RESUMEN
Introduction: The glucagon stimulation test (GST) is widely used to assess growth hormone (GH) and cortisol secretion, nevertheless the precise mechanisms underpinning these hormonal responses remain unclear. We have endeavoured to explore the relationship between glucose and insulin fluctuations during GST and their impact on GH and cortisol secretion. Subjects and methods: We retrospectively studied 139 subjects (mean age 35.5 ± 15.1 years, BMI 26.6 ± 6.61 kg/m²), including 62 individuals with a history of pituitary disease (27 with an intact adrenal axis) and 77 healthy controls. Standard dose intramuscular GST was performed in all subjects. Results: Once BMI and age were excluded from multivariate model, the nadir of glucose concentration during GST was the sole variable associated with maximal GH secretion (ΔGH, p<0.0003), while neither glucose/insulin peak, nor Δglucose/Δinsulin concentrations contributed to ΔGH. 100% pass rate for GH secretion above 3 ng/ml or 1.07 ng/ml cut-offs was observed for glucose concentrations at, or below 60 mg/dl (3.33 mmol/l) (for Controls), or 62 mg/dl (3.44 mmol/l) (for Controls and patients with an intact adrenocortical axis). Such low glucose concentrations were obtained, however, only in about 30% of studied individuals. Conversely, cortisol secretion did not correlate with glucose or insulin fluctuations, suggesting alternative regulatory mechanisms. Conclusions: This study reveals that glucose nadir below 3.33 mmol/l is the only biochemical biovariable linked with optimal GH secretion during GST, whereas mechanisms responsible for cortisol secretion remain unclear. We emphasize the importance of glucose monitoring during GST to validate GH stimulation and support clinical decisions in GH deficiency management.
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Glucemia , Glucagón , Hormona de Crecimiento Humana , Hidrocortisona , Humanos , Glucagón/sangre , Masculino , Adulto , Femenino , Estudios Retrospectivos , Glucemia/análisis , Glucemia/metabolismo , Hormona de Crecimiento Humana/sangre , Hormona de Crecimiento Humana/metabolismo , Persona de Mediana Edad , Hidrocortisona/sangre , Hidrocortisona/metabolismo , Insulina/sangre , Adulto Joven , Estudios de Casos y Controles , Enfermedades de la Hipófisis/sangre , Enfermedades de la Hipófisis/metabolismo , Enfermedades de la Hipófisis/diagnósticoRESUMEN
Background: Skeletal fragility is characterized by increased frequency of vertebral fractures (VFs) in acromegaly. Several trials were conducted to identify modifiable risk factors and predictors of VFs, with limited data on the prognostic role of GH receptor (GHR) isoforms. In this study, we investigated the potential role of GHR polymorphism on the occurrence of incidental VFs (i-VFs), in patients treated with second-line medical therapies. Methods: A longitudinal, retrospective, observational study was conducted on a cohort of 45 acromegalic patients not-responsive to first-generation somatostatin receptor ligands (fg-SRLs) and treated with GHR antagonist (Pegvisomant) or with the second-generation SRLs (Pasireotide long-acting release). Results: Second line treatments were Pegvisomant plus fg-SRLs in 26 patients and Pasireotide LAR in 19 patients. From the group treated with fg-SRLs+Peg-V, the fl-GHR isoform was identified in 18 patients (69.2%) and the d3-GHR isoform in 8 patients (30.8%). I-VFs arose exclusively in fl-GHR isoform carriers (p=0.039). From the group treated with Pasireotide LAR, the fl-GHR isoform was identified in 11 patients (57.9%), and the d3-GHR isoform in 8 patients (42.1%). I-VFs arose exclusively in d3-GHR isoform carriers (p=0.018). Patients with fl-GHR isoform had a higher risk for i-VFs if treated with fg-SRL+Peg-V (OR: 1.6 95%IC: 1.1-2.3, p=0.04), and a lower risk if treated with Pasi-LAR (OR: 0.26 IC95%: 0.11-0.66, p=0.038). Conclusions: Our data support a predictive role of the GHR isoforms for the occurrence of i-VFs in acromegalic patients treated with second-line drugs, tailored to the individual patient. The knowledge of the GHR polymorphism may facilitate the choice of second-line therapies, improving the therapeutic approach, in the context of personalized medicine.
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Acromegalia , Hormona de Crecimiento Humana , Receptores de Somatotropina , Somatostatina , Humanos , Acromegalia/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Proyectos Piloto , Receptores de Somatotropina/genética , Receptores de Somatotropina/metabolismo , Receptores de Somatotropina/antagonistas & inhibidores , Somatostatina/análogos & derivados , Somatostatina/uso terapéutico , Adulto , Hormona de Crecimiento Humana/uso terapéutico , Hormona de Crecimiento Humana/metabolismo , Hormona de Crecimiento Humana/análogos & derivados , Anciano , Polimorfismo Genético , Estudios LongitudinalesRESUMEN
BACKGROUND: Growth hormone (GH) positive pituitary neuroendocrine tumors do not always cause acromegaly. Approximately one-third of GH-positive pituitary tumors are classified as non-functioning pituitary tumors in clinical practice. They typically have GH and serum insulin-like growth factor 1 (IGF-1) levels in the reference range and no acromegaly-like symptoms. However, normal hormone levels might not exclude the underlying hypersecretion of GH. This is a rare and paradoxical case of pituitary tumor causing acromegaly-associated symptoms despite normal GH and IGF-1 levels. CASE PRESENTATION: We report a case of a 35-year-old woman with suspicious acromegaly-associated presentations, including facial changes, headache, oligomenorrhea, and new-onset diabetes mellitus and dyslipidemia. Imaging found a 19 × 12 × 8 mm pituitary tumor, but her serum IGF-1 was within the reference, and nadir GH was 0.7ng/ml after glucose load at diagnosis. A thickened skull base, increased uptake in cranial bones in bone scan, and elevated bone turnover markers indicated abnormal bone metabolism. We considered the pituitary tumor, possibly a rare subtype in subtle or clinically silent GH pituitary tumor, likely contributed to her discomforts. After the transsphenoidal surgery, the IGF-1 and nadir GH decreased immediately. A GH and prolactin-positive pituitary neuroendocrine tumor was confirmed in the histopathologic study. No tumor remnant was observed three months after the operation, and her discomforts, glucose, and bone metabolism were partially relieved. CONCLUSIONS: GH-positive pituitary neuroendocrine tumors with hormonal tests that do not meet the diagnostic criteria for acromegaly may also cause GH hypersecretion presentations. Patients with pituitary tumors and suspicious acromegaly symptoms may require more proactive treatment than non-functioning tumors of similar size and invasiveness.
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Acromegalia , Tumores Neuroendocrinos , Neoplasias Hipofisarias , Humanos , Femenino , Adulto , Acromegalia/diagnóstico , Acromegalia/complicaciones , Acromegalia/etiología , Tumores Neuroendocrinos/complicaciones , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/patología , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/patología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/complicaciones , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/diagnóstico , Hormona de Crecimiento Humana/sangre , Hormona de Crecimiento Humana/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Enfermedades Óseas/etiología , Enfermedades Óseas/diagnóstico , Enfermedades Óseas/patologíaRESUMEN
Acromegaly is a rare endocrine disease caused by hypersecretion of growth hormone, most commonly arising due to a pituitary adenoma. Diabetes mellitus is a common complication of acromegaly, occurring in approximately one-third of patients. The risk of diabetes mellitus in acromegaly is driven by increased exposure to growth hormone, which directly attenuates insulin signalling and stimulates lipolysis, leading to decreased glucose uptake in peripheral tissues. Acromegaly is a unique human model, where insulin resistance occurs independently of obesity and is paradoxically associated with a lean phenotype and reduced body adipose tissue mass. Diabetes mellitus in patients with acromegaly is associated with an increased risk of cardiovascular morbidity and mortality. Therefore, preventive measures and optimized treatment of diabetes mellitus are essential in these patients. However, specific recommendations for the management of diabetes mellitus secondary to acromegaly are lacking due to limited research on this subject. This Review explores the underlying mechanisms for diabetes mellitus in acromegaly and its effect on morbidity and mortality. We also discuss treatment modalities for diabetes mellitus that are suited for patients with acromegaly. Improved understanding of these issues will lead to better management of acromegaly and its associated metabolic complications.
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Acromegalia , Diabetes Mellitus , Humanos , Acromegalia/terapia , Acromegalia/complicaciones , Acromegalia/fisiopatología , Diabetes Mellitus/fisiopatología , Diabetes Mellitus/terapia , Diabetes Mellitus/epidemiología , Diabetes Mellitus/etiología , Hormona de Crecimiento Humana/metabolismo , Resistencia a la Insulina/fisiologíaRESUMEN
BACKGROUND: Ultraviolet-B (UVB) radiation is the leading environmental cause of skin damage and photoaging. The epidermis and dermis layers of the skin mainly absorb UVB. UVB stimulates apoptosis, cell cycle arrest, generation of reactive oxygen species, and degradation of collagen and elastin fibers. OBJECTIVE: This study investigated the potential of human growth hormone (hGH) in protecting the skin fibroblasts and keratinocytes (HFFF-2 and HaCaT cell lines) from UVB-induced damage. METHODS: The MTT assay was performed to evaluate UVB-induced mitochondrial damage via assessing the mitochondrial dehydrogenase activity, and flow cytometry was carried out to investigate the effects of UVB and hGH on the cell cycle and apoptosis of UVB-irradiated cells. In addition, the fold change mRNA expression levels of Type I collagen and elastin in HFFF-2 cells were evaluated using the qRT-PCR method following UVB exposure. RESULTS: We observed that treatment of cells with hGH before UVB exposure inhibited UVB-induced loss of mitochondrial dehydrogenase activity, apoptosis, and sub-G1 population formation in both cell lines. We also found that hGH-treated HFFF-2 cells showed up-regulated mRNA expression of Type I collagen, elastin, and IGF-1 in response to UVB irradiation. CONCLUSION: These findings suggest hGH as a potential anti-UVB compound that can protect skin cells from UVB-induced damage. Our findings merit further investigation and can be used to better understand the role of hGH in skin photoaging.
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Apoptosis , Colágeno Tipo I , Elastina , Fibroblastos , Hormona de Crecimiento Humana , Queratinocitos , Rayos Ultravioleta , Humanos , Elastina/metabolismo , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Línea Celular , Fibroblastos/efectos de la radiación , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/citología , Colágeno Tipo I/metabolismo , Colágeno Tipo I/genética , Queratinocitos/efectos de la radiación , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Queratinocitos/citología , Hormona de Crecimiento Humana/metabolismo , Hormona de Crecimiento Humana/farmacología , Piel/efectos de la radiación , Piel/efectos de los fármacos , Piel/metabolismo , Piel/citología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de la radiación , Mitocondrias/efectos de los fármacos , ARN Mensajero/metabolismo , ARN Mensajero/genéticaRESUMEN
Although growth hormone (GH) and prolactin (PRL) are usually recognized as pituitary hormones, their expression is not restricted to the adenohypophysis and can also be found in extra-pituitary tissues including placenta. Furthermore, GH, PRL, and their receptors structurally belong to the cytokine family of proteins, and indeed they have remarkable pleiotropic effects. In this review, we analyzed the biological roles of GH/PRL from an evolutionary perspective. We have recognized that the biological significance of GH/PRL can be summarized as follows: cytokines (metabokines) that regulate the shift of nutrients and even of whole bodies to live in the most appropriate environment(s) for conducting growth and reproduction. In this sense, the common keyword of the two metabokines is "shift" for environmental adaptation. Considering that these metabokines flexibly changed their biological roles, GH/PRL may have played important roles during vertebrate evolution.
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Evolución Biológica , Hormona del Crecimiento , Prolactina , Humanos , Prolactina/metabolismo , Prolactina/fisiología , Animales , Hormona del Crecimiento/metabolismo , Hormona del Crecimiento/fisiología , Femenino , Reproducción/fisiología , Hormona de Crecimiento Humana/metabolismo , Hormona de Crecimiento Humana/fisiologíaRESUMEN
OBJECTIVE: Spermatozoa are susceptible to oxidative radicals when antioxidant defenses are inadequate. The extent to which oxidative radicals contribute to sperm damage in patients with acromegaly remains unclear. This study aimed to investigate and elucidate this relationship. METHODS: The overall status of oxidants and antioxidants in both seminal plasma and serum of patients with acromegaly compared to a control group of healthy individuals was investigated. In addition, sperm parameters, including important measures such as growth hormone and insulin-like growth factor-1 concentrations. RESULTS: Twenty-two patients with acromegaly with controlled disease and 14 healthy controls were included. The total oxidant status was significantly higher in the semen samples of the patients with acromegaly. A negative correlation was found between sperm total oxidant status and total sperm count and sperm concentration. Similarly, a negative correlation was found between the total sperm count and the sperm oxidative stress index. In individuals diagnosed with acromegaly, there was a statistically significant increase in sperm growth hormone levels. Conversely, the level of insulin-like growth factor 1 was significantly increased in the sperm of the control group, which consisted of healthy individuals. The correlation analysis revealed a significant relationship between venous total oxidant status and growth hormone levels in semen. CONCLUSION: The elevated levels of reactive oxygen radicals in individuals with acromegaly suggest a possible link between oxidative stress and its effects on semen quality.
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Acromegalia , Estrés Oxidativo , Espermatozoides , Humanos , Masculino , Estrés Oxidativo/fisiología , Acromegalia/metabolismo , Acromegalia/sangre , Adulto , Persona de Mediana Edad , Espermatozoides/metabolismo , Análisis de Semen , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/análisis , Recuento de Espermatozoides , Semen/metabolismo , Hormona de Crecimiento Humana/sangre , Hormona de Crecimiento Humana/metabolismoRESUMEN
Objective: Individuals with hypopituitarism (HPs) have an increased risk of developing non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) due to growth hormone deficiency (GHD). We aimed to investigate the possible mechanisms underlying the relationship between GHD and NAFLD using proteomic and metabolomic insights. Methods: Serum metabolic alternations were assessed in male HPs using untargeted metabolomics. A rat model of HP was established through hypophysectomy, followed by recombinant human growth hormone (rhGH) intervention. The mechanisms underlying GHD-mediated NAFLD were elucidated through the application of label-free proteomics and phosphorylation proteomics. Results: Metabolomic analysis revealed that biomarkers of mitochondrial dysfunction and oxidative stress, such as alanine, lactate, and creatine, were significantly elevated in HPs compared to age-matched controls. In rats, hypophysectomy led to marked hepatic steatosis, lipid peroxidation, and reduced glutathione (GSH), which were subsequently modulated by rhGH replacement. Proteomic analysis identified cytochrome P450s, mitochondrial translation elongation, and PPARA activating genes as the major distinguishing pathways in hypophysectomized rats. The processes of fatty acid transport, synthesis, oxidation, and NADP metabolism were tightly described. An enhanced regulation of peroxisome ß-oxidation and ω-oxidation, together with a decreased NADPH regeneration, may exacerbate oxidative stress. Phosphoproteome data showed downregulation of JAK2-STAT5B and upregulation of mTOR signaling pathway. Conclusions: This study identified proteo-metabolomic signatures associated with the development of NAFLD in pituitary GHD. Evidence was found of oxidative stress imbalance resulting from abnormal fatty acid oxidation and NADPH regeneration, highlighting the role of GH deficiency in the development of NAFLD.
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Hipopituitarismo , Metabolómica , Enfermedad del Hígado Graso no Alcohólico , Estrés Oxidativo , Proteómica , Animales , Masculino , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Ratas , Hipopituitarismo/metabolismo , Hipopituitarismo/etiología , Ratas Sprague-Dawley , Hormona de Crecimiento Humana/deficiencia , Hormona de Crecimiento Humana/metabolismo , HumanosRESUMEN
The objective was to assess the potential differential effects of human versus mouse growth hormone in vivo, given that human unlike mouse growth hormone can bind prolactin as well as the growth hormone receptor. To this end, a transgenic CD-1 mouse expressing human but not mouse growth hormone was generated, and the phenotypes of male mice fed with a regular chow or high-fat diet were assessed. Pancreas and epididymal white adipose tissue gene expression and/or related function were targeted as the pancreas responds to both prolactin and growth hormone receptor signaling, and catabolic effects like lipolytic activity are more directly attributable to growth hormone and growth hormone receptor signaling. The resulting human growth hormone-expressing mice are smaller than wild-type CD-1 mice, despite higher body fat and larger adipocytes, but both mouse types grow at the same rate with similar bone densities. Unlike wild-type mice, there was no significant delay in glucose clearance in human growth hormone-expressing mice when assessed at 8 versus 24 weeks on a high-fat diet. However, both mouse types showed signs of hepatic steatosis that correlated with elevated prolactin but not growth hormone RNA levels. The larger adipocytes in human growth hormone-expressing mice were associated with modified leptin (higher) and adiponectin (lower) RNA levels. Thus, while limited to observations in the male, the human growth hormone-expressing mice exhibit signs of growth hormone insufficiency and adipocyte dysfunction as well as an initial resistance to the negative effects of high-fat diet on glucose clearance.
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Tejido Adiposo , Dieta Alta en Grasa , Hígado Graso , Glucosa , Homeostasis , Resistencia a la Insulina , Ratones Transgénicos , Animales , Humanos , Dieta Alta en Grasa/efectos adversos , Resistencia a la Insulina/genética , Hígado Graso/metabolismo , Hígado Graso/etiología , Hígado Graso/genética , Ratones , Masculino , Glucosa/metabolismo , Tejido Adiposo/metabolismo , Hormona de Crecimiento Humana/metabolismo , Hormona de Crecimiento Humana/genética , Hormona del Crecimiento/metabolismo , Hormona del Crecimiento/genética , Prolactina/metabolismo , Leptina/metabolismo , Adipocitos/metabolismo , Tejido Adiposo Blanco/metabolismoRESUMEN
Acromegaly is a rare endocrine disorder caused by hypersecretion of growth hormone (GH) from a pituitary adenoma. Elevated GH levels stimulate excess production of insulin-like growth factor 1 (IGF-1) which leads to the insidious onset of clinical manifestations. The most common primary central nervous system (CNS) tumors, meningiomas originate from the arachnoid layer of the meninges and are typically benign and slow-growing. Meningiomas are over twice as common in women as in men, with age-adjusted incidence (per 100,000 individuals) of 10.66 and 4.75, respectively. Several reports describe co-occurrence of meningiomas and acromegaly. We aimed to determine whether patients with acromegaly are at elevated risk for meningioma. Investigation of the literature showed that co-occurrence of a pituitary adenoma and a meningioma is a rare phenomenon, and the majority of cases involve GH-secreting adenomas. To the best of our knowledge, a systematic review examining the association between meningiomas and elevated GH levels (due to GH-secreting adenomas in acromegaly or exposure to exogenous GH) has never been conducted. The nature of the observed coexistence between acromegaly and meningioma -whether it reflects causation or mere co-association -is unclear, as is the pathophysiologic etiology. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022376998.
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Acromegalia , Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/complicaciones , Meningioma/etiología , Meningioma/patología , Meningioma/epidemiología , Acromegalia/complicaciones , Neoplasias Meníngeas/complicaciones , Neoplasias Meníngeas/epidemiología , Neoplasias Meníngeas/patología , Hormona de Crecimiento Humana/metabolismo , Hormona de Crecimiento Humana/sangre , Factores de Riesgo , Adenoma/complicaciones , Adenoma/metabolismo , Adenoma/patología , Adenoma/epidemiologíaRESUMEN
Pituitary gigantism is a rare manifestation of chronic growth hormone (GH) excess that begins before closure of the growth plates. Nearly half of patients with pituitary gigantism have an identifiable genetic cause. X-linked acrogigantism (X-LAG; 10% of pituitary gigantism) typically begins during infancy and can lead to the tallest individuals described. In the 10 years since its discovery, about 40 patients have been identified. Patients with X-LAG usually develop mixed GH and prolactin macroadenomas with occasional hyperplasia that secrete copious amounts of GH, and frequently prolactin. Circulating GH-releasing hormone is also elevated in a proportion of patients. X-LAG is caused by constitutive or sporadic mosaic duplications at chromosome Xq26.3 that disrupt the normal chromatin architecture of a topologically associating domain (TAD) around the orphan G-protein-coupled receptor, GPR101. This leads to the formation of a neo-TAD in which GPR101 overexpression is driven by ectopic enhancers ("TADopathy"). X-LAG has been seen in 3 families due to transmission of the duplication from affected mothers to sons. GPR101 is a constitutively active receptor with an unknown natural ligand that signals via multiple G proteins and protein kinases A and C to promote GH/prolactin hypersecretion. Treatment of X-LAG is challenging due to the young patient population and resistance to somatostatin analogs; the GH receptor antagonist pegvisomant is often an effective option. GH, insulin-like growth factor 1, and prolactin hypersecretion and physical overgrowth can be controlled before definitive adult gigantism occurs, often at the cost of permanent hypopituitarism.
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Enfermedades Genéticas Ligadas al Cromosoma X , Gigantismo , Humanos , Gigantismo/genética , Gigantismo/terapia , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Hormona de Crecimiento Humana/metabolismo , Hormona de Crecimiento Humana/genética , Acromegalia/genética , Acromegalia/terapiaRESUMEN
INTRODUCTION: Growth hormone (GH)-secreting pituitary tumors (GHomas) are the most common acromegaly cause. At diagnosis, most of them are macroadenomas, and up to 56% display cavernous sinus invasion. Biomarker assessment associated with tumor growth and invasion is important to optimize their management. OBJECTIVES: The study aims to identify clinical/hormonal/molecular biomarkers associated with tumor size and invasiveness in GHomas and to analyze the influence of pre-treatment with somatostatin analogs (SSAs) or dopamine agonists (DAs) in key molecular biomarker expression. METHODS: Clinical/analytical/radiological variables were evaluated in 192 patients from the REMAH study (ambispective multicenter post-surgery study of the Spanish Society of Endocrinology and Nutrition). The expression of somatostatin/ghrelin/dopamine system components and key pituitary/proliferation markers was evaluated in GHomas after the first surgery. Univariate/multivariate regression studies were performed to identify association between variables. RESULTS: Eighty percent of patients harbor macroadenomas (63.8% with extrasellar growth). Associations between larger and more invasive GHomas with younger age, visual abnormalities, higher IGF1 levels, extrasellar/suprasellar growth, and/or cavernous sinus invasion were found. Higher GH1 and lower PRL/POMC/CGA/AVPR1B/DRD2T/DRD2L expression levels (P < .05) were associated with tumor invasiveness. Least Absolute Shrinkage and Selection Operator's penalized regression identified combinations of clinical and molecular features with areas under the curve between 0.67 and 0.82. Pre-operative therapy with DA or SSAs did not alter the expression of any of the markers analyzed except for DRD1/AVPR1B (up-regulated with DA) and FSHB/CRHR1 (down-regulated with SSAs). CONCLUSIONS: A specific combination of clinical/analytical/molecular variables was found to be associated with tumor invasiveness and growth capacity in GHomas. Pre-treatment with first-line drugs for acromegaly did not significantly modify the expression of the most relevant biomarkers in our association model. These findings provide valuable insights for risk stratification and personalized management of GHomas.
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Acromegalia , Adenoma , Adenoma Hipofisario Secretor de Hormona del Crecimiento , Invasividad Neoplásica , Humanos , Masculino , Femenino , Acromegalia/metabolismo , Persona de Mediana Edad , Adulto , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Adenoma/metabolismo , Adenoma/patología , Anciano , Agonistas de Dopamina/uso terapéutico , Biomarcadores de Tumor/metabolismo , Somatostatina/análogos & derivados , Somatostatina/uso terapéutico , Hormona de Crecimiento Humana/metabolismoRESUMEN
CONTEXT: Epidemiological studies involving patients with acromegaly have yielded conflicting results regarding cancer incidence and causes of mortality in relation to control of growth hormone (GH) excess. OBJECTIVE: The objective of this retrospective cohort study is to clarify these questions and identify goals for treatment and monitoring patients. METHODS: We studied 1845 subjects from the UK Acromegaly Register (1970-2016), obtaining cancer standardised incidence rates (SIR) and all causes standardised mortality rates (SMR) from UK Office for National Statistics, to determine the relationship between causes of mortality-age at diagnosis, duration of disease, post-treatment and mean GH levels. RESULTS: We found an increased incidence of all cancers (SIR, 1.38; 95% CI: 1.06-1.33, p < .001), but no increase in incidence of female breast, thyroid, colon cancer or any measure of cancer mortality. All-cause mortality rates were increased (SMR, 1.35; 95% CI: 1.24-1.46, p < .001), as were those due to vascular and respiratory diseases. All-cause, all cancer and cardiovascular deaths were highest in the first 5 years following diagnosis. We found a positive association between post-treatment and mean treatment GH levels and all-cause mortality (p < .001 and p < .001), which normalised with posttreatment GH levels of <1.0 µg/L or meantreatment GH levels of <2.5 µg/L. CONCLUSION: Acromegaly is associated with increased incidence of all cancers but not thyroid or colon cancer and no increase in cancer mortality. Excess mortality is due to vascular and respiratory disease. The risk is highest in the first 5 years following diagnosis and is mitigated by normalising GH levels.
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Acromegalia , Hormona de Crecimiento Humana , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Acromegalia/sangre , Acromegalia/complicaciones , Acromegalia/terapia , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/complicaciones , Hormona de Crecimiento Humana/sangre , Hormona de Crecimiento Humana/metabolismo , Incidencia , Neoplasias/complicaciones , Sistema de Registros , Enfermedades Respiratorias/complicaciones , Estudios Retrospectivos , Reino Unido , Enfermedades Vasculares/complicacionesRESUMEN
Hybridization and polyploid breeding are the main approaches used to obtain new aquaculture varieties. Allotriploid crucian carp (3n) with rapid growth performance was generated by mating red crucian carp (RCC) with allotetraploids (4n). Fish growth is controlled by the growth hormone (GH)/insulin-like growth factor (IGF) axis. In the present study, we examined the expression characteristics of GH/IGF axis genes in hybrids F1, 4n, 3n, RCC and common carp (CC). The results showed that GHRa, GHRb, IGF1, IGF2, and IGF-1Ra were highly expressed in 3n compared with RCC and CC, whereas IGF3 was undetectable in the liver in RCC, CC and 3n. GHRa and GHRb had low expression in the 4n group. In hybrid F1, GHRa expression was low, whereas GHRb was highly expressed compared to the levels in RCC and CC. Moreover, in hybrid F1, the expression of IGF3 was higher, and the expression of IGF1 and IGF2 was lower than that in the RCC and CC, whereas the expression of IGF-1Ra was similar to that in RCC and CC. For the IGFBP genes, IGFBP1 had higher expression in 3n compared than that in RCC and CC, while other IGFBP genes were not high expressed in 3n. Among the genes detected in this study, 11 genes were nonadditively expressed in 3n, with 5 genes in the transgressive upregulation model. We proposed that the 11 nonadditive expression of GH/IGF axis genes is related to growth heterosis in 3n. This evidence provides new insights into hybridization and polyploid breeding from the perspective of hormone regulation.
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Carcinoma de Células Renales , Carpas , Hormona de Crecimiento Humana , Neoplasias Renales , Animales , Carpas/genética , Carpas/metabolismo , Triploidía , Hormona del Crecimiento/genética , Hormona del Crecimiento/metabolismo , Vigor Híbrido/genética , Péptidos Similares a la Insulina , Hormona de Crecimiento Humana/metabolismo , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina , Perfilación de la Expresión GénicaRESUMEN
INTRODUCTION: Previous brain studies of growth hormone deficiency (GHD) often used single-modal neuroimaging, missing the complexity captured by multimodal data. Growth hormone affects gut microbiota and metabolism in GHD. However, from a gut-brain axis (GBA) perspective, the relationship between abnormal GHD brain development and microbiota alterations remains unclear. The ultimate goal is to uncover the manifestations underlying GBA abnormalities in GHD and idiopathic short stature (ISS). METHODS: Participants included 23 GHD and 25 ISS children. The fusion independent component analysis was applied to integrate multimodal brain data (high-resolution structural, diffusion tensor, and resting-state functional MRI) covering regional homogeneity (ReHo), amplitude of low frequency fluctuations (ALFF), and white matter fractional anisotropy (FA). Gut microbiome diversity and metabolites were analyzed using 16S sequencing and proton nuclear magnetic resonance (1H-NMR). Associations between multimodal neuroimaging and cognition were assessed using moderation analysis. RESULTS: Six independent components (IC) of ReHo, ALFF, and FA differed significantly between GHD and ISS patients, with three functional components linked to the processing speed index. GHD individuals showed higher levels of acetate, nicotinate, and lysine in microbiota metabolism. Higher alpha diversity in GHD strengthened connections between ReHo-IC1, ReHo-IC5, ALFF-IC1, and the processing speed index, while increasing agathobacter levels in ISS weakened the link between ALFF-IC1 and the speech comprehension index. CONCLUSIONS: Our findings uncover differing brain structure and functional fusion in GHD, alongside microbiota metabolism of short-chain fatty acids. Additionally, microbiome influences connections between neuroimaging and cognition, offering insight into diverse GBA patterns in GHD and ISS, enhancing our understanding of the disease's pathophysiology and interventions.
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Encéfalo , Cognición , Microbioma Gastrointestinal , Imagen por Resonancia Magnética , Humanos , Microbioma Gastrointestinal/fisiología , Masculino , Niño , Femenino , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Cognición/fisiología , Adolescente , Eje Cerebro-Intestino/fisiología , Hormona de Crecimiento Humana/deficiencia , Hormona de Crecimiento Humana/metabolismo , Imagen de Difusión TensoraRESUMEN
BACKGROUND: Growth hormone deficiency(GHD) and idiopathic short stature(ISS) are the primary causes of short stature in children. Animal experiments have revealed a link between growth hormone(GH), gut microbiota and metabolism, however, limited information is available from human trials. METHODS: Fecal samples collected from GHD (n = 36), ISS (n = 32) and healthy control (HC) children(n = 16) were subjected to microbiome (16 S rRNA gene sequencing) and metabolome (nuclear magnetic resonance,NMR) analyses. RESULTS: GHD, ISS and HC exhibit distinct differences in beta diversity of gut microbiota.In addition, short stature (GHD and ISS) exhibit higher relative abundance of Prevotellaceae_NK3B31_group at genus level compared to HC, whereas Rodentibacter, Rothia, and Pelomonas showed lower abundance. Additionally,Fusobacterium_mortiferum was identified as the characteristic species of GHD. Moreover, glucose metabolism, pyruvate metabolism and pyrimidine metabolism might play significant roles for distinguishing between GHD and normal GH groups (ISS and HC). Furthermore, a disease prediction model based on differential bacteria and metabolites between GHD and ISS exhibited high diagnostic value. CONCLUSION: These findings highlight the characteristics of different GH levels on the gut microbiota and metabolism in children, providing novel perspectives for early diagnosis and prognostic treatment of short stature with abnormal GH levels. IMPACT: The key message of our study is to identify human-relevant gut microbiota and host metabolic patterns that are interfered with growth hormone levels, and to develop biomarker models to identify short stature associated with growth hormone deficiency. We used idiopathic short stature as a control group for growth hormone deficiency, complementing the absence of height as a factor in the existing literature. Our study ultimately hopes to shed new light on the diagnosis and treatment of short stature children associated with growth hormone deficiency.
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Heces , Microbioma Gastrointestinal , Trastornos del Crecimiento , Hormona de Crecimiento Humana , Humanos , Niño , Masculino , Femenino , Heces/microbiología , Hormona de Crecimiento Humana/metabolismo , Trastornos del Crecimiento/microbiología , Estudios de Casos y Controles , Metaboloma , Estatura , ARN Ribosómico 16S/genética , Enanismo Hipofisario/metabolismo , Enanismo Hipofisario/tratamiento farmacológico , Hormona del Crecimiento/metabolismo , Hormona del Crecimiento/sangre , Bacterias/metabolismoRESUMEN
Glucagon is best known for its contribution to glucose regulation through activation of the glucagon receptor (GCGR), primarily located in the liver. However, glucagon's impact on other organs may also contribute to its potent effects in health and disease. Given that glucagon-based medicine is entering the arena of anti-obesity drugs, elucidating extrahepatic actions of glucagon are of increased importance. It has been reported that glucagon may stimulate secretion of arginine-vasopressin (AVP)/copeptin, growth hormone (GH) and adrenocorticotrophic hormone (ACTH) from the pituitary gland. Nevertheless, the mechanisms and whether GCGR is present in human pituitary are unknown. In this study we found that intravenous administration of 0.2â¯mg glucagon to 14 healthy subjects was not associated with increases in plasma concentrations of copeptin, GH, ACTH or cortisol over a 120-min period. GCGR immunoreactivity was present in the anterior pituitary but not in cells containing GH or ACTH. Collectively, glucagon may not directly stimulate secretion of GH, ACTH or AVP/copeptin in humans but may instead be involved in yet unidentified pituitary functions.
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Hormona Adrenocorticotrópica , Glucagón , Glicopéptidos , Humanos , Glicopéptidos/metabolismo , Glucagón/metabolismo , Glucagón/sangre , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/metabolismo , Masculino , Adulto , Femenino , Hipófisis/metabolismo , Hipófisis/efectos de los fármacos , Hidrocortisona/sangre , Receptores de Glucagón/metabolismo , Hormona de Crecimiento Humana/metabolismo , Hormona del Crecimiento/metabolismo , Hormona del Crecimiento/sangre , Persona de Mediana EdadRESUMEN
Although predictors of response to first-generation somatostatin receptor ligands (fg-SRLs), and to a lesser extent to pasireotide, have been studied in acromegaly for many years, their use is still not recommended in clinical guidelines. Is there insufficient evidence to use them? Numerous biomarkers including various clinical, functional, radiological and molecular markers have been identified. The first ones are applicable pre-surgery, while the molecular predictors are utilized for patients not cured after surgery. In this regard, factors predicting a good response to fg-SRLs are specifically: low basal GH, a low GH nadir in the acute octreotide test, T2 MRI hypointensity, a densely granulated pattern, high immunohistochemistry staining for somatostatin receptor 2 (SSTR2), and E-cadherin. However, there is still a lack of consensus regarding which of these biomarkers is more useful or how to integrate them into clinical practice. With classical statistical methods, it is complex to define reliable and generalizable cut-off values for a single biomarker. The potential solution to the limitations of traditional methods involves combining systems biology with artificial intelligence, which is currently providing answers to such long-standing questions that may eventually be finally included into the clinical guidelines and make personalized medicine a reality. The aim of this review is to describe the current knowledge of the main fg-SRLs and pasireotide response predictors, discuss their current usefulness, and point to future directions in the research of this field.