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Concept: Endocrine gland

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Current guidelines for follow-up of adrenal incidentalomas are extensive and hampered by lack of follow-up studies. We tested the hypothesis that small lipid-rich adrenal incidentalomas, initially characterized by tumor size < 40 mm and < 10 Hounsfield Units (HU) on unenhanced computed tomography (CT) may not demon-strate excessive growth / hormonal hypersecretion on follow-up.

Concepts: Medical imaging, Radiography, Radiology, Endocrine gland

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IMPORTANCE Growing evidence of cell-to-cell transmission of neurodegenerative disease (ND)-associated proteins (NDAPs) (ie, tau, Aβ, and α-synuclein) suggests possible similarities to the infectious prion protein (PrPsc) in spongiform encephalopathies. There are limited data on the potential human-to-human transmission of NDAPs associated with Alzheimer disease (AD) and other non-PrPsc ND. OBJECTIVE To examine evidence for human-to-human transmission of AD, Parkinson disease (PD), and related NDAPs in cadaveric human growth hormone (c-hGH) recipients. DESIGN We conducted a detailed immunohistochemical analysis of pathological NDAPs other than PrPsc in human pituitary glands. We also searched for ND in recipients of pituitary-derived c-hGH by reviewing the National Hormone and Pituitary Program (NHPP) cohort database and medical literature. SETTING University-based academic center and agencies of the US Department of Health and Human Services. PARTICIPANTS Thirty-four routine autopsy subjects (10 non-ND controls and 24 patients with ND) and a US cohort of c-hGH recipients in the NHPP. MAIN OUTCOME MEASURES Detectable NDAPs in human pituitary sections and death certificate reports of non-PrPsc ND in the NHPP database. RESULTS We found mild amounts of pathological tau, Aβ, and α-synuclein deposits in the adeno/neurohypophysis of patients with ND and control patients. No cases of AD or PD were identified, and 3 deaths attributed to amyotrophic lateral sclerosis (ALS) were found among US NHPP c-hGH recipients, including 2 of the 796 decedents in the originally confirmed NHPP c-hGH cohort database. CONCLUSIONS AND RELEVANCE Despite the likely frequent exposure of c-hGH recipients to NDAPs, and their markedly elevated risk of PrPsc-related disease, this population of NHPP c-hGH recipients does not appear to be at increased risk of AD or PD. We discovered 3 ALS cases of unclear significance among US c-hGH recipients despite the absence of pathological deposits of ALS-associated proteins (TDP-43, FUS, and ubiquilin) in human pituitary glands. In this unique in vivo model of human-to-human transmission, we found no evidence to support concerns that NDAPs underlying AD and PD transmit disease in humans despite evidence of their cell-to-cell transmission in model systems of these disorders. Further monitoring is required to confirm these conclusions.

Concepts: Hypothalamus, Pituitary gland, Growth hormone, Prion, Amyotrophic lateral sclerosis, Neurodegenerative disorders, Transmissible spongiform encephalopathy, Endocrine gland

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Human pluripotent stem cells (hPSCs) provide an unlimited cell source for regenerative medicine. Hormone-producing cells are particularly suitable for cell therapy, and hypopituitarism, a defect in pituitary gland function, represents a promising therapeutic target. Previous studies have derived pituitary lineages from mouse and human ESCs using 3D organoid cultures that mimic the complex events underlying pituitary gland development in vivo. Instead of relying on unknown cellular signals, we present a simple and efficient strategy to derive human pituitary lineages from hPSCs using monolayer culture conditions suitable for cell manufacturing. We demonstrate that purified placode cells can be directed into pituitary fates using defined signals. hPSC-derived pituitary cells show basal and stimulus-induced hormone release in vitro and engraftment and hormone release in vivo after transplantation into a murine model of hypopituitarism. This work lays the foundation for future cell therapy applications in patients with hypopituitarism.

Concepts: Pituitary gland, Developmental biology, Stem cell, Cell biology, Growth hormone, Induced pluripotent stem cell, Pluripotency, Endocrine gland

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Recombinant human growth hormone (rhGH) increases protein synthesis, therefore it is used in burns with a total body surface area (TBSA) greater than 40%, where there is frequently an increase in protein breakdown and a decrease in protein synthesis. This change in protein metabolism correlates with poor wound healing of the burn and donor sites.

Concepts: Immune system, Protein, Metabolism, Wound healing, Recombinant DNA, Growth hormone, Endocrine gland

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Some gastrointestinal and pancreatic hormones are potently secreted by meal intake and reduce food intake, therefore these hormones play a role in the meal-evoked satiety peptides. Previous reports have demonstrated that peripheral administration of these gastrointestinal or pancreatic hormones decrease feeding and the anorectic effects are abolished by lesions of vagal afferent nerves using surgical or chemical protocols, indicative of the involvement of the vagal afferents. Vagal afferent nerves link between several peripheral organs and the nucleus tractus solitarius of the brainstem. The present review focuses on cholecystokinin, peptide YY(3-36), pancreatic polypeptide, and nesfatin-1 released from endocrine cells of the gut and pancreas. These hormonal peptides directly act on and increase cytosolic Ca(2+) in vagal afferent nodose ganglion neurons and finally suppress food intake via vagal afferents. Therefore, peripheral terminals of vagal afferents could sense gastrointestinal and pancreatic hormones and regulate food intake. Here, we review how the vagal afferent neurons sense a variety of gastrointestinal and pancreatic hormones and discuss its physiological significance in regulation of feeding.

Concepts: Nervous system, Protein, Insulin, Pancreas, Peptide, Cranial nerves, Solitary nucleus, Endocrine gland

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The glucagonlike peptide 1 receptor (GLP-1R) is mainly expressed on β-cells in the islets of Langerhans and is therefore an attractive target for imaging of the β-cell mass. In the present study, (68)Ga-labeled exendin-4 was evaluated for PET imaging and quantification of GLP-1R in the pancreas. METHODS: Dose escalation studies of (68)Ga-labeled 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetyl (DO3A)-exendin-4 were performed in rats (organ distribution) and cynomolgus monkeys (PET/CT imaging) to determine the GLP-1R-specific tissue uptake in vivo. Pancreatic uptake (as determined by organ distribution) in healthy rats was compared with that in diabetic rats. GLP-1R occupancy in the cynomolgus pancreas was quantified with a 1-tissue-compartment model. RESULTS: In rodents, uptake in the pancreas was decreased from the baseline by up to 90% (P < 0.0001) by coadministration of DO3A-exendin-4 at 100 μg/kg. Pancreatic uptake in diabetic animals was decreased by more than 80% (P < 0.001) compared with that in healthy controls, as measured by organ distribution. GLP-1R occupancy in the cynomolgus pancreas after coinjection of DO3A-exendin-4 at 0.15-20 μg/kg ranged from 49% to 97%, as estimated by compartment modeling. CONCLUSION: These results strongly support the notion that (68)Ga-DO3A-exendin-4 uptake in the pancreas is mediated by specific receptor binding. In addition, pancreatic uptake was decreased by selective destruction of β-cells. This result suggests that GLP-1R can be quantified in vivo, which has major implications for the prospect of imaging of native β-cells.

Concepts: Insulin, Islets of Langerhans, Glucagon, Pancreas, Beta cell, Ligand, Endocrine gland, Alpha cell

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PURPOSE: The purpose of this study was to investigate the efficacy and safety of LB03002, a sustained-release growth hormone (SR-hGH), compared to that of daily rhGH for 12 months in children with growth hormone deficiency. METHODS: Total of 73 children with growth hormone deficiency (GHD) were screened and 63 eligible subjects were randomized in a 1:1 ratio to LB03002 (sustained-release human growth hormone, SR-hGH) or daily rhGH treatment group. LB03002 was administered once weekly at a dose of 0.5 mg/kg while daily hGH was administered for 6 consecutive days with the equally divided doses to make a total of 0.21 mg/kg/wk. Treatments were administered for 12 months by subcutaneous injections. Injection site reactions and adverse events were investigated throughout the study period. RESULTS: The mean (standard deviation, SD) height velocity (HV) showed clinically significant increase after 6-month treatment: 3.00 (1.15) cm/year at screening to 9.78 (1.98) cm/year at 6-month in LB03002 group; 2.39 (1.63) cm/year at screening to 10.56 (2.65) cm/year at 6-month in daily hGH group. Increased HV at 12-month was still maintained in both groups: 9.06 (1.63) cm/year at 12 month in LB03002 group; 9.72 (2.32) cm/year at 12 month in daily rhGH group. Most of the adverse drug reactions were mild and tolerable. No subjects were withdrawn due to adverse events. CONCLUSION: Weekly injection of LB03002 at a dose of 0.5 mg/kg/wk was confirmed to have comparable efficacy to daily injection of daily rhGH at a dose of 0.21 mg/kg/wk. Both formulations were well tolerated.

Concepts: Immune system, Growth hormone, Adverse drug reaction, Endocrine gland, Growth hormone deficiency

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Background: Patients with mutations or deletions of the SHOX gene present variable growth impairment, with or without mesomelic skeletal dysplasia. If untreated, short patients with SHOX haplodeficiency (SHOXD) remain short into adulthood. Although recombinant human growth hormone (rhGH) treatment improves short-term linear growth, there are episodic data on the final height of treated SHOXD subjects. Patients & methods: After a thorough search of the published literature for pertinent studies, we undertook a meta-analysis evaluation of the efficacy and safety of rhGH treatment in SHOXD patients. Results: In SHOXD patients, administration of rhGH progressively improved the height deficit from baseline to 24 months, although the major catch-up growth was detected after 12 months. The rhGH-induced growth appeared constant until final height. Conclusion: Our meta-analysis suggested rhGH therapy improves height outcome of SHOXD patients, though future studies using carefully titrated rhGH protocols are needed. Original submitted 29 October 2012; Revision submitted 22 February 2013.

Concepts: Immune system, Recombinant DNA, Growth hormone, Turner syndrome, Endocrine gland, Growth hormone deficiency, Idiopathic short stature

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Accumulating evidence clearly indicates both thyroid hormone and estrogen have a pivotal role in bone metabolism. Pituitary hormones, TSH and FSH, regulate circulating levels of thyroid hormone and estrogen, respectively. Recent works raise a possibility that either TSH or FSH also has its own direct effects on bone cells involved in bone resorption and formation. More recently, it is suggested that oxytocin and vasopressin are also involved in bone metabolism. However, several investigations of genetically manipulated model mice and clinical data from patients with certain diseases have provided inconsistent results. Thus, we need more data that answer the question whether or not each pituitary hormone is physiologically and pathophysiologically involved in controlling bone metabolism in human.

Concepts: Hypothalamus, Pituitary gland, Hormone, Menopause, Oxytocin, Vasopressin, Thyroid hormone, Endocrine gland

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Acromegaly is a rare disease characterized by hypersecretion of growth hormone (GH), typically from a benign pituitary somatotroph adenoma, that leads to subsequent hypersecretion of insulin-like growth factor 1 (IGF-1). Patients with acromegaly have an increased risk of mortality and progressive worsening of comorbidities. Surgery, medical therapy, and radiotherapy are treatment approaches currently available for patients with acromegaly, with overall therapeutic goals of lowering GH levels and achieving normal levels of IGF-1, reducing tumor size, improving comorbidities, and minimizing mortality risk. The objective is to discuss that, although surgery can lead to biochemical remission in some patients with acromegaly, many patients will continue to have uncontrolled disease and require additional treatment.

Concepts: Immune system, Medicine, Cure, Therapy, Insulin-like growth factor 1, Growth hormone, Insulin-like growth factor, Endocrine gland