for 6, 12 and 18 months, respectively (p 3 (0·057; p=0·353). Interpretation Pegvisomant is an effective medical treatment for acromegaly.
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Treatment of acromegaly with the Growth Hormone-Receptor antagonist pegvisomant.
The New England journal of medicine, 2000Co-Authors: Peter J Trainer, W. M. Drake, Laurence Katznelson, Pamela U. Freda, Vivien Herman-bonert, A. J. Van Der Lely, Eleni V. Dimaraki, Paul M. Stewart, K. E. Friend, Mary Lee VanceAbstract:Background Patients with acromegaly are treated with surgery, radiation therapy, and drugs to reduce hypersecretion of Growth Hormone, but the treatments may be ineffective and have adverse effects. Pegvisomant is a genetically engineered Growth Hormone–Receptor antagonist that blocks the action of Growth Hormone. Methods We conducted a 12-week, randomized, double-blind study of three different daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly. Results The mean (±SD) serum concentration of insulin-like Growth factor I (IGF-I) decreased from base line by 4.0±16.8 percent in the placebo group, 26.7± 27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1±26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5±21.3 percent in the group that received 20 mg of pegvisomant per day (P
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Pegvisomant: a Growth Hormone Receptor antagonist for the treatment of acromegaly.
Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society, 2000Co-Authors: Craig Parkinson, Peter J TrainerAbstract:Growth Hormone Receptor (GHR) dimerization is a prerequisite to the generation of Growth Hormone (GH) action. Pegvisomant is a GHR antagonist that has been designed to bind to the GHR at the cell surface and hence block this process. Initial studies suggest that pegvisomant is a highly effective antagonist of GH action in patients with acromegaly. The blockade of GH action, rather than the inhibition of pituitary GH secretion, represents a novel concept in the medical management of acromegaly. In this review, the design, efficacy, challenges and future role of pegvisomant are discussed.
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Growth Hormone Receptor antagonists therapy for acromegaly.
Bailliere's best practice & research. Clinical endocrinology & metabolism, 1999Co-Authors: Craig Parkinson, Peter J TrainerAbstract:Knowledge of the interaction between Growth Hormone (GH) and the Growth Hormone Receptor (GHR) has led to the rational design of a GHR antagonist. An analogue of GH able to block the action of GH at the cellular level offers greater specificity of effect compared with current medical therapies and is not dependent on tumour characteristics. This chapter reviews the interaction between GH and the GHR, and discusses the outstanding issues regarding GHR antagonist therapy in acromegaly.
Matthew C. Lucy - One of the best experts on this subject based on the ideXlab platform.
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Expression of Growth Hormone Receptor 1A messenger ribonucleic acid in liver of dairy cows during lactation and after administration of recombinant bovine somatotropin.
Journal of dairy science, 1999Co-Authors: Y. Kobayashi, Michael J. Vandehaar, H.a. Tucker, B. K. Sharma, Matthew C. LucyAbstract:The mRNA for Growth Hormone Receptor is transcribed from at least three different promoters in cattle. The first promoter (P1) is liver-specific and transcribes Growth Hormone Receptor mRNA containing exon 1A (Growth Hormone Receptor 1A). The second and third promoters (P2 and P3) are active in a variety of tissues and transcribe Growth Hormone Receptor mRNA containing exon 1B and 1C. The objective was to characterize P1 activity by measuring the amount of Growth Hormone Receptor 1A mRNA in liver of dairy cows at different stages of lactation as well as after administration of recombinant bovine somatotropin (rbST). In study 1, liver RNA was isolated from Holstein cows during the dry period (nonlactating, n = 6) and during early (n = 6), mid (n = 6), and late (n = 11) stages of lactation. Six of the late-lactation cows received injections of rbST (25 mg/d) for 7 d prior to collection of liver tissue. In study 2, lactating Holstein cows received either no infusion (control, n = 10) or continuous infusion of rbST (29 mg/d, n = 10) for 63 d. The amount of Growth Hormone Receptor 1A mRNA was decreased in early- and mid-lactation cows compared with late-lactation cows or nonlactating cows (study 1). Administration of rbST increased Growth Hormone Receptor 1A mRNA (studies 1 and 2). The total amount of Growth Hormone Receptor transcribed from alternative promoters (Growth Hormone Receptor P2 and P3) remained unchanged during different stages of lactation or in response to rbST. We conclude that changes in liver Growth Hormone Receptor mRNA in lactating dairy cattle primarily depend on Growth Hormone Receptor P1 activity.
