Journal Of Neuroendocrinology[JOURNAL]
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200 papers
Non-synaptically released oxytocin regulates social communication by acting on vasopressin V1a receptors.
Aspesi D, Walton JC, Grieb ZA … +6 more , Kirchner MK, Song Z, Long MR, Larkin TE, Stern JE, Albers HE
J Neuroendocrinol · 2026 Jan · PMID 41249098 · Publisher ↗
How neuropeptides act within the neural circuits that control social behavior is not well understood. While the prevailing view is that neuropeptides act through synaptic release and then activation of their canonical re...
How neuropeptides act within the neural circuits that control social behavior is not well understood. While the prevailing view is that neuropeptides act through synaptic release and then activation of their canonical receptors on postsynaptic membranes, we investigated the role of a very different form of neuropeptide action in a neural circuit regulating social communication. Specifically, we tested the hypothesis that non-synaptically released oxytocin (OT) can act via the non-canonical receptors vasopressin V1a receptors (V1aR) to regulate social communication in Syrian hamsters. Scent marking, a key form of hamster social communication, can be enhanced by the α-melanocortin stimulating hormone (α-MSH), which stimulates OT but not arginine-vasopressin (AVP) release. Here, we employed hypothalamic injections of α-MSH and the α-MSH MC4R receptor antagonist MCL-0020 to determine the role of α-MSH in the expression of flank marking. To determine if these effects were intracellular calcium (iCa) dependent, hamsters were injected with AVP to induce flank marking and with the iCa antagonist TMB-8 to test whether it was possible to block this behavioral effect. Further, a highly selective AVP V1a receptor (V1aR) antagonist and an OT receptor (OTR) antagonist were injected into the hypothalamus to investigate the receptor responsible for activating flank marking. Finally, we employed an in vitro hypothalamic slice preparation using "Sniffer cells" biosensors to confirm that α-MSH induced the release of OT but not AVP. First, we found that the in vivo hypothalamic injection of α-MSH increased odor-stimulated scent marking, whereas blockade of its receptor with MCL-0020 reduced this behavior. Hypothalamic infusion of the iCa antagonist TMB-8 significantly reduced both AVP-induced and α-MSH-induced flank marking. Moreover, only the V1aR antagonist, and not the OTR antagonist, significantly decreased scent marking in response to hypothalamic infusion of α-MSH. Finally, biosensor recordings from hypothalamic slices confirmed that α-MSH stimulates OT, but not AVP, release. Together, these results demonstrate that α-MSH triggers non-synaptic OT release that regulates scent marking via V1aR activation, revealing a novel mechanism by which neuropeptides modulate social behavior.
Magnetic resonance imaging features of hypophysitis in patients with cancer treated with immune checkpoint inhibitors.
Angelousi A, Asimakopoulou S, Bourgioti C … +8 more , Anastasopoulou A, Kazanas S, Diamantopoulos P, Karabela A, Tasouli E, Moulopoulos LA, Ziogas DC, Gogas H
J Neuroendocrinol · 2026 Jan · PMID 41243162 · Full text
Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in several solid malignancies but are associated with endocrine immune-related adverse events (irAEs), particularly hypophysitis. This retrospectiv...
Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in several solid malignancies but are associated with endocrine immune-related adverse events (irAEs), particularly hypophysitis. This retrospective real-world data study aimed to assess the magnetic resonance imaging (MRI) findings in cases with immune-related (ir) hypophysitis. Sixty-six cancer patients treated with ICIs at Laikon General Hospital between January 2016 and September 2024, presenting with anterior pituitary hormone deficiencies, were included. All patients underwent baseline pituitary MRI at the time of ir-hypophysitis diagnosis (median time: 2 weeks post-diagnosis). A follow-up MRI was also available in 37 patients (median time: 1.6 years post-diagnosis). All scans were centrally reviewed by radiologists blinded to clinical data. Baseline MRI abnormalities demonstrated pituitary enlargement (25%), reduced enhancement (10%), empty sella (8.3%), heterogeneous enhancement (5%), reduced size (3.3%), and stalk deviation (1.7%). Among 31 patients with both baseline and follow-up MRIs, 45% showed imaging changes (partially empty sella, size alterations). No specific ICI regimen was associated with characteristic imaging patterns. Patients with multiple hormonal axis deficiencies had more frequent MRI abnormalities than those with isolated ACTH deficiency (68.4% vs. 46.3% initially; 71.3% vs. 56.4% at follow-up). Pituitary MRI abnormalities are present in approximately half of patients with ir-hypophysitis, with dynamic changes observed in follow-up imaging. However, the absence of findings in a substantial proportion highlights the limited sensitivity of MRI in this irAE and underscores the importance of clinical and biochemical evaluation.
From eyes to brain: A genetic and imaging exploration of thyroid eye disease neurological effects.
Yao J, Lu X, Ma J … +3 more , Liu Y, Hao L, Liu J
J Neuroendocrinol · 2026 Jan · PMID 41243140 · Publisher ↗
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...
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.
Somatostatin analogs in neuroendocrine tumors with Ki-67 index of ≥10.
Braegelmann J, Mathew A, Schmidt B … +4 more , Kalisch H, Fendler WP, Führer-Sakel D, Lahner H
J Neuroendocrinol · 2026 Jan · PMID 41239827 · Full text
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%. Th...
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.
Unraveling the impact of oxytocin receptor gene methylation on stress and inflammation in older adults.
Wright KA, Polk RJ, Lin T … +7 more , Chen S, Yang J, Krol K, Perkeybile A, Mendez A, Connelly J, Ebner NC
J Neuroendocrinol · 2026 Jan · PMID 41239825 · Full text
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...
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 = 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.
Epidemiology of acquired hypothalamic obesity following traumatic brain injury and nonspecific hypothalamic microinjury: A nationwide German claims data analysis.
Witte J, Touchot N, Batram M … +3 more , Diekmannshemke J, Flume M, Müller HL
J Neuroendocrinol · 2026 Jan · PMID 41236025 · Full text
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...
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.
The adverse effect of a hypercaloric high-fat diet feeding on hypothalamic cellular energy homeostasis is attenuated by a hypoglycemiant.
Vivero A, Espinoza S, Álvarez-Indo J … +7 more , Catalán-Aguilera J, Llontop N, Jara C, Porras O, Tapia-Rojas C, Yáñez MJ, Kerr B
J Neuroendocrinol · 2025 Dec · PMID 41220189 · Publisher ↗
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...
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 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 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 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.
The relationship between dose, concentration and toxicity of everolimus in the treatment of neuroendocrine tumors: A prospective observational study.
Folkestad OH, Sponheim J, Åvitsland TL … +3 more , Mordal KS, Vethe NT, Thiis-Evensen E
J Neuroendocrinol · 2026 Jan · PMID 41204799 · Publisher ↗
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 toler...
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), 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) 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 (p < .001), but considerable interindividual variability was observed. Median C 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 ≥ 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.
Systematic review and meta-analysis of the efficacy and safety of [Lu]Lu-edotreotide ([Lu]Lu-DOTATOC) for the treatment of neuroendocrine tumors.
Baum RP, Fricke JG, Ruhwedel T … +9 more , Amthauer H, Azorin-Vega EP, Hörsch D, Laudicella R, Maheshwari V, Walter MA, Polack BD, Spiegl SF, Nicolas GP
J Neuroendocrinol · 2026 Jan · PMID 41204752 · Full text
[Lu]Lu-edotreotide is a radiopharmaceutical therapy (RPT) targeting somatostatin receptors, which are commonly overexpressed on neuroendocrine tumors (NETs). This systematic literature review and meta-analysis describes...
[Lu]Lu-edotreotide is a radiopharmaceutical therapy (RPT) targeting somatostatin receptors, which are commonly overexpressed on neuroendocrine tumors (NETs). This systematic literature review and meta-analysis describes the efficacy and safety of [Lu]Lu-edotreotide in patients with NETs. To date, there has been no meta-analysis of data for this specific RPT. PubMed, EMBASE, Cochrane databases, and abstracts from select congresses were searched for eligible studies (February/October 2024). Meta-analysis was performed using fixed and random-effects models. The primary objective was to evaluate the efficacy of [Lu]Lu-edotreotide in terms of objective response rate (ORR; complete + partial response) in the subgroup of patients with gastro-enteropancreatic NETs (GEP-NETs) and those with any NETs, irrespective of origin (All-NETs). Secondary outcomes included disease control rate (DCR; best overall response of complete response + partial response + stable disease), median progression-free survival (mPFS), and median overall survival (mOS). Unpublished/updated data were requested from the investigators of the included publications where needed to provide missing information/enable evaluation of additional outcomes. Safety/tolerability data for [Lu]Lu-edotreotide were also reviewed. Eight eligible studies were identified for inclusion in the meta-analysis, all in the advanced disease setting (5/8 included patients with progressive NETs). Most patients had grade 1/2 NETs (grade 1: 11%-63%; 2: 30%-79%; 3: 4%-11%). Updated data were provided for four of these studies. Overall, ORR and DCR were reported in six studies (GEP-NETs, n = 222; All-NETs, n = 423), mPFS in five studies (GEP-NETs, n = 294; All-NETs, n = 267), and mOS in six studies (GEP-NETs, n = 256; All-NETs, n = 408). Meta-analysis revealed consistently high heterogeneity (I >70%) across outcomes/patient populations. Patients with GEP-NETs appeared to have better outcomes than those with All-NETs in terms of ORR (34% vs. 19%), DCR (78% vs. 57%), mPFS (24.9 vs. 18.6 months), and mOS (44.8 vs. 39.1 months), respectively. Safety/tolerability data were inconsistently reported, but grade 3/4 toxicities were rarely noted during [Lu]Lu-edotreotide treatment. These results support the effectiveness and safety of [Lu]Lu-edotreotide as a treatment for patients with advanced NETs and suggest a potentially more favorable prognosis for those with GEP-NETs than for the broader All-NETs population. However, these results should be interpreted with caution due to the high level of heterogeneity. Encouraging ORRs and high DCRs were noted, indicating that [Lu]Lu-edotreotide effectively stabilized disease in most patients. Although safety/tolerability data were inconsistently published across studies, [Lu]Lu-edotreotide was generally well tolerated. Overall, these findings suggest that the efficacy and safety of [Lu]Lu-edotreotide are in line with those reported for other RPTs in similar clinical settings. Clinical Trial Registration: PROSPERO 2024 CRD42024518028.
Stress-induced hyperphagia? Characterising the activity of the ghrelin axis in male rats with high anxiety behaviour.
Hornsby AKE, Haywood-Sheldrake B, Gryksa K … +6 more , Havasi A, Roberts LD, Humby T, Neumann ID, Davies JS, Wells T
J Neuroendocrinol · 2026 Jan · PMID 41199581 · Full text
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...
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.
Acute V vasopressin receptor antagonism ameliorates cardiovascular parameters in ovariectomized female rats subjected to chronic mild unpredictable stress.
Siddiqui SH, Komnenov D, Olayonwa A … +1 more , Rossi NF
J Neuroendocrinol · 2026 Jan · PMID 41195507 · Publisher ↗
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 val...
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 receptor (VR) 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 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, VR 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 R antagonism ameliorates aortic compliance in both male and OVX rats.
Food and the brain: Neural and endocrine control of feeding, metabolism, and reproduction.
da Silva Mansano N, Lieu CV, Abizaid A
J Neuroendocrinol · 2026 Jan · PMID 41151834 · Full text
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 evide...
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.
The p75 neurotrophin receptor is expressed in brain regions mastering reproduction but not in kisspeptin or GnRH neurons.
Derouin-Tochon F, Robert V, Lomet D … +4 more , Fleurot R, Hellier V, Beltramo M, Dufourny L
J Neuroendocrinol · 2026 Jan · PMID 41137779 · Publisher ↗
Neurotrophins (BDNF, NGF, NT3, and NT4/5) acting through different receptors are able to impact numerous functions, including cell fate and morphological plasticity, an asset for the maturation and differentiation of cel...
Neurotrophins (BDNF, NGF, NT3, and NT4/5) acting through different receptors are able to impact numerous functions, including cell fate and morphological plasticity, an asset for the maturation and differentiation of cells from neurogenic niches. They bind to the neurotrophin receptor p75 (p75), which could either heterodimerize with Trk receptors or act on its own to relay the varied physiological functions of neurotrophins. Published data suggest a preponderant role of p75 for NGF stimulation of GnRH neurons in vitro. We therefore focused on this receptor and its relationships with neuronal populations involved in the central control of reproduction. Here we investigated the distribution and phenotype of p75 cells in the hypothalamus of ovariectomized estrogen-replaced mice using several combinations of immunohistochemical labeling. We found that p75 is expressed mainly in neurons of the organum vasculosum of the lamina terminalis (OVLT)-medial septum continuum and in the arcuate nucleus (ARC). In this latter region, p75 was also seen in tanycytic cells lining the third ventricle. Co-distribution of p75 with TrkA was only seen in the OVLT, an area in which p75 is present in 16% of nitric oxide synthase-expressing neurons. In the ARC, 33% of p75 neurons were colocalized with tyrosine hydroxylase, an enzyme essential for catecholamine production. Anatomical distribution and co-expression with neurotransmitters involved in reproduction control, together with data suggesting that β-NGF induced ovulation in camelidae, prompted us to perform immunohistochemical double labeling against p75 and kisspeptin or GnRH, two neuropeptides essential for the central control of ovulation. However, no colocalization of p75 with kisspeptin or GnRH neurons was seen. These results suggest that neurotrophins, acting via the p75 receptor, do not directly modulate GnRH or Kp neurons. On the other hand, they may influence dopamine and nitric oxide production, and possibly induce remodeling of tanycytic endfeet, ultimately impacting indirectly the central regulation of reproduction in mice.
Optogenetic stimulation of the median preoptic nucleus: Effects on hypothalamic paraventricular nucleus magnocellular neurons after chronic intermittent hypoxia exposure.
Paundralingga OT, Jia S, Farmer GE … +2 more , Toney GM, Cunningham JT
J Neuroendocrinol · 2026 Jan · PMID 41111248 · Full text
Median preoptic nucleus (MnPO) neurons projecting to the hypothalamic paraventricular nucleus (PVN) are linked to hypertension induced by chronic intermittent hypoxia (CIH), a model of obstructive sleep apnea. The modula...
Median preoptic nucleus (MnPO) neurons projecting to the hypothalamic paraventricular nucleus (PVN) are linked to hypertension induced by chronic intermittent hypoxia (CIH), a model of obstructive sleep apnea. The modulation of MnPO-driven synaptic activity in PVN magnocellular neurons (MNCs) by CIH remains unexamined. We hypothesized that single and repetitive activation of MnPO-PVN projections causes differential synaptic plasticity in MnPO-PVN synapses with and without CIH exposure. Adult male rats were prepared using an intersectional viral approach to induce Cre-dependent channelrhodopsin expression in PVN-projecting MnPO neurons. Two weeks after stereotaxic surgery, some rats were exposed to 7 days of CIH. All rats were anesthetized and their brains were prepared for in vitro electrophysiological recording from PVN MNCs and optogenetic stimulation of the MnPO. We observed distinct EPSC and IPSC response patterns to the optogenetic stimulation of the MnPO. Low-frequency optogenetic stimulation (15 Hz) resulted in short-term potentiation manifested in increased poststimulatory spontaneous EPSC (sEPSC) frequency without altering amplitude while gradually increasing poststimulatory sIPSC frequency and amplitude, shifting some neurons to a more inhibitory state. CIH increased the amplitude of both sEPSCs and stimulation-evoked EPSCs while reducing their frequency. In contrast, CIH enhanced both the amplitude and frequency of sIPSCs and stimulation-evoked IPSC. Stimulation-evoked currents recorded during train protocols reflected a mixture of spontaneous and evoked events. Optogenetic stimulation increased the intrinsic excitability of MNCs in rats exposed to CIH. Activation of the MnPO-PVN pathway recruits both excitatory and inhibitory synaptic circuits converging onto PVN MNCs. CIH induces metaplasticity within this pathway, manifested as strengthened excitatory synaptic drive and heightened intrinsic excitability of PVN MNCs, which is counterbalanced by an adaptive increase in inhibitory tone. These parallel changes could explain why CIH is not associated with increased neurohypophysial hormone release.
Chronic circadian disruption in female mice induces a long-term alteration of the preovulatory LH surge.
Simonneaux M, Simonneaux V
J Neuroendocrinol · 2026 Jan · PMID 41111065 · Publisher ↗
In female mammals, many aspects of the reproductive function require precise synchronization of neuroendocrine and behavioral events for optimal fertility. To this end, the circadian timing system entrained by light expo...
In female mammals, many aspects of the reproductive function require precise synchronization of neuroendocrine and behavioral events for optimal fertility. To this end, the circadian timing system entrained by light exposure, in addition to the cyclical variations of sex steroid hormones, sets the pace of the hypothalamic-pituitary-ovarian axis. This is best illustrated by the preovulatory LH surge triggered by a daily signal generated by the master circadian clock at the resting-active period transition combined with the positive feedback from estradiol produced by maturing ovarian follicles at the end of the follicular phase. This ensures that ovulation occurs when sexual arousal is maximal, optimizing the chances for reproductive success. Although increasing evidence reports the direct impact of circadian disruption on female reproductive function in animals and humans, the potential long-term consequences remain unknown. Using a light-based shift work model in which adult female mice experienced a 10-h phase advance and a 10-h phase delay each week for 4 weeks (rotating shift condition), we investigated the long-term effects of such circadian disruption by monitoring reproductive rhythms after light exposure was normalized. Our results report a significant alteration in the timing and amplitude of the LH surge on the day of proestrus for up to 3 weeks after pre-exposure to disrupted light-dark cycles, despite regular estrous cycles. This long-lasting dysregulation of LH secretion may be linked to a delayed resynchronization of the internal timing system after exposure to rotating shift condition since locomotor activity also takes approximately 2 weeks to recover a robust daily rhythm. Given the significance of temporal homeostasis to proper reproduction, these findings emphasize the importance of investigating the long-lasting negative impacts of shift work on women's reproductive health.
A male-dominant cell group expressing calbindin-D28K and androgen receptor in the mouse preoptic area requires postnatal testicular androgens and histone deacetylation.
Arai Y, Tsukahara S
J Neuroendocrinol · 2025 Nov · PMID 41065218 · Full text
The mouse brain is masculinized by postnatal testicular androgens, which are active after conversion to estrogens and modulate gene expression epigenetically, at least in part. The preoptic area contains a sexually dimor...
The mouse brain is masculinized by postnatal testicular androgens, which are active after conversion to estrogens and modulate gene expression epigenetically, at least in part. The preoptic area contains a sexually dimorphic nucleus (SDN) comprising calbindin D-28K (Calb) neurons with a male-biased sex difference in cell number (Calb-SDN), although the mechanisms responsible for the sex difference are not fully understood. We have previously demonstrated that Calb neurons expressing the androgen receptor (AR) are a male-dominant cell group of the Calb-SDN in pubertal mice, while Calb neurons without AR exist in both sexes with equal cell numbers. In this study, we investigated the mechanisms by which more Calb/AR neurons emerge in the male Calb-SDN than in the female one. Immunohistochemistry for Calb and AR was performed using the brain sections from pubertal male mice subjected to sham surgery or neonatal orchidectomy, from pubertal female mice treated with vehicle, testosterone, or estradiol during the postnatal period, and from pubertal male mice whose brains were treated with trichostatin A, a histone deacetylase inhibitor, during the postnatal period. Immunostained brain sections were analyzed stereologically to determine the numbers of Calb-immunopositive and AR-immunopositive cells (Calb/AR cells) and Calb-immunopositive and AR-immunonegative cells (Calb/AR cells) in the Calb-SDN. The number of Calb/AR cells in the Calb-SDN during the pubertal period was significantly decreased in neonatally orchidectomized males compared with sham males and increased in testosterone- or estradiol-treated females compared with vehicle-treated females; however, the number of Calb/AR cells remained unchanged. Trichostatin A treatment significantly reduced the number of Calb/AR cells, but not the number of Calb/AR cells, in the Calb-SDN of males. These findings suggest that estrogens synthesized from postnatal testicular androgens act selectively on the AR-expressing subpopulation of Calb neurons, contributing to the sex difference in the number of Calb neurons in the mouse Calb-SDN. Epigenetic regulation of gene expression, possibly mediated by histone deacetylation, may be involved in the emergence of the AR-expressing subpopulation of Calb neurons.
GHSRs in the olfactory bulb suppress food motivation and promote exploration without altering spatial memory in male mice.
Stark R, Zigman JM, Andrews ZB
J Neuroendocrinol · 2025 Dec · PMID 41062075 · Full text
The olfactory bulb (OB) is an emerging neuroendocrine centre regulating appetite, metabolism, and behaviours such as those linked to anxiety, motivation and spatial navigation. These processes are likely mediated by one...
The olfactory bulb (OB) is an emerging neuroendocrine centre regulating appetite, metabolism, and behaviours such as those linked to anxiety, motivation and spatial navigation. These processes are likely mediated by one or more of the many hormone receptors found in the OB. For instance, recent studies show that selective OB deletion of the receptor for ghrelin and LEAP2 (GHSR; growth hormone secretagogue receptor) increases anxiety-like behaviour and impacts peripheral glucose and energy homeostasis. As GHSR function has been linked to motivated behaviours and spatial navigation, we decided to investigate whether OB-selective GHSR (OB) deletion affects motivation, using an operant progressive ratio schedule, and/or spatial navigation, using a Y maze and radial arm maze. In contrast to wild-type mice, our study shows that OB deletion increased motivated sucrose seeking after a short fast, but not in ad libitum fed mice, and had a mild effect to delay extinction learning. In both Y-maze and radial arm maze studies for spatial navigation, OB deletion reduced spatial exploration in terms of distance moved and arm entries. However, the proportion of correct and incorrect arm entries relative to the total number of entries was not affected in either the Y-maze or the radial arm maze, suggesting that spatial memory was not affected. Our study demonstrates that intact OB in male mice normally restrain motivated sucrose seeking in a metabolic state-dependent manner and optimise spatial navigation by increasing exploration, without affecting spatial memory.
Dopamine and prolactin in migraine: Mechanisms and potential therapeutic targets.
Hjelholt AJ, Tei RMH, Diener HC … +1 more , Jørgensen JOL
J Neuroendocrinol · 2025 Dec · PMID 41052788 · Full text
Migraine is a complex neurovascular disorder characterized by activation and sensitization of the trigeminovascular system. Hyperprolactinemia is associated with headache, and improvement following prolactin-lowering the...
Migraine is a complex neurovascular disorder characterized by activation and sensitization of the trigeminovascular system. Hyperprolactinemia is associated with headache, and improvement following prolactin-lowering therapy has been reported in observational studies. Preclinical evidence indicates that prolactin promotes neuronal excitability and sensitization within trigeminal pathways, particularly in females. Downregulation of the protective long prolactin receptor isoform further increases susceptibility to migraine-relevant triggers. Prolactin secretion is under tonic inhibition by dopamine, a key hypothalamic regulator that also modulates central pain pathways. The role of dopamine in migraine pathophysiology is complex. On one hand, prodromal symptoms such as nausea and yawning are considered dopamine-mediated. On the other hand, experimental studies show that dopamine directly inhibits nociceptive trigeminovascular activity in addition to lowering prolactin. Dopamine receptor agonists are established treatments for hyperprolactinemia and have demonstrated a positive effect on hyperprolactinemia-associated headache. A recent placebo-controlled randomized clinical trial suggests that dopamine agonist treatment can be used as a preventive migraine treatment. In conclusion, prolactin and dopamine may modulate migraine via distinct but converging neuroendocrine pathways, which could represent targets for migraine prevention.
Mild increase of temperature from the thermoneutral zone inhibits reproductive activation in Syrian hamsters through epigenetic inhibition.
Hnamler L, Trivedi AK
J Neuroendocrinol · 2025 Nov · PMID 41035131 · Publisher ↗
The rapid increase in urbanization is drastically altering the habitat composition of the wild population. Urbanization is predominantly changing the landscape, composition of flora and fauna, availability of night light...
The rapid increase in urbanization is drastically altering the habitat composition of the wild population. Urbanization is predominantly changing the landscape, composition of flora and fauna, availability of night light, and the rise in temperature. In the natural habitat, photoperiod and temperature are inseparable. In the present study, we examined the effect of mild temperature change from the thermoneutral zone of Syrian hamsters on reproduction-linked activities. To investigate the neuroendocrine mechanisms underlying heat stress effects on reproduction in hamsters, two experiments were performed on adult male animals. In experiment one, animals were divided into two groups (n = 5/group) and exposed to a long photoperiod (15L:9D) with either low (LT; 20 ± 2°C) or high temperature (HT; 32 ± 2°C). After 21 days, all animals were sampled. In experiment two, hamsters (n = 20) were divided equally into two groups and were exposed to the first short photoperiod of 8L:16D, but with low temperature (LT; 20 ± 2°C) or high temperature (HT; 32 ± 2°C). After 30 days, all animals were exposed to a long day (15L:9D), but animals from each temperature treatment were divided equally into two groups (n = 5/group). Half of the animals (n = 5) of low temperature remained in low temperature (LL group) while the remaining animals were moved to high temperature (LH group). Similarly, half of the animals (n = 5) of high temperature remained in high temperature (HH group), and the rest of the animals were moved to low temperature (HL group). Body mass and testicular volume were measured at different intervals. After 30 days of long-day treatment, the animals were sampled. Findings suggest that exposure to 3 weeks of high temperature attenuates testicular growth, coupled with low testosterone levels and downregulation of Kiss1, Eya3, Tshβ, GnRh, Tet1, Tet2, and Hat1, while upregulation of Dio3, GnIh, Dnmt1, Dnmt3A, Hdac1, and Hdac5 occurs in HT groups. Results from experiment two suggest that low temperature promotes, while high temperature attenuates reproduction and the linked phenomenon. Together, these findings suggest that high temperature modulates the reproductive responses of Syrian hamsters.
Telotristat ethyl affects tumour-fibroblast crosstalk in small intestinal neuroendocrine tumours.
Hodgetts H, Martins MC, Chen L … +5 more , Hall AR, Luong TV, Mandair D, Caplin M, Rombouts K
J Neuroendocrinol · 2025 Nov · PMID 40998421 · Full text
Small intestinal neuroendocrine tumours (SI-NETs) are associated with mesenteric fibrosis, which causes significant morbidity and mortality. Telotristat ethyl was developed to treat carcinoid syndrome in SI-NET patients....
Small intestinal neuroendocrine tumours (SI-NETs) are associated with mesenteric fibrosis, which causes significant morbidity and mortality. Telotristat ethyl was developed to treat carcinoid syndrome in SI-NET patients. Recent studies indicated telotristat ethyl could have anti-tumour activity; however, the mechanism remains unclear. This study aimed to investigate the effects of telotristat ethyl on SI-NET-fibroblast crosstalk in tumour progression and mesenteric fibrosis. A co-culture paracrine model with GOT1 (tumour) cells and LX2 (stromal) cells was optimized. Cells were treated with conditioned medium with/without telotristat ethyl followed by RNA sequencing and Gene Set Enrichment Analysis. Quantitative RT-PCR, immunohistochemistry, and Western blot were performed on first and second tier targets in tissue from 34 SI-NET patients grouped into categories of mesenteric fibrosis severity. Telotristat ethyl significantly decreased proliferation and serotonin secretion in a dose-dependent manner in GOT1 cells. GSEA data indicated ECM-related reactomes were downregulated in GOT1 cells grown in conditioned medium of LX2 cells with telotristat ethyl. LAMA5, COL6A2, and COL12A1 expression was significantly increased in mild and severely fibrotic patients. Immunohistochemistry determined the localization of proteins such as COL4A2 in the stroma and ADAM12 in tumour cells. Protein analysis of second tier targets showed differences in expression, including β-catenin, which was significantly upregulated, and pAKT/AKT, which tended to increase in primary tumour compared to normal SI. Telotristat ethyl affects the expression of genes associated with the ECM and interferes with SI-NET-fibroblast crosstalk. Further analysis is required; however, this study represents an important step in understanding the mechanisms of telotristat ethyl when treating SI-NET patients.
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