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1.
PLoS One ; 15(7): e0236788, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735629

RESUMO

This study aimed to establish and reproduce transgenic pigs expressing human growth hormone (hGH) in their milk. We also aimed to purify hGH from the milk, to characterize the purified protein, and to assess the potential of our model for mass production of therapeutic proteins using transgenic techniques. Using ~15.5 L transgenic pig milk, we obtained proteins with ≥ 99% purity after three pre-treatments and five column chromatography steps. To confirm the biosimilarity of our milk-derived purified recombinant hGH (CGH942) with commercially available somatropin (Genotropin), we performed spectroscopy, structural, and biological analyses. We observed no difference between the purified protein and Genotropin samples. Furthermore, rat models were used to assess growth promotion potential. Our results indicate that CGH942 promotes growth, by increasing bone development and body weight. Toxicity assessments revealed no abnormal findings after 4 weeks of continuous administration and 2 weeks of recovery. The no-observed-adverse-effect level for both males and females was determined to be 0.6 mg/kg/day. Thus, no toxicological differences were observed between commercially available somatropin and CGH942 obtained from transgenic pig milk. In conclusion, we describe a transgenic technique using pigs, providing a new platform to produce human therapeutic proteins.


Assuntos
Animais Geneticamente Modificados/metabolismo , Hormônio do Crescimento Humano , Proteínas Recombinantes , Animais , Cromatografia de Afinidade , Feminino , Técnicas de Transferência de Genes , Hormônio do Crescimento Humano/química , Hormônio do Crescimento Humano/genética , Hormônio do Crescimento Humano/metabolismo , Humanos , Ratos , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/toxicidade , Suínos
2.
Expert Opin Pharmacother ; 21(15): 1883-1895, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32633582

RESUMO

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.


Assuntos
Acromegalia/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Glucose/metabolismo , Somatostatina/uso terapêutico , Acromegalia/complicações , Acromegalia/epidemiologia , Acromegalia/metabolismo , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Hormônio do Crescimento Humano/metabolismo , Humanos , Resistência à Insulina , Fator de Crescimento Insulin-Like I/metabolismo , Prevalência , Somatostatina/análogos & derivados
3.
J Med Case Rep ; 14(1): 34, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32079542

RESUMO

BACKGROUND: Lipodystrophies are a group of diseases which are characterized by abnormal adipose tissue deposition and are frequently associated with metabolic changes. Congenital generalized lipodystrophy is an autosomal recessive syndrome, with a prevalence < 1:10 million. Acromegaly is a rare disease, secondary to the chronic hypersecretion of growth hormone and insulin-like growth factor-1, with characteristic metabolic and somatic effects. "Acromegaloidism" is a term used for patients who manifest clinical features of acromegaly, but do not present a demonstrable hormone growth hypersecretion. The extreme shortage of subcutaneous adipose tissues and muscle hypertrophy confer an acromegaloid-like appearance in these patients. CASE PRESENTATION: We describe a case of a patient with the rare combination of Berardinelli-Seip congenital lipodystrophy and acromegaly; our patient is a 63-year-old white man, who was referred to an endocrinology consultation for suspected lipodystrophy. He had lipoatrophy of upper and lower limbs, trunk, and buttocks, with muscular prominence, acromegaloid facial appearance, large extremities, and soft tissue tumescence. In addition, he had dyslipidemia and prediabetes. His fat mass ratio (% trunk fat mass/% lower limbs fat mass) was 1.02 by densitometry and he also had hepatomegaly, with mild steatosis (from an abdominal ultrasound), and left ventricular hypertrophy (from an electrocardiogram). His first oral glucose tolerance test had growth hormone nadir of 0.92 ng/mL, and the second test, 10 months afterwards, registered growth hormone nadir of 0.64 ng/mL (growth hormone nadir < 0.3 ng/mL excludes acromegaly). Pituitary magnetic resonance imaging identified an area of hypocaptation of contrast product in relation to a pituitary adenoma and he was subsequently submitted to transsphenoidal surgical resection of the mass. A pathological evaluation showed pituitary adenoma with extensive expression of growth hormone and adrenocorticotropic hormone, as well as a rare expression of follicle-stimulating hormone and prolactin. A genetic study revealed an exon 3/exon 4 deletion of the AGPAT2 gene in homozygosity. CONCLUSIONS: Congenital generalized lipodystrophy is a rare disease which occurs with acromegaloid features. As far as we know, we have described the first case of genetic lipodystrophy associated with true acromegaly. Although this is a rare association, the presence of congenital generalized lipodystrophy should not exclude the possibility of simultaneous acromegaly.


Assuntos
Acromegalia/complicações , Adenoma/patologia , Hormônio do Crescimento Humano/metabolismo , Lipodistrofia Generalizada Congênita/complicações , Neoplasias Hipofisárias/patologia , Aciltransferases/genética , Hormônio Adrenocorticotrópico/metabolismo , Dislipidemias/complicações , Éxons , Hormônio Foliculoestimulante/metabolismo , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/complicações , Prolactina/metabolismo
4.
Ann Endocrinol (Paris) ; 81(1): 11-17, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31982107

RESUMO

OBJECTIVE: The aim of this study was to describe endocrinological outcome in patients operated on for acromegaly. METHODS: A retrospective study included 167 patients. Patients were assessed in the early postoperative period (EPP), at 3 months (M3), at 1 year (Y1), and then annually. They were classified as grade I (IGF-1 level normal-for-age and positive GH response on oral glucose tolerance test [nadir <0.4ng/L]); grade II (discordant); or grade III or IV (acromegaly, controlled or uncontrolled under medical therapy, respectively). RESULTS: Taking all patients with all grades, 35% changed grades between EPP and M3, 26% between M3 and Y1 and 9% after Y1. In grade I, respectively 22%, 15% and 2% of patients changed grades between EPP and M3, between M3 and Y1, and after Y1, compared to 31%, 6% and 6% in grade IV. Respectively 57%, 67%, and 47% of grade II patients changed grades between EPP and M3, between M3 and Y1, and after Y1; between EPP or M3 and last follow-up (>1 year), respectively 74% and 75% of grade II patients changed grades. Knosp category, resection quality and abnormal GH response (vs. abnormal IGF-1) significantly impacted grade II patients' outcome. CONCLUSIONS: Whereas outcome in grades I and III-IV seems to be determined by 1 year, grade II discordant patients' outcome remains uncertain even after 1 year.


Assuntos
Acromegalia/metabolismo , Acromegalia/cirurgia , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Acromegalia/diagnóstico , Acromegalia/patologia , Adenoma/diagnóstico , Adenoma/metabolismo , Adenoma/patologia , Adenoma/cirurgia , Adulto , Idoso , Feminino , Seguimentos , Teste de Tolerância a Glucose , Adenoma Hipofisário Secretor de Hormônio do Crescimento/diagnóstico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Hormônio do Crescimento Humano/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Prognóstico , Recidiva , Estudos Retrospectivos , Via Secretória/fisiologia , Resultado do Tratamento
5.
Eur J Med Genet ; 63(1): 103614, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30654153

RESUMO

In everyday practice, a pediatric endocrinologist will face a variety of different endocrine issues (such as short or tall stature, dysthyroidism, abnormal pubertal timing or impaired glucose metabolism), which relevantly contribute to the global care of a number of syndromic conditions. On the other hand, the presence of endocrine features may assist in the diagnostic process, leading to final diagnosis of a syndromic disorder. The intention of this review is to provide a referenced overview of different genetic syndromes characterized by endocrine features, and to present a possible classification, based on whether the endocrinopathy or the syndrome is typically recognized first. Thus, the first part of the manuscript deals with the most common syndromes associated with endocrine dysfunctions, while the second part describes the conditions by which a syndrome is most frequently diagnosed after an endocrine finding. The aim is to provide a practical overview of the assessment of syndromic patients, so that they can be recognized and managed in an integrated, multidisciplinary fashion.


Assuntos
Doenças do Sistema Endócrino/genética , Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/genética , Estatura/genética , Criança , Doenças do Sistema Endócrino/metabolismo , Doenças do Sistema Endócrino/patologia , Endocrinologistas , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/patologia , Hormônio do Crescimento Humano/metabolismo , Humanos , Pediatria/tendências
6.
J Clin Endocrinol Metab ; 105(1)2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31529097

RESUMO

CONTEXT: Women with polycystic ovarian syndrome (PCOS) have decreased growth hormone (GH), which can result in increased visceral adiposity (VAT) and impaired vascular function. GH-releasing hormone, a dipeptidyl peptidase-4 (DPP4) substrate, stimulates GH secretion. OBJECTIVE: We tested the hypothesis that DPP4 inhibition increases GH and improves glucose levels and vascular function in women with PCOS. METHODS: Eighteen women with PCOS participated in a double-blind, crossover study. They received sitagliptin either 100 mg or placebo daily for 1 month, with crossover treatments separated by an 8-week washout. During each treatment, women underwent a 75-gram oral glucose tolerance test (OGTT) and assessments of vascular function and body composition. Overnight GH secretion was assessed via venous sampling every 10 minutes for 12 hours and analyzed using an automated deconvolution algorithm. RESULTS: During OGTT, sitagliptin increased glucagon-like peptide-1 (P < 0.001), early insulin secretion (from mean [± SD] insulinogenic index 1.9 ± 1.2 to 3.2 ± 3.1; P = 0.02), and decreased peak glucose (mean -17.2 mg/dL [95% CI, -27.7 to -6.6]; P < 0.01). At 1 month, sitagliptin decreased VAT (from 1141.9 ± 700.7 to 1055.1 ± 710.1 g; P = 0.02) but did not affect vascular function. Sitagliptin increased GH half-life (from 13.9 ± 3.6 to 17.0 ± 6.8 min, N = 16; P = 0.04) and interpulse interval (from 53.2 ± 20.0 to 77.3 ± 38.2 min, N = 16; P < 0.05) but did not increase mean overnight GH (P = 0.92 vs placebo). CONCLUSIONS: Sitagliptin decreased the maximal glucose response to OGTT and VAT. Sitagliptin did not increase overnight GH but increased GH half-life and the interpulse interval. CLINICAL TRIAL REGISTRATION: This study was registered at www.clinicaltrials.gov as NCT02122380 prior to enrollment of the first participant.


Assuntos
Glicemia/metabolismo , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Gordura Intra-Abdominal/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Fosfato de Sitagliptina/uso terapêutico , Adolescente , Adulto , Biomarcadores/análise , Glicemia/análise , Glicemia/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Seguimentos , Teste de Tolerância a Glucose , Hormônio do Crescimento Humano/metabolismo , Humanos , Pessoa de Meia-Idade , Síndrome do Ovário Policístico/patologia , Prognóstico , Adulto Jovem
7.
J Clin Endocrinol Metab ; 105(1)2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31544947

RESUMO

BACKGROUND: Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. AIM: To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. METHODS: Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, ß-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: Total FGF21, active FGF21 and ß-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000). CONCLUSION: 1) Circulating FGF21 and ß-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover. CLINICAL TRIALS REGISTRATION: NCT00647179.


Assuntos
Acromegalia/metabolismo , Biomarcadores/metabolismo , Colágeno/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Gelatinases/metabolismo , Hormônio do Crescimento Humano/metabolismo , Proteínas de Membrana/metabolismo , Serina Endopeptidases/metabolismo , Acromegalia/patologia , Acromegalia/terapia , Adulto , Idoso , Estudos de Casos e Controles , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
8.
Genomics ; 112(1): 721-728, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078717

RESUMO

Personalized medicine, one of the main promises of the Human Genome Project (HGP) that began three decades ago, is now a new therapeutic paradigm. With its arrival the era of developing drugs to suit all patients, yet often having to withdraw a promising new one because a minority of patients was at risk, even though it had proved valuable for the majority was consigned to history as were trial-and-error strategies being the predominant means of tailoring therapy. But how did it originate and the earliest examples emerge? Is it true that the first personalized diagnostic test was the companion test for Herceptin®? This account of a remarkable journey from genomic and translational research to therapeutic and diagnostic innovations, describes how sequencing the human growth hormone (hGH) locus provided proof of principle for HGP-inspired personalized medicine. Sequencing this locus and the resultant biomanufacture of HGH and the development of a test capable of detecting which patients would benefit from its administration helped silence the skeptics who questioned the validity of such an approach. The associated companion diagnostic was created four years before the invention of the HercepTest® (registered as the first companion diagnostics ever developed). By cultivating genomic research with passion and pursuing its applications, we and many others contributed to the emergence of a new diagnostics industry, the discovery of better actionable gene-targets and to a revitalized pharmaceutical industry capable of developing safer and more effective therapies. In combination, these developments are beginning to fulfill the promise of the HGP, offering each patient the opportunity to adopt the right treatment at the correct dosage in an opportune manner.


Assuntos
Loci Gênicos , Genômica , Medicina de Precisão , Hormônio do Crescimento Humano/genética , Hormônio do Crescimento Humano/metabolismo , Humanos , Estudo de Prova de Conceito
9.
J Cell Biol ; 219(1)2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31825461

RESUMO

The surfacing of the glucose transporter GLUT4 driven by insulin receptor activation provides the prototypic example of a homeostasis response dependent on mobilization of an intracellular storage compartment. Here, we generalize this concept to a G protein-coupled receptor, somatostatin receptor subtype 2 (SSTR2), in pituitary cells. Following internalization in corticotropes, SSTR2 moves to a juxtanuclear syntaxin-6-positive compartment, where it remains until the corticotropes are stimulated with corticotropin releasing factor (CRF), whereupon SSTR2 exits the compartment on syntaxin-6-positive vesicular/tubular carriers that depend on Rab10 for their fusion with the plasma membrane. As SSTR2 activation antagonizes CRF-mediated hormone release, this storage/resurfacing mechanism may allow for a physiological homeostatic feedback system. In fact, we find that SSTR2 moves from an intracellular compartment to the cell surface in pituitary gland somatotropes, concomitant with increasing levels of serum growth hormone (GH) during natural GH cycles. Our data thus provide a mechanism by which signaling-mediated plasma membrane resurfacing of SSTR2 can fine-tune pituitary hormone release.


Assuntos
Corticotrofos/metabolismo , Hormônio do Crescimento Humano/metabolismo , Hipófise/metabolismo , Proteínas Qa-SNARE/metabolismo , Receptores de Somatostatina/metabolismo , Proteínas rab de Ligação ao GTP/fisiologia , Animais , Hormônio Liberador da Corticotropina , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hipófise/citologia , Proteínas Qa-SNARE/genética , Receptores de Somatostatina/genética , Transdução de Sinais
11.
Metabolism ; 101: 153998, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31666193

RESUMO

BACKGROUND: The incidence of growth hormone deficiency (GHD) in adamantinomatous craniopharyngioma (aCP) is significantly higher than in other sellar region tumors, but the possible mechanism is still elusive. A high level of inflammatory responses is another feature of aCP. We investigated the internal connection between interleukin-1α (IL-1α) and GHD, while focusing on its biological activities in pituitary fibrosis. MATERIALS AND METHODS: To diagnosis of GHD, the Body Mass Index (BMI), Insulin Like Growth Factor-1(IGF-1) and peak growth hormone (GH) values after insulin stimulation test of 15 aCP patients were recorded. Histological staining was performed on the aCP samples. Levels of 9 proinflammatory cytokines in tumor tissue and cell supernatant were detected using Millipore bead arrays. The effect of IL-1α on GH secretion was evaluated in vivo and in vitro. Western blot, qRT-PCR and cell functional assays were used to explore the potential mechanism through which IL-1α acts on GH secretion. The stereotactic ALZET osmotic pump technique was used to simulate aCP secretion of proinflammatory cytokines in rats. Recombinant IL-1α (rrIL-1α) and conditioned media (CM) prepared from the supernatant of aCP cells was infused directly into the intra-sellar at a rate of 1 µl/h over 28 days, and then the effects of IL-1α treatment on pathological changes of pituitary gland and GH secretion were measured. To further confirm whether IL-1α affects GH secretion through IL-1R1, an IL-1R1 blocker (IL-1R1a, 10 mg/kg body weight, once daily) was administered subcutaneously from the first day until day 28. RESULTS: There was a significant positive correlation between pituitary fibrosis and GHD (rS = 0.756, P = 0.001). A number of cytokines, in particular IL-1α, interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1), were elevated in tumor tissue and cell supernatant. Only IL-1α showed a significant difference between the GHD group and the No-GHD group (P < 0.001, F = 6.251 in tumor tissue; P = 0.003, F = 1.529 in cell supernatant). IL-1α significantly reduced GH secretion in coculture of GH3 and pericytes. The activation of pericytes induced by IL-1α was mediated by the IL-1R1 signaling pathway. In vivo, IL-1α induces pituitary fibrosis, further leading to a decreased level of GH. This pathological change was antagonized by IL-1R1a. CONCLUSION: This study found that the cross talk between aCP cells and stroma cells in the pituitary, i.e. pericytes, is an essential factor in the formation of GHD, and we propose that neutralization of IL-1α signaling might be a potential therapy for GHD in aCP.


Assuntos
Comunicação Celular , Craniofaringioma/patologia , Hormônio do Crescimento Humano/deficiência , Interleucina-1alfa/farmacologia , Pericitos/efeitos dos fármacos , Adulto , Animais , Craniofaringioma/etiologia , Citocinas/metabolismo , Feminino , Fibrose , Hormônio do Crescimento Humano/efeitos dos fármacos , Hormônio do Crescimento Humano/metabolismo , Humanos , Inflamação , Masculino , Pericitos/citologia , Hipófise/metabolismo , Hipófise/patologia , Ratos
12.
Physiol Rep ; 7(21): e14285, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31724339

RESUMO

Fasting in human subjects shifts skeletal muscle metabolism toward lipid utilization and accumulation, including intramyocellular lipid (IMCL) deposition. Growth hormone (GH) secretion amplifies during fasting and promotes lipolysis and lipid oxidation, but it is unknown to which degree lipid deposition and metabolism in skeletal muscle during fasting depends on GH action. To test this, we studied nine obese but otherwise healthy men thrice: (a) in the postabsorptive state ("CTRL"), (b) during 72-hr fasting ("FAST"), and (c) during 72-hr fasting and treatment with a GH antagonist (GHA) ("FAST + GHA"). IMCL was assessed by magnetic resonance spectroscopy (MRS) and blood samples were drawn for plasma metabolomics assessment while muscle biopsies were obtained for measurements of regulators of substrate metabolism. Prolonged fasting was associated with elevated GH levels and a pronounced GHA-independent increase in circulating medium- and long-chain fatty acids, glycerol, and ketone bodies indicating increased supply of lipid intermediates to skeletal muscle. Additionally, fasting was associated with a release of short-, medium-, and long-chain acylcarnitines to the circulation from an increased ß-oxidation. This was consistent with a ≈55%-60% decrease in pyruvate dehydrogenase (PDHa) activity. Opposite, IMCL content increased ≈75% with prolonged fasting without an effect of GHA. We suggest that prolonged fasting increases lipid uptake in skeletal muscle and saturates lipid oxidation, both favoring IMCL deposition. This occurs without a detectable effect of GHA on skeletal muscle lipid metabolism.


Assuntos
Jejum/metabolismo , Metabolismo dos Lipídeos/fisiologia , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Glucose/metabolismo , Hormônio do Crescimento Humano/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Metaboloma , Proteínas Mitocondriais/metabolismo , Oxirredução , Receptores Ativados por Proliferador de Peroxissomo/metabolismo
13.
Arch. endocrinol. metab. (Online) ; 63(6): 549-556, Nov.-Dec. 2019. graf
Artigo em Inglês | LILACS | ID: biblio-1055020

RESUMO

ABSTRACT Growth hormone (GH) is best known for its effect stimulating tissue and somatic growth through the regulation of cell division, regeneration and proliferation. However, GH-responsive neurons are spread over the entire central nervous system, suggesting that they have important roles in the brain. The objective of the present review is to summarize and discuss the potential physiological importance of GH action in the central nervous system. We provide evidence that GH signaling in the brain regulates the physiology of numerous functions such as cognition, behavior, neuroendocrine changes and metabolism. Data obtained from experimental animal models have shown that disruptions in GH signaling in specific neuronal populations can affect the reproductive axis and impair food intake during glucoprivic conditions, neuroendocrine adaptions during food restriction, and counter-regulatory responses to hypoglycemia, and they can modify gestational metabolic adaptions. Therefore, the brain is an important target tissue of GH, and changes in GH action in the central nervous system can explain some dysfunctions presented by individuals with excessive or deficient GH secretion. Furthermore, GH acts in specific neuronal populations during situations of metabolic stress to promote appropriate physiological adjustments that restore homeostasis. Arch Endocrinol Metab. 2019;63(6):549-56


Assuntos
Humanos , Encéfalo/metabolismo , Fármacos Neuroprotetores/metabolismo , Hormônio do Crescimento Humano/metabolismo , Redes e Vias Metabólicas/fisiologia , Transdução de Sinais , Regeneração Nervosa/fisiologia
14.
Ann Endocrinol (Paris) ; 80 Suppl 1: S10-S18, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31606057

RESUMO

Acromegaly is characterized by increased release of growth hormone (GH) and, consequently, Insulin-Like Growth Factor I (IGF-I), most often by a pituitary adenoma. Prolonged exposure to excess hormone leads to progressive somatic disfigurement and a wide range of systemic manifestations that are associated with increased mortality. Transsphenoidal adenomectomy is the treatment of choice of GH-secreting pituitary tumors but surgical cure is not achieved in around 50% of patients, then adjuvant treatment is necessary. Mortality in acromegaly is normalized with biochemical control and has decreased in the last decade with the increased use of adjuvant therapy. Both GH and IGF-I are currently biomarkers for assessing disease activity in patients with acromegaly. However, discordance between GH and IGF-I results is encountered in a quarter of treated patients. The impacts of such a discrepancy over mortality and morbidity and the risk of biochemical and/or clinical recurrence are unclear. Moreover, despite a good biochemical control, some symptoms persist, leading to a decreased quality of life. Back pain due to vertebral fractures seem to be frequent in these patients and underdiagnosed. In patients with acromegaly, bone mineral density is not a reliable predictor of fracture risk. A more accurate evaluation of bone microstructural alterations associated with GH hypersecretion and vertebral fractures may be provided by new radiological devices analyzing alteration of trabecular microarchitecture, leading to a better prevention. © 2019 Published by Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Les Must de l'Endocrinologie 2019 réalisé avec le soutien institutionnel de Ipsen-Pharma.


Assuntos
Acromegalia/terapia , Garantia da Qualidade dos Cuidados de Saúde , Melhoria de Qualidade , Acromegalia/diagnóstico , Acromegalia/epidemiologia , Acromegalia/etiologia , Adenoma/complicações , Adenoma/epidemiologia , Adenoma/metabolismo , Adenoma/terapia , Técnicas de Diagnóstico Endócrino/tendências , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/epidemiologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/terapia , Hormônio do Crescimento Humano/metabolismo , Humanos , Garantia da Qualidade dos Cuidados de Saúde/métodos , Garantia da Qualidade dos Cuidados de Saúde/tendências
15.
Artigo em Inglês | MEDLINE | ID: mdl-31574933

RESUMO

Ensuring normal linear growth is one of the major therapeutic aims in the management of type one diabetes mellitus (T1DM) in children and adolescents. Many studies in the literature have shown that pediatric patients with T1DM frequently present some abnormalities in their growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis compared to their healthy peers. Data on the growth of T1DM children and adolescents are still discordant: Some studies have reported that T1DM populations, especially those whose diabetes began in early childhood, are taller than healthy pediatric populations at diagnosis, while other studies have not found any difference. Moreover, many reports have highlighted a growth impairment in T1DM patients of prepubertal and pubertal age, and this impairment seems to be influenced by suboptimal glycemic control and disease duration. However, the most recent data showed that children treated with modern intensive insulin therapies reach a normal final adult height. This narrative review aims to provide current knowledge regarding linear growth in children and adolescents with T1DM. Currently, the choice of the most appropriate therapeutic regimen to achieve a good insulin level and the best metabolic control for each patient, together with the regular measurement of growth parameters, remains the most important available tool for a pediatric diabetologist. Nevertheless, since new technologies are the therapy of choice in young children, especially those of pre-school age, it would be of great interest to evaluate their effects on the growth pattern of children with T1DM.


Assuntos
Desenvolvimento do Adolescente , Desenvolvimento Infantil , Diabetes Mellitus Tipo 1 , Adolescente , Estatura , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Hormônio do Crescimento Humano/metabolismo , Humanos , Insulina/uso terapêutico , Fator de Crescimento Insulin-Like I/metabolismo , Puberdade
16.
PLoS One ; 14(10): e0223024, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31647849

RESUMO

AIM: To examine global gene expression response to profound metabolic and hormonal stress induced by acute sprint exercise. METHODS: Healthy men and women (n = 14) performed three all-out cycle sprints interspersed by 20 min recovery. Muscle biopsies were obtained before the first, and 2h and 20 min after last sprint. Microarray analysis was performed to analyse acute gene expression response and repeated blood samples were obtained. RESULTS: In skeletal muscle, a set of immediate early genes, FOS, NR4A3, MAFF, EGR1, JUNB were markedly upregulated after sprint exercise. Gene ontology analysis from 879 differentially expressed genes revealed predicted activation of various upstream regulators and downstream biofunctions. Gene signatures predicted an enhanced turnover of skeletal muscle mass after sprint exercise and some novel induced genes such as WNT9A, FZD7 and KLHL40 were presented. A substantial increase in circulating free fatty acids (FFA) was noted after sprint exercise, in parallel with upregulation of PGC-1A and the downstream gene PERM1 and gene signatures predicting enhanced lipid turnover. Increase in growth hormone and insulin in blood were related to changes in gene expressions and both hormones were predicted as upstream regulators. CONCLUSION: This is the first study reporting global gene expression in skeletal muscle in response to acute sprint exercise and several novel findings are presented. First, in line with that muscle hypertrophy is not a typical finding after a period of sprint training, both hypertrophy and atrophy factors were regulated. Second, systemic FFA and hormonal and exposure might be involved in the sprint exercise-induced changes in gene expression.


Assuntos
Ácidos Graxos não Esterificados/genética , Proteínas Musculares/genética , Músculo Esquelético/fisiopatologia , Transcriptoma/genética , Adulto , Glicemia/metabolismo , Exercício Físico/fisiologia , Ácidos Graxos não Esterificados/metabolismo , Feminino , Hormônio do Crescimento Humano/genética , Hormônio do Crescimento Humano/metabolismo , Humanos , Insulina/metabolismo , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Corrida/fisiologia
17.
Pediatr Endocrinol Rev ; 17(1): 4-16, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31599132

RESUMO

Growth hormone (GH) is a pleiotropic hormone that coordinates an array of physiological processes including growth and metabolism. GH promotes anabolic action in all tissues except adipose, where it catabolizes stored fat to release energy for the promotion of growth in other tissues. However, chronic stimulation of lipolysis by GH results in an increased flux of free fatty acids (FFAs) into systemic circulation. Hence, a sustained release of high levels of GH contributes significantly to the development of insulin resistance by antagonizing the anti-lipolytic action of insulin. The molecular pathways associated with the lipolytic effect of GH in adipose tissue however, remain elusive. Recent studies have provided molecular insights into GH-induced lipolysis and impairment of insulin signaling. This review discusses the physiological and metabolic actions of GH on adipose tissue as well as GH-mediated deregulation of the FSP27-PPARγ axis which alters adipose tissue homeostasis and contributes to the development of insulin resistance and Type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Hormônio do Crescimento Humano , Resistência à Insulina , Lipólise , Tecido Adiposo/efeitos dos fármacos , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/fisiopatologia , Hormônio do Crescimento Humano/metabolismo , Hormônio do Crescimento Humano/farmacologia , Humanos , Lipólise/efeitos dos fármacos
18.
Pediatr Endocrinol Rev ; 17(1): 41-46, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31599135

RESUMO

The somatotropic axis is intricately involved in normal sleep, as evidenced by the fact that hypothalamic growth hormone-releasing hormone (GHRH) has sleep promoting effects and pituitary growth hormone (GH) release is strongly associated with slow-wave sleep (SWS). Abnormalities in the somatotropic axis, such as GH deficiency of hypothalamic or pituitary origin, result in an alteration of normal sleep patterns which may explain the fatigue reported in these individuals. Sleep disorders such as narcolepsy, in which individuals abnormally enter rapid eye movement (REM) sleep at sleep onset are also associated with an altered GHRH circadian rhythm and abnormal GH secretion. While few studies are available, this review explores what is known about sleep abnormalities in GH deficiency, the effect of treatment on sleep in patients with GH deficiency, and GH secretion in narcolepsy. Emerging evidence suggests a hypothalamic link between narcolepsy and GH secretion. We also describe the unique constellation of isolated idiopathic GH deficiency and severe excessive sleepiness in adopted Nicaraguan siblings, one of which has narcolepsy and the other idiopathic hypersomnia.


Assuntos
Hormônio do Crescimento Humano , Sonolência , Criança , Nanismo Hipofisário/tratamento farmacológico , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Hormônio do Crescimento Humano/efeitos adversos , Hormônio do Crescimento Humano/metabolismo , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Narcolepsia/fisiopatologia
19.
Horm Res Paediatr ; 92(1): 15-27, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31509834

RESUMO

BACKGROUND: The reason for the insufficient catch-up growth seen in 10% of children born small for gestational age (SGA) is poorly understood. Disturbances in the growth hormone (GH) - insulin-like growth factor (IGF) axis might underlie this failure to show sufficient catch-up growth. CONCLUSION: This review summarizes insights gained in the molecular and (epi) genetic mechanisms of the GH-IGF axis in short children born SGA. The most notable anomalies of the IGF system are the lowered IGF-I levels in both cord blood and the placenta, and the increased expression of IGF-binding proteins (IGFBP)-1 and IGFBP-2, which inhibit IGF-I, in the placenta of SGA neonates. These observations suggest a decreased bioactivity of IGF-I in utero. IGF-I levels remain reduced in SGA children with short stature, as well as IGFBP-3 and acid-labile subunit levels. Proteolysis of IGFBP-3 appears to be increased.


Assuntos
Epigênese Genética , Hormônio do Crescimento Humano , Recém-Nascido Pequeno para a Idade Gestacional/metabolismo , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina , Fator de Crescimento Insulin-Like I , Proteólise , Criança , Feminino , Hormônio do Crescimento Humano/genética , Hormônio do Crescimento Humano/metabolismo , Humanos , Recém-Nascido , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino
20.
BMC Endocr Disord ; 19(1): 94, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477080

RESUMO

BACKGROUND: Acromegaly is highly associated with thyroid disorders. However, the clinical characteristics of thyroid nodules in individuals with acromegaly who present with thyroid diseases have not been completely elucidated. METHODS: Overall, 134 consecutive participants with growth hormone (GH)-secreting adenoma (n = 67) and non-functioning (NF) pituitary adenoma (n = 67) were recruited from the outpatient and inpatient patient department of The First Affiliated Hospital, Jinan University from August 2015 to August 2017. Thyroid ultrasonography was performed using an ultrasound system. The cytopathological results of fine-needle aspiration biopsy were analyzed by a pathologist according to the Bethesda system. Twenty-one patients with GH-secreting adenoma and thyroid disease underwent transsphenoidal pituitary adenoma resection and were followed up for 1 year. RESULTS: The prevalence of thyroid disease increased in the GH-secreting adenoma group compared with that in the NF pituitary adenoma group. The number of hypoechoic, isoechogenic, heterogeneous, and vascular thyroid nodules increased in patients with GH-secreting adenoma plus thyroid disease compared with that in patients with NF pituitary adenoma plus thyroid disease. Finally, we found significant decreases in the morphology of solid nodules and significant increases in the morphology of cystic nodules after surgery compared with those before surgery in the cured group. Moreover, the numbers of heterogeneous and vascular thyroid nodules decreased significantly after surgery compared with those before surgery in the cured group. However, the characteristics of the thyroid nodules did not change after surgery compared with those before surgery in the non-cured group. CONCLUSIONS: The numbers of hypoechoic, isoechoic, heterogeneous, and vascular thyroid nodules increased in patients with GH-secreting adenomas. In these patients, surgery resulted in significant changes from solid to cystic nodules and also reduced the numbers of heterogeneous and vascular thyroid nodules.


Assuntos
Adenoma/fisiopatologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/fisiopatologia , Hormônio do Crescimento Humano/metabolismo , Doenças da Glândula Tireoide/epidemiologia , Hormônios Tireóideos/metabolismo , Nódulo da Glândula Tireoide/patologia , Adenoma/metabolismo , Adulto , Idoso , Feminino , Seguimentos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taiwan/epidemiologia , Doenças da Glândula Tireoide/diagnóstico , Doenças da Glândula Tireoide/diagnóstico por imagem , Doenças da Glândula Tireoide/metabolismo , Nódulo da Glândula Tireoide/diagnóstico por imagem , Nódulo da Glândula Tireoide/metabolismo , Ultrassonografia , Adulto Jovem
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