Journal of Neuroendocrinology最新文献

Data on the risk of stroke in patients with hyperprolactinemia are limited. This study aimed to evaluate the association between hyperprolactinemia and ischemic stroke in a large cohort and identify predictors of stroke in this population. This was a retrospective cohort study comparing the incidence of ischemic stroke in patients with dopamine agonist-treated hyperprolactinemia to matched controls in a 1:5 ratio. The primary outcome was the diagnosis of ischemic stroke. The cohort included 2440 patients with DA-treated hyperprolactinemia patients (mean age ± SD: 38.42 ± 14.57 years, 60.2% women) matched to 12,022 controls (mean age ± SD: 38.15 ± 14.36 years, 60.8% women). Ischemic stroke occurred in 195 patients with hyperprolactinemia (8.0%) and 747 controls (6.21%) (adjusted HR 1.24, 95% CI 1.06-1.46). Patients with hyperprolactinemia developed stroke at a younger age (57.75 ± 15.88 years vs. 60.18 ± 15.20 years, p = .05). Patients with PRL levels >5× ULN at diagnosis had a higher stroke incidence than those with lower levels (9.73% vs. 6.85%; HR 1.48, 95% CI 1.11-1.97). Longer time to prolactin normalization was associated with a higher incidence of stroke (median 21.88 vs. 13.78 months; p = .0005). In multivariate analysis, age ≥60 years, male gender, hypertension, type 1 or type 2 diabetes mellitus, and ischemic heart disease were significant predictors of stroke in patients with hyperprolactinemia. Dopamine agonist-treated hyperprolactinemia is associated with an increased risk of ischemic stroke compared to well-matched controls from the general population. Higher prolactin levels at diagnosis and a longer time to normalization were linked to a greater risk of stroke.

The term "carcinoid tumour" is no longer used and has given up its place to neuroendocrine neoplasms (NENs). Primary hepatic neuroendocrine neoplasms (PHNENs) are as rare as compromising 0.4% of all neuroendocrine neoplasms (NENs). Searching the central medical databases of PubMed/Medline, Web of Science, Scopus, Google Scholar, and the references of the articles, we have collected 10 cases of pediatric PHNENs of children. The inclusion criteria were full-text available literature in English and those under and equal to 19 years old. Diseases found during autopsy, carcinoma, and isolated gall bladder involvement also made the exclusion criteria. The mean age of the patients was 13.86 years, ranging from 8 to 19 years. Six female patients (55%) were in front of 5 males (45%). The right lobe was the most frequent site of involvement and surgery in four cases. Abdominal pain comprised the main symptom, and CT scans of most of them were common which helped in diagnosis. While a hepatic tumour is considered NEN, a detailed systemic evaluation of a primary tumour is mandatory to exclude metastatic HNEN. Secondary hepatic NENs are more common than primary ones. Surgical resection has had the most long-term success.

We recently showed that Crh-Crhr1 signalling is essential for acute stress-related locomotor activity in zebrafish larvae. However, the possibility that Crhr1 activation may also initiate the acute metabolic demands for stress coping was unexplored. Here, we tested the hypothesis that Crhr1 signalling is essential for the thermal stressor-induced increases in the acute metabolic rate, a key response for coping with the enhanced energy demands during stress. We tested this by using a wildtype (WT) and a ubiquitous Crhr1 knockout (crhr1^-/-) zebrafish and subjecting them to an acute thermal stressor (TS: +5°C above ambient for 60 min). The TS induced the heat shock proteins response in both genotypes, but the elevated cortisol response observed in the WT was absent in the crhr1^-/- mutant. The TS also increased the locomotor activity and the metabolic rate in the WT fish, but this response was inhibited in the crhr1^-/- mutants. To test if this was due to a lack of TS-induced cortisol elevation in the crhr1^-/- mutant, we mimicked the response in the WT fish by treating them with metyrapone, an 11β-hydroxylase inhibitor. While metyrapone inhibited the TS-induced cortisol elevation in the WT, it did not affect the metabolic rate. The lack of Crhr1 also reduced the swimming performance, and the lower U_crit in the mutants corresponded with alterations in muscle energy metabolism. Together, our results indicate that Crh-Crhr1 signalling, independent of downstream cortisol action, is essential for the TS-induced acute hyperlocomotor activity and the associated increases in the metabolic demand for stress coping.

Colonic neuroendocrine tumors (NETs), excluding rectal NETs, are often described as relatively common and aggressive, with inferior median survival compared with other gastrointestinal (GI) primary sites. However, epidemiological databases may conflate well-differentiated NETs with poorly differentiated neuroendocrine carcinomas (NECs), leading to a lack of precise data on the prevalence, clinical behavior, and prognosis of well-differentiated colonic NETs. We analyzed a large institutional database to identify patients with well-differentiated NETs originating in the colon, excluding rectal NETs. Cecal NETs were included; however, ileocecal NETs (overlapping the ileocecal valve) were not. We assessed their prevalence compared with other primary sites, grade, stage, and prognosis. Among 3639 patients with gastroenteropancreatic (GEP) NETs, only 19 (0.5%) had well-differentiated colonic NETs. This included 11 cecal and eight sigmoid colon primaries (two described as "rectosigmoid"). No tumors originated in the ascending, transverse, or descending colon. Sigmoid NETs were typically early-stage polyps discovered incidentally during colonoscopy. In contrast, eight of the 11 cecal NETs metastasized (p = .04). Six of the cecal primary patients (55%) exhibited carcinoid syndrome versus none of the sigmoid primary cases (p = .01). Well-differentiated colon NETs are exceptionally rare, comprising approximately 0.5% of GEP-NETs. These tumors fall into two distinct categories: cecal NETs, which resemble ileal NETs in behavior, and sigmoid NETs, which appear similar to rectal NETs. The broad categorization of colonic "NETs" in epidemiologic databases likely includes NECs, obscuring the true clinical picture.

Gonadotroph neuroendocrine pituitary tumors are among the most common intracranial neoplasms. A notable proportion of these tumors is characterized by invasive growth which hampers the treatment results and worsens prognoses of patients. Increased hsa-miR-184 expression was observed in invasive as compared to non-invasive gonadotroph tumors. This study aimed to determine the role of hsa-miR-184 expression in invasive growth of gonadotroph tumors. QRT-PCR and bisulfite pyrosequencing were used for evaluating hsa-miR-184 expression and MIR184 DNA methylation levels, respectively, in tumors and normal pituitary samples. LβT2 and αT3-1 gonadotroph cells were used to test the effect of miR-184 on cell viability (MTT test), proliferation (BrdU incorporation), and migration (scratch assay). RNA sequencing was applied for transcriptome profiling in miR-184-treated and untreated LβT2 cells. Differential genes expression analysis combined with target prediction served for identification of miR-184 targets. MiRNA-mRNA interaction was subsequently validated with Luciferase reporter assay. Analysis of tissue samples showed that hsa-miR-184 is upregulated in gonadotroph tumors and its expression is higher in invasive than in noninvasive ones. Promoter of MIR184 is demethylated in tumors, and the methylation level is negatively correlated with hsa-miR-184 expression. Transfecting LβT2 and αT3-1 with miR-184 mimic resulted in increased cellular proliferation and viability. Differentially expressed genes were identified when comparing miR-184-treated and untreated cells, including Nus1 as the only predicted miR-184 target. The interaction between miR-184 and 3'UTR of Nus1 was confirmed in vitro in both LβT2 and αT3-1. Overexpression of Nus1 resulted in lowering cell viability in both cell lines and proliferation in LβT2. The expression level of NUS1 was lower in invasive than in noninvasive tumors. Our results indicate that DNA hypomethylation-related increase of hsa-mir-184 expression contributes to invasive growth of gonadotroph pituitary tumors through targeting NUS1, being one of the various molecular mechanisms involved in conferring aggressive growth potential.

Alzheimer's disease (AD) is associated with early metabolic dysfunction and adiponectin, which may play a pathophysiological role. Adiponectin is implicated in the regulation of energy homeostasis, carbohydrate, and lipid metabolism, as well as in inflammation modulation. The aim of this study was to study whether plasma adiponectin levels were different between patients with AD confirmed by biomarkers and neurological control subjects. We performed a monocentric, retrospective, cross-sectional, observational study in AD patients and neurological controls recruited from daily clinical practice in a tertiary memory clinic. Plasma adiponectin levels were measured using a chemiluminescent enzyme immunoassay. We analyzed the relationship between adiponectin and AD using linear regression models including age, gender, and BMI. We also described the distribution of adiponectin concentrations, across age, and gender categories. Two hundred and six patients (142 AD patients and 64 neurological controls) were included, with mean age = 68.8 ± 10.0 years, and 56% were women. Higher adiponectin concentrations were observed in females and in older adults. Plasma adiponectin levels were significantly higher in AD patients (mean = 6.45 ± 3.42 μg/mL) than neurological controls (4.85 ± 3.54 μg/mL) (p < .001). This association was mediated by age, gender, and BMI, which were significantly and independently associated with plasma adiponectin levels (p < .01 for each), while adiponectin was no longer associated with AD in multivariate models. Patients with AD showed higher adiponectin levels, but this association was driven by older age, female gender, and lower BMI in the AD group. Further studies are needed to better characterize the hormonal signature of AD.

The placenta is a fetal endocrine organ that secretes many neuroactive factors, including steroids, that play critical roles in brain development. The study of the placenta-brain axis and the links between placental function and brain development represents an emerging research area dubbed "neuroplacentology." The placenta drives many circulating fetal steroids to very high levels during gestation. Recent studies have highlighted the critical role of placental steroids in shaping specific brain structures and behaviors. This review uses a cross-species framework to discuss the genomic factors, in-utero environmental changes, and placental conditions that alter placental steroidogenesis, leading to changes in early developmental trajectories relevant for psychiatric conditions such as autism, in a sex-linked manner.

Kisspeptin (KISS1) and its cognate receptor (KISS1R) are implicated in the progression of various cancers. A gallium-68 labelled kisspeptin-10 (KP10), the minimal biologically active structure, has potential as a pan-tumour radiopharmaceutical for the detection of cancers. Furthermore, a lutetium-177 labelled KP10 could find therapeutic application in treating oncological diseases. DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) was attached to the NH2-terminus of KP10 as we posited from our previous publications that this modification would not impair biological activity. Here, we showed that the biological activity, as monitored by stimulation of inositol phosphate accumulation in HEK293 transfected with the KISS1R gene, was indeed similar for KP10 and DOTA-KP10. The optimisation of radiolabelling with gallium-68 and lutetium-177 is described. Stability in serum, plasma and whole blood was also investigated. Pharmacokinetics and biodistribution were established with micro-PET/CT (positron emission tomography/computerised tomography) and ex vivo measurements. Dynamic studies with micro-PET/CT demonstrated that background clearance for the radiopharmaceutical was rapid with a blood half-life of 18 ± 3 min. DOTA-KP10 demonstrated preserved functionality at KISS1R and good blood clearance. These results lay the foundation for the further development of DOTA-KP10 analogues that have high binding affinity along with proteolytic resistance.

Among contributors to diffusible signaling are portal systems which join two capillary beds through connecting veins. Portal systems allow diffusible signals to be transported in high concentrations directly from one capillary bed to the other without dilution in the systemic circulation. Two portal systems have been identified in the brain. The first was discovered almost a century ago and connects the median eminence to the anterior pituitary gland. The second was discovered a few years ago and links the suprachiasmatic nucleus to the organum vasculosum of the lamina terminalis, a sensory circumventricular organ (CVO). Sensory CVOs bear neuronal receptors for sensing signals in the fluid milieu. They line the surface of brain ventricles and bear fenestrated capillaries thereby lacking blood-brain barriers. It is not known whether the other sensory CVOs, namely the subfornical organ (SFO), and area postrema (AP) form portal neurovascular connections with nearby parenchymal tissue. To preserve the integrity of the vasculature of CVOs and their adjacent neuropil, we combined iDISCO clearing and light-sheet microscopy to acquire volumetric images of blood vessels and traced the vasculature in two experiments. In the first, the whole brain vasculature was registered to the Allen Brain Atlas in order to identify the nuclei to which the SFO and AP are attached. In the second study, regionally specified immunolabeling was used to identify the attachment sites and vascular connections between the AP, and the SFO to their respective parenchymal attachment sites. There are venous portal pathways linking the capillary vessels of the SFO and the posterior septal nuclei, namely the septofimbrial nucleus and the triangular nucleus of the septum. Unlike the arrangement of portal vessels, the AP and the nucleus of the solitary tract share a common capillary bed. Taken together, the results reveal that all three sensory CVOs bear direct capillary connections to adjacent neuropil, providing a direct route for diffusible signals to travel from their source to their targets.

Small intestine neuroendocrine tumours (SI-NETs) are often diagnosed late with a UK median of 3 years and high misdiagnosis rates. Previous studies, largely based on patient surveys, offer little data on improving diagnosis. In 2017, the South Wales NET service underwent a nationally commissioned, systematic transformation, aiming to improve diagnosis through the development of a gastroenterology and surgical referral network, and education of these specialities. This study aims to assess the impact of the transformation on SI-NET diagnosis times and misdiagnosis rates using accurate hospital data, along with the diagnostic routes and investigations used for SI-NETs. We retrospectively analysed the hospital records of 224 patients diagnosed with SI-NETs referred to the South Wales NET service (110 pre-transformation and 114 post-transformation). Following the service transformation, there was a significant reduction in diagnosis times from a median of 12.5-5.2 months (p < .05), at an earlier stage (cases with metastases reduced from 77% to 62%), and reduced misdiagnosis rates from 40% to 25%. Colonoscopy, used to investigate the presenting gastrointestinal symptoms in 42% of patients prior to diagnosis, identified an abnormality in only 28%, compared with 97% with computed tomography (CT) scans. A gastroenterology and surgical referral network across hospitals may improve diagnosis in SI-NETs, leading to earlier detection and reducing misdiagnosis rates. Further exploration of GP interactions is needed. Caution is needed following negative colonoscopy in patients with persistent lower gastrointestinal symptoms as this could lead to missed SI-NET diagnosis if further abdominal imaging is not undertaken.