Journal of Neuroendocrinology最新文献

Pulsatile gonadotropin-releasing hormone (GnRH) release is critical for reproduction. Disruptions to GnRH secretion patterns may contribute to polycystic ovary syndrome (PCOS). Prenatally androgenized (PNA) female mice recapitulate many neuroendocrine abnormalities observed in PCOS patients. PNA and development induce changes in spontaneous GnRH neuron firing rate, response to synaptic input, and the afterhyperpolarization potential of the action potential. We hypothesized potassium currents are altered by PNA treatment and/or development. Whole-cell patch-clamp recordings were made of transient and residual potassium currents of GnRH neurons in brain slices from 3-week-old and adult control and PNA females. At 3 weeks of age, PNA treatment increased transient current density versus controls. Development and PNA altered voltage-dependent activation and inactivation of the transient current. In controls, transient current activation and inactivation were depolarized at 3 weeks of age versus in adulthood. In GnRH neurons from 3-week-old mice, transient current activation and inactivation were more depolarized in control than PNA mice. Development and PNA treatment interacted to shift the time-dependence of inactivation and recovery from inactivation. Notably, in cells from adult PNA females, recovery was prolonged compared to all other groups. Activation of the residual current occurred at more depolarized membrane potentials in 3-week-old than adult controls. PNA depolarized activation of the residual current in adults. These findings demonstrate the properties of GnRH neuron potassium currents change during typical development, potentially contributing to puberty, and further suggest PNA treatment may both alter some typical developmental changes and induce additional modifications, which together may underlie aspects of the PNA phenotype. There was not any clinical trial involved in this work.

Patients with neuroendocrine tumours located in the gastroenteropancreatic tract (GEP-NETs) and treatment with somatostatin analogues (SSA's) are at risk of malnutrition which has been reported previously evaluating weight loss or body mass index (BMI) only. The global leadership into malnutrition (GLIM) criteria include weight loss, BMI, and sarcopenia, for diagnosing malnutrition. These GLIM criteria have not been assessed in patients with GEP-NETs on SSA. The effect of malnutrition on overall survival has not been explored before. The aim of this study is to describe the presence of malnutrition in patients with GEP-NET on SSA based on the GLIM criteria and associate this with overall survival. Cross-sectional study screening all patients with GEP-NETs on SSA's for malnutrition using the GLIM criteria. Body composition analysis for sarcopenia diagnosis were performed. Bloods including vitamins, minerals, and lipid profile were collected. Overall survival since the date of nutrition screening was calculated. Uni- and multivariate Cox regression analysis were performed to identify malnutrition as risk factor for overall survival. A total of 118 patients, 47% male, with median age 67 years (IQR 56.8–75.0) were included. Overall, malnutrition was present in 88 patients (75%); based on low BMI in 26 (22%) patients, based on weight loss in 35 (30%) patients, and based on sarcopenia in 83 (70%) patients. Vitamin deficiencies were present for vitamin D in 64 patients (54%), and vitamin A in 29 patients (25%). The presence of malnutrition demonstrated a significantly worse overall survival (p-value = .01). In multivariate analysis meeting 2 or 3 GLIM criteria was significantly associated with worse overall survival (HR 2.16 95% CI 1.34–3.48, p-value = .002). Weight loss was the most important risk factor out of the 3 GLIM criteria (HR 3.5 95% CI 1.14–10.85, p-value = .03) for worse overall survival. A high percentage (75%) of patients with GEP-NETs using a SSA meet the GLIM criteria for malnutrition. Meeting more than 1 GLIM criterium, especially if there is weight loss these are risk factors for worse overall survival.

In temperate-zone songbirds, the neuroanatomical changes which occur in advance of breeding, including the growth of nuclei of the vocal control system, are believed to occur downstream of gonadal recrudescence. However, evidence from wild birds is mixed. Here, we captured black-capped chickadees from the wild in early spring (March-April), summer (August-September), and winter (December-January); in addition to measuring the volumes of two vocal control nuclei (Area X and HVC), we also quantified two indicators of reproductive state (gonads and circulating gonadal steroids). Most birds captured in early spring had regressed gonads and low levels of circulating gonadal steroids, indicating these birds were not yet in full breeding condition. However, these early spring birds still had a significantly larger Area X than winter birds, while HVC did not differ in size across groups. Using data from a previously published seasonal study of black-capped chickadees (Phillmore et al., Developmental Neurobiology, 2015;75:203-216), we then compared Area X and HVC volumes from our early spring group to a breeding group of chickadees captured 3-4 weeks later in the spring. While Area X volume did not differ between the studies, breeding males in Phillmore et al. (2015) had a significantly larger HVC. Taken together, this suggests that the vernal growth of Area X occurs ahead of HVC in black-capped chickadees, and that the overall vernal changes in the vocal control system occur at least partially in advance of the breeding-associated upregulation of the hypothalamic-pituitary-gonadal axis.

A good and accessible biomarker is of great clinical value in neuroendocrine tumor (NET) patients, especially considering its frequently indolent nature and long-term follow-up. Plasma chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are currently used as biomarkers in NET, but their sensitivity and specificity are restricted. 5-HIAA is the main metabolite of serotonin, an important neurotransmitter of the tryptophan pathway. The aim of this study is to estabish a sensitive and accurate method for the quantification of tryptophan pathway metabolites in plasma. We further aimed to evaluate its utility as a clinical tool in NET disease. We obtained plasma samples from NET patients and healthy controls recruited from the University Hospital of North Norway, Tromsø. Samples were analyzed by liquid chromatography-tandem mass spectrometry (LC–MS/MS), and eight metabolites of the tryptophan pathway were quantified. We included 130 NET patients (72/130 small intestinal [SI] NET, 35/130 pancreatic NET, 23/130 other origin) and 20 healthy controls. In the SI-NET group, 26/72 patients presented with symptoms of carcinoid syndrome (CS). We found that combining tryptophan metabolites into a serotonin/kynurenine pathway ratio improved diagnostic sensitivity (92.3%) and specificity (100%) in detecting CS patients from healthy controls compared with plasma 5-HIAA alone (sensitivity 84.6%/specificity 100%). Further, a clinical marker based on the combination of plasma serotonin, 5-HIAA, and 5OH-tryptophan, increased diagnostic capacity identifying NET patients with metastasized disease from healthy controls compared with singular plasma 5-HIAA, serotonin, or CgA. In addition, this marker was positive in 61% of curatively operated SI-NET patients compared with only 10% of healthy controls (p < .001). Our results indicate that simultaneous quantification of several tryptophan metabolites in plasma, using LC–MS/MS, may represent a clinically useful diagnostic tool in NET disease.

Excess levels of circulating androgens during prenatal or peripubertal development are an important cause of polycystic ovary syndrome (PCOS), with the brain being a key target. Approximately half of the women diagnosed with PCOS also experience metabolic syndrome; common features including obesity, insulin resistance and hyperinsulinemia. Although a large amount of clinical and preclinical evidence has confirmed this relationship between androgens and the reproductive and metabolic features of PCOS, the mechanisms by which androgens cause this dysregulation are unknown. Neuron-specific androgen receptor knockout alleviates some PCOS-like features in a peripubertal dihydrotestosterone (DHT) mouse model, but the specific neuronal populations mediating these effects are undefined. A candidate population is the agouti-related peptide (AgRP)-expressing neurons, which are important for both reproductive and metabolic function. We used a well-characterised peripubertal androgenized mouse model and Cre-loxP transgenics to investigate whether deleting androgen receptors specifically from AgRP neurons can alleviate the induced reproductive and metabolic dysregulation. Androgen receptors were co-expressed in 66% of AgRP neurons in control mice, but only in <2% of AgRP neurons in knockout mice. The number of AgRP neurons was not altered by the treatments. Only 20% of androgen receptor knockout mice showed rescue of DHT-induced androgen-induced anovulation and acyclicity. Furthermore, androgen receptor knockout did not rescue metabolic dysfunction (body weight, adiposity or glucose and insulin tolerance). While we cannot rule out developmental compensation in our model, these results suggest peripubertal androgen excess does not markedly influence Agrp expression and does not dysregulate reproductive and metabolic function through direct actions of androgens onto AgRP neurons.

Thyroid hormones play a critical role in brain development, but paradoxically, patients with hyperthyroidism often exhibit cognitive decline and irritability. This study aims to explore the pattern of atrophy in hyperthyroid patients, changes in specific areas of the brain, including hypothalamic subfields and limbic structures, and their relationships with hormonal levels and psychometric tests. This prospective cross-sectional study involves 19 newly diagnosed, untreated hyperthyroid patients, and 15 age and gender-matched control subjects. The participants underwent psychometric and cognitive tests and volumetric MRI. The hypothalamic subfield (anterior-inferior, anterior-superior, superior-tubular, inferior-tubular, and posterior hypothalamus) and limbic structures (fornix, basal forebrain, nucleus accumbens, and septal nucleus) were segmented using voxel-based morphometry, surface-based morphometry, and deep learning algorithms. The groups were compared using the t-test, and correlation analyses were performed between clinical parameters and volumetric measurements. The correlation between hormonal parameters and volumetric measurements in patient and control groups was assessed with the Meng test. Hyperthyroid patients displayed widespread grey matter loss and sulcal shallowing in the left hemisphere. However, no local gyrification index changes or cortical thickness variations were detected. The limbic structures and hypothalamic subunits did not show any volume discrepancies. Free thyroxine in the patient group negatively correlated with bilateral anterior-inferior and right septal nucleus, but positively correlated with left anterior-inferior in the control group. Thyroid stimulating hormone in the patient group showed a positive correlation with bilateral fornix volume, a correlation absent in the control group. Disease duration negatively correlated with right anterior-inferior, right tubular inferior, and right septal nucleus. Changes in cognitive and psychometric test scores in the patient group correlated with the bilateral septal nucleus volume. Hyperthyroidism primarily leads to a reduction in grey matter volume and sulcal shallowing. Thyroid hormones have differing volumetric effects in limbic structures and hypothalamic subunits under physiological and hyperthyroid conditions.

Espen Thiis-Evensen¹, Magnus Kjellman², Ulrich Knigge³, Henning Gronbaek⁴, Camilla Schalin-Jäntti⁵, Staffan Welin⁶, Halfdan Sorbye⁷, Maria del Pilar Schneider⁸ and Roger Belusa⁹ on behalf of The Nordic NET Biomarker Group

Due to the use of a wrong version of the informed consent form four patients have to be excluded from the analyses. This has unfortunately led to other results than previously published. We sincerely apologize for this. In paragraph 2 of the “Abstract” section, the text “Methods: At time of diagnosis blood samples were collected and analysed from 34 patients with PanNET, 135 with SI-NET, (WHO Grade 1-2) and 144 controls. Exclusion criteria were other malignant diseases, chronic inflammatory diseases, reduced kidney or liver function. Proseek Oncology-II (OLink) was used to measure 92 cancer related plasma proteins. Chromogranin A (CgA) was analysed separately.” was incorrect.

This should have read: “Methods: At time of diagnosis blood samples were collected and analysed from 34 patients with PanNET, 135 with SI-NET, (WHO Grade 1-2) and 144 controls. Exclusion criteria were other malignant diseases, chronic inflammatory diseases, reduced kidney or liver function. Proseek Oncology-II (OLink) was used to measure 92 cancer related plasma proteins. Chromogranin A (CgA) was analysed separately.”

In paragraph 3 of the “Abstract” section, the text “Results: Median age in all groups was 65-67 years and with a similar gender distribution (Female; PanNET 51%, SI-NET 42%, controls 42%). Tumour grade (G1/G2): PanNET 39/61%, SI-NET 46/54%. Patients with liver metastases: PanNET 78%, SI-NET 63%. The classification model of PanNET versus controls provided a sensitivity (SEN) of 0.84, specificity (SPE) 0., positive predictive value (PPV) of 0.92 and negative predictive value (NPV) of 0.95, and area under ROC (AUROC) of 0.99; the model for the discrimination of PanNET versus SI-NET providing a SEN 0.61, SPE 0.9, PPV 0.83, NPV 0.90 and AUROC 0.98).” was incorrect.

This should have read: “Results: Median age in all groups was 65-67 years and with a similar gender distribution (Female; PanNET 53%, SI-NET 42%, controls 42%). Tumour grade (G1/G2): PanNET 35/53%, SI-NET 46/54%. Patients with liver metastases: PanNET 71%, SI-NET 63%. The classification model of PanNET versus controls provided a sensitivity (SEN) of 0.71, specificity (SPE) 0.98, positive predictive value (PPV) of 0.91 and negative predictive value (NPV) of 0.94, and area under ROC (AUROC) of 0.99; the model for the discrimination of PanNET versus SI-NET providing a SEN 0.48, SPE 0.96, PPV 0.76, NPV 0.88 and AUROC 0.90).”

In line 116 of the “Materials and Methods” section, the text “A total of 135 patients with SI-NETs and 39 with PanNET were included in the study.” was incorrect. This should have read: “A total of 135 patients with SI-NE

The hypothalamic paraventricular nucleus (PVN) is a highly complex brain region that is crucial for homeostatic regulation through neuroendocrine signaling, outflow of the autonomic nervous system, and projections to other brain areas. In the past years, single-cell datasets of the hypothalamus have contributed immensely to the current understanding of the diverse hypothalamic cellular composition. While the PVN has been adequately classified functionally, its molecular classification is currently still insufficient. To address this, we created a detailed atlas of PVN transcriptomic cell types by integrating various PVN single-cell datasets into a recently published hypothalamus single-cell transcriptome atlas. Furthermore, we functionally profiled transcriptomic cell types, based on relevant literature, existing retrograde tracing data, and existing single-cell data of a PVN-projection target region. Finally, we validated our findings with immunofluorescent stainings. In our PVN atlas dataset, we identify the well-known different neuropeptide types, each composed of multiple novel subtypes. We identify Avp-Tac1, Avp-Th, Oxt-Foxp1, Crh-Nr3c1, and Trh-Nfib as the most important neuroendocrine subtypes based on markers described in literature. To characterize the preautonomic functional population, we integrated a single-cell retrograde tracing study of spinally projecting preautonomic neurons into our PVN atlas. We identify these (presympathetic) neurons to cocluster with the Adarb2⁺ clusters in our dataset. Further, we identify the expression of receptors for Crh, Oxt, Penk, Sst, and Trh in the dorsal motor nucleus of the vagus, a key region that the pre-parasympathetic PVN neurons project to. Finally, we identify Trh-Ucn3 and Brs3-Adarb2 as some centrally projecting populations. In conclusion, our study presents a detailed overview of the transcriptomic cell types of the murine PVN and provides a first attempt to resolve functionality for the identified populations.

The arcuate nucleus is a crucial hypothalamic brain region involved in regulating body weight homeostasis. Neurons within the arcuate nucleus respond to peripheral metabolic signals, such as leptin, and relay these signals via neuronal projections to brain regions both within and outside the hypothalamus, ultimately causing changes in an animal's behaviour and physiology. There is a substantial amount of evidence to indicate that leptin is intimately involved with the postnatal development of arcuate nucleus melanocortin circuitry. Further, it is clear that leptin signalling directly in the arcuate nucleus is required for circuitry development. However, as leptin receptor long isoform (Leprb) mRNA is expressed in multiple nuclei within the developing hypothalamus, including the postsynaptic target regions of arcuate melanocortin projections, this raises the possibility that leptin also signals in these nuclei to promote circuitry development. Here, we used RT-qPCR and RNAscope® to reveal the spatio-temporal pattern of Leprb mRNA in the early postnatal mouse hypothalamus. We found that Leprb mRNA expression increased significantly in the arcuate nucleus, ventromedial nucleus and paraventricular nucleus of the hypothalamus from P8, in concert with the leptin surge. In the dorsomedial nucleus of the hypothalamus, increases in Leprb mRNA were slightly later, increasing significantly from P12. Using duplex RNAscope®, we found Leprb co-expressed with Sim1, Pou3f2, Mc4r and Bdnf in the paraventricular nucleus at P8. Together, these data suggest that leptin may signal in a subset of neurons postsynaptic to arcuate melanocortin neurons, as well as within the arcuate nucleus itself, to promote the formation of arcuate melanocortin circuitry during the early postnatal period.