Journal of Neuroendocrinology最新文献

Observational studies have reported that thyroid eye disease (TED) may cause structural and functional disorders in the brain, However, it remains uncertain whether this relationship is causal. Genetic data were obtained from the Finn Gen R11 database, yielding 587 imaging-derived phenotypes (IDPs). Single-nucleotide polymorphisms associated with TED were selected as instrumental variables, and multi-variable regression models combined with sensitivity analyses (including Cochran's Q test, MR-Egger regression, and leave-one-out analysis) were applied to evaluate the potential causal relationships between TED and these IDPs. In addition, we recruited 90 patients with TED (49 with mild disease and 41 with moderate to severe disease) along with 50 healthy controls to establish a clinical cohort. White matter microstructural alterations across different disease stages were assessed using tract-based spatial statistics (TBSS) based on diffusion tensor imaging and neurite orientation dispersion and density imaging, and these changes were further correlated with clinical indicators and rating scales. Inverse Mendelian randomization analysis revealed a significant causal relationship between TED and 26 IDPs associated with correlated fibers, brainstem nerve bundles, joint fiber regions, and projection fiber regions (false discovery rate <0.05). TBSS further revealed the evolutionary pattern of white matter structure at different levels of disease and was strongly associated with visual function, ocular symptoms, and emotional state. The combination of the two revealed abnormalities in the microstructure of white matter pathways in the anterior thalamic radiation, superior longitudinal fasciculus, and uncinate fasciculus. This study is the first to systematically assess the causal relationship between TED and cerebral white matter microstructure from both genetic and imaging levels. The two perspectives systematically reveal the potential impact of TED on the central nervous system, providing new evidence for the study of the neural mechanisms of TED and a theoretical basis for future clinical early screening and multidisciplinary intervention strategies.

Oxytocin (OT) is a neuropeptide involved, among other functions, in the regulation of stress and inflammation. OT's impact on inflammatory and stress-related processes is particularly relevant in older adults, given that elevated levels of systemic inflammation typically associated with age can be amplified by stress. Methylation of the OT receptor gene (OXTRm) is an epigenetic process that reduces the availability of receptors to bind with OT. While acute stress has been shown to increase OXTRm levels in older adults, the interplay of OXTRm and stress on inflammation remains unexamined. This study collected blood samples from 116 generally healthy older adults (M_age = 71.2 years, SD = 7.51 years, range = 55–95 years) to quantify methylation OXTRm at CpG site -924 and tumor necrosis factor (TNF)-α as biomarkers of systemic inflammation, as well as assessed self-reported levels of stress. Moderated linear regression revealed that higher OXTRm methylation levels and greater perceived stress were associated with greater systemic inflammation (B = 0.24, p = 0.006). These findings highlight OXTRm as an epigenetic pathway linking stress and inflammation in aging.

Somatostatin analogs (SSAs) are an established first-line therapy in intestinal and pancreatic neuroendocrine tumors (NETs). Based on Phase III studies, their use is recommended in NET with a Ki-67 index of up to 10%. The effect of first-line SSA therapy on differentiated NET with a Ki-67 index ≥10% is poorly understood. This study aimed to investigate the outcomes of SSA therapy in differentiated NETs with a Ki-67 index of ≥10%. A retrospective analysis of a prospectively created dataset of consecutive patients with NETs was performed. Patients with first-line SSA monotherapy in advanced NET with a Ki-67 index ≥10% were included. The study endpoints were progression-free survival (PFS), overall survival (OS), and clinical benefit rate, defined as partial remission (PR) or stable disease (SD). Of 362 consecutive patients with a Ki-67 index ≥10%, 67 received first-line SSA therapy. The Ki-67 index was 10–20% (G2) in 57 (85%) patients and >20% (G3) in 10 (15%). SD as the best response was reached in 40 (59.7%) patients and PR in 3 (4.5%), irrespective of the NET origin, time from the diagnosis, or somatostatin receptor-based tracer uptake. The median PFS was 18 (95% confidence interval [CI], 5.7–30.3) months, and the median OS was 60 (95% CI, 38.2–81.8) months after the initiation of SSA therapy. Median PFS was significantly longer in patients with a Ki-67 index of 10–20% (19 months; 95% CI, 6.2–31.8) compared to those with G3 NETs (6 months; 95% CI, 2.9–9.1; p = .015, log-rank test), and in patients with a liver tumor burden of ≤10% (24 months; 95% CI, 12.7–35.3) versus >10% (4 months; 95% CI, 2.3–5.7; p = .007). First-line SSA therapy can provide meaningful disease control in patients with G2 NETs and low tumor burden, despite a Ki-67 index ≥10%. It may be a reasonable alternative to more intensive therapies in selected patients.

Acquired hypothalamic obesity (aHO) is characterized by rapid and persistent weight gain resulting from structural or functional damage to the hypothalamus, typically accompanied by neuroendocrine dysfunction. While aHO is well described in the context of hypothalamic or suprasellar tumors, particularly craniopharyngioma, little is known about its epidemiology in non-tumor–related etiologies such as traumatic brain injury (TBI) or subtle, unrecognized hypothalamic injuries. This study estimates the incidence and clinical characteristics of aHO in patients with traumatic brain injury (TBI-aHO) and hypothalamic–pituitary axis dysfunction of unclear origin, referred to as unspecified microinjury (UM-aHO). We conducted a retrospective cohort study using German statutory health insurance claims data (N = 6.3 million, 2010–2022). Patients were included based on either an incident diagnosis of TBI or a diagnostic algorithm indicating hypothalamic–pituitary axis dysfunction without a documented causal event. aHO was defined via incident obesity coding and validated by concomitant arginine vasopressin deficiency (AVP-D) and desmopressin prescription. For UM-aHO, additional validation required at least three concurrent neuroendocrine replacement therapies. Sensitivity analyses assessed the robustness of case definitions. The estimated incidence of TBI-aHO was 1.78 per million persons (mean age: 42 years; 27% female), corresponding to approximately 520 prevalent cases in Germany. UM-aHO showed a slightly higher incidence of 2.12 per million (mean age: 37 years; 55% female), with an estimated 660 prevalent cases. Following the diagnosis of incident obesity, most patients in both cohorts received at least two neuroendocrine therapies in addition to desmopressin, most commonly including hydrocortisone and levothyroxine sodium. This is the first population-based study to characterize aHO following non-tumor–related hypothalamic injury. Both TBI and subtle, nonspecific hypothalamic microinjuries contribute meaningfully to the burden of aHO in clinical practice. These findings underscore the need for increased clinical awareness and early recognition of hypothalamic dysfunction in patients beyond classical tumor etiologies.

Obesity is a global public health challenge emerging from an energy homeostasis (EO) disruption. EO is primarily driven by neurons residing in the hypothalamus, whose function is critical to integrate neural and humoral signals that account for energy balance. Obesogenic diets induce a loss of function in the mechanism through which these neurons sense the energy status, leading to the systemic accumulation of excess energy. This could result from altered cellular EO involving mitochondria and molecular energy sensors, such as AMP-activated protein kinase (AMPK) and/or K_ATP channels. In this line, hyperglycemia induced by obesogenic diets alters the central regulation of energy balance in the hypothalamus, possibly due to the loss of sensing anorexigenic signals induced by hyperinsulinemia and hyperleptinemia, mediated by deficient energy control involving mitochondria, AMPK, and K_ATP channels. Therefore, reducing elevated glycemia in a mouse model of hypercaloric feeding could restore cellular energy sensing and normalize energy homeostasis. To test this hypothesis, this work aims to evaluate whether the loss of body energy balance induced by hypercaloric 45% high-fat diet (D45%) feeding is prevented by oral hypoglycemiant, metformin (MT), by restoring mitochondrial function, AMPK sensitivity, and K_ATP levels in the hypothalamus of mice. For this purpose, mice were fed a D45% and supplemented with MT for 12 weeks. Metabolic, physiological, and molecular parameters were assessed. The treatment with MT decreased food intake and body weight gain induced by D45% feeding; besides, MT increased horizontal locomotor activity and attenuated insulin resistance and glucose intolerance after 12 weeks of treatment. Regarding energy sensors, MT attenuated the increased phosphorylation of AMPK and reduced the expression of Kir6.2 induced by D45% feeding. These results show that reduced glycemia can partially reverse the decreased energy sensor function and the altered energy metabolism induced by feeding with a hypercaloric diet.

Everolimus is used in the treatment of patients with advanced neuroendocrine tumors (NET) and is administered at fixed doses despite known interpatient pharmacokinetic variability. This may affect both efficacy and tolerability. We wanted to investigate the relationship between prescribed dose, blood trough concentrations (C_trough), and toxicity in NET patients receiving everolimus in routine clinical practice. In this prospective observational study NET patients were treated with everolimus, mostly as third- or fourth-line therapy. Dose was adjusted according to adverse effects and tumor response. Concentrations (C_trough) of everolimus were measured at each routine follow-up and correlated to dose and cumulative adverse event (cAE) scores. Associations were evaluated using linear and generalized linear mixed models which accounted for repeated measurements within patients and varying dose regimens over time. Thirty-six patients were included. Everolimus dose was a significant predictor of C_trough (p < .001), but considerable interindividual variability was observed. Median C_trough levels increased with dose: 3.9, 5.1, 7.4, and 16.4 ng/mL for 2.5, 5.0, 7.5, and 10.0 mg per day, respectively. Considerable overlap in blood concentration was observed across dose groups; patients receiving 2.5 mg reached levels as high as 8.6 ng/mL, while those on 5 mg exhibited a wide range from 1.1 to 21.2 ng/mL. C_trough ≥ 6.0 ng/mL was associated with increased toxicity (p = .03), whereas nominal dose was not a reliable independent predictor of adverse events. Although median blood concentrations increased with higher doses, there was considerable variation between patients, resulting in overlapping concentration ranges across all dose groups. This indicates that fixed-dose regimens may not reliably predict systemic drug exposure. Everolimus blood concentrations were superior to dose levels in predicting adverse events. Therapeutic drug monitoring and individualized dose adjustment may improve the balance between efficacy and toxicity in NET patients treated with everolimus.

Depression is a recognized non-traditional risk factor for adverse cardiovascular disease (CVD) outcomes. The risk for CVD increases in women after menopause. The chronic mild unpredictable stress (CMS) paradigm is a validated rodent model of depression. In male rats, CMS results in higher blood pressure and sympathoexcitation that is mitigated by direct inhibition of the vasopressin V_1b receptor (V_1bR) within the paraventricular nucleus. In the present study we tested the hypothesis that ovariectomized (OVX) but not gonadally intact female rats display cardiovascular responses similar to male CMS rats and that these responses will be mitigated by systemic V_1b R inhibition. Intact and OVX female rats and male rats were subjected to a 4-week CMS protocol or standard housing (control). Hemodynamics were assessed by telemetry. Left ventricular (LV) function and aortic pulse wave velocity (aPWV) were assessed 1 h after either vehicle or nelivaptan, 10 mg/kg i.p. mean arterial pressure and heart rate were similar in gonadally intact control and CMS female rats but were significantly elevated from baseline values in CMS OVX and male rats. aPWV was elevated in CMS male and OVX rats and improved after treatment with nelivaptan independent of blood pressure. Neither systolic nor diastolic LV function was impaired; however, V_1bR inhibition increased LF ejection fraction in gonadally intact female rats. These findings support the concept that OVX females display cardiovascular responses similar to male rats when subjected to CMS. Systemic V_1b R antagonism ameliorates aortic compliance in both male and OVX rats.

While evidence is emerging that the temporal pattern of feeding may influence anxiety, it is unclear to what extent anxiety may itself impact spontaneous feeding behaviour. To address this, we have quantified spontaneous feeding, ghrelin secretion and adult hippocampal neurogenesis (AHN) in male low (LAB) and high (HAB) anxiety-behaviour rats. LAB and HAB rats showed the expected anxiogenic profile in the elevated plus-maze, HAB rats avoiding the open arms entirely. A 16% reduction in total food intake in HAB rats (p = .017) was due to a 35% reduction in light phase food consumption (p = .004). However, there were no significant changes in the number or duration of individual feeding events, and the 24-h feeding profile remained largely unaltered. Although basal circulating ghrelin was comparable in HAB and LAB rats, the 57% elevation in circulating ghrelin induced by a 24-h fast in LAB rats (p = .022) was completely abolished in HAB rats. In comparison with adult LAB rats, the number of newborn neurones (BrdU⁺/NeuN⁺) in the dentate gyrus of HAB rats was elevated by 68% and 103% in the sub-granular zone and granule cell layer, respectively (p = .0004 and p < .0001), these increases being observed across the rostro-caudal extent of the hippocampus. In contrast, the number of newborn non-neuronal (BrdU⁺/NeuN⁻) cells was unaltered. Thus, even in the context of the marked anxiety in HAB rats, mild hypophagia occurs without significant alteration in feeding patterns. Despite a blunting of fasting-induced ghrelin release, elevated AHN suggests an appropriate feedback response to the increased anxiety-related behaviour.

Feeding and reproductive function are regulated by intricate systems that monitor food availability and energy stores, and on the basis of energy status, promote or put a brake on reproduction. This is particularly evident in the systems that regulate feeding and reproductive state in female mammals. Here we describe some of the systems that regulate feeding and reproductive state focusing on how metabolic hormones impact the onset of puberty as discussed in the panel session presented at the recent Panamerican Neuroendocrine Society meeting in Santos, Brazil. Indeed, hormones like leptin and insulin, which are released when levels of energy resources are increasing, may be critical signals that activate hypothalamic pathways related to ovulation in females to cause the onset of puberty. In adults, increasing levels of these hormones signal to the hypothalamus to reduce food intake and increase energy expenditure. In contrast, hormones like ghrelin impact hypothalamic and extrahypothalamic brain regions to drive hunger and the motivation to eat ultimately increasing feeding behavior and decreasing energy expenditure. Based on these actions, we describe some potential targets for the treatment of obesity and the mechanisms by which these targets work to improve human health.