Journal Of Neuroendocrinology[JOURNAL]
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200 papers
The emerging role of chemokines and chemokine receptors in the biological and clinical behaviour of pituitary neuroendocrine tumours: An exploratory transcriptomic study.
Silva AL, Barry S, Hipólito A … +11 more , de Griné Severino M, Joaquim R, Hall C, Oliveira T, López-Presa D, Borrecho G, Tortosa F, Nobre E, Faria CC, Korbonits M, Marques P
J Neuroendocrinol · 2026 Apr · PMID 41967485 · Full text
The chemokine network in the microenvironment of pituitary neuroendocrine tumours (PitNETs) may modulate tumour biology, aggressiveness, and treatment responses. We aimed to study the role of various chemokines and chemo...
The chemokine network in the microenvironment of pituitary neuroendocrine tumours (PitNETs) may modulate tumour biology, aggressiveness, and treatment responses. We aimed to study the role of various chemokines and chemokine receptors in defining PitNET phenotype and clinical outcomes. We included 96 patients (51 females) with available snap-frozen PitNET tissue from surgery between 2014 and 2020. Chemokine and chemokine receptors were studied by RT-qPCR. Fold difference in mRNA expression was calculated using the ΔΔCt method; chemokine and receptor expression levels were normalised to the expression of the control gene TBP, and expressed relative to a reference sample. Ten chemokines and receptors were studied (CCL2, CCL3, CCL4, CXCL8, CX3CL1, CCR2, CCR4, CCR5, CXCR1, CXCR2), and their expression correlated with clinico-pathological and outcome data, as well as other available microenvironment-related data. We found strong positive correlations between all chemokines and chemokine receptors. Higher chemokine and receptor expression levels were seen in patients who had pituitary apoplexy (CCR2, CXCR1), hypopituitarism at diagnosis (CCL2, CCR4), Ki-67 >3% (CCL4, CXCR2), as well as in patients who required re-operation (CCL3, CXCL8, CXCR2), multimodal therapy (CCL2), and had active disease at last-follow-up (CCL2). There was a positive correlation between the number of pituitary surgeries and expression levels of CCL3, CXCL8, CX3CL1, CXCR1, and CXCR2. Compared to nonfunctioning-PitNETs, somatotropinomas had higher expression of CCL2, CCL4, and CCR2, and lower expression of CX3CL1 and CCR4. Expression of CDH1 (encoding E-cadherin) correlated negatively with CCL2, CCL4, CCR2, CCR4, and CXCR2, while the expression of ZEB1 (mesenchymal marker) positively correlated with CCL3, CCL4, and CX3CL1. PitNETs expressing higher levels of CCL4, CX3CL1, CCR4, CCR5, and CXCR1 had more and bigger vessels. Somatotropinomas treated pre-operatively with somatostatin analogues were associated with higher expression of CCL2, CCR4, CXCR1, and CXCR2, while nonfunctioning-PitNETs pre-surgically treated with dopamine agonists were associated with lower expression of CCL3, CCL4, CX3CL1, CCR5, CXCR1, and CXCR2. Our data suggests that chemokines and chemokine receptors may be involved in the modulation of different tumorigenic mechanisms in PitNETs, including tumour proliferation, epithelial-to-mesenchymal transition, and angiogenesis, and may be associated with more aggressive and difficult-to-treat disease.
Effect of gonadectomy and hormone replacement on habenula-induced dopamine inhibition in female and male rats.
Waldron VJ, Suttawireesan M, Fatimah S … +2 more , Merchenthaler IJ, Brown PL
J Neuroendocrinol · 2026 Apr · PMID 41964284 · Full text
Sex differences have been noted in the prevalence and severity of several neurological and mental health disorders. Midbrain dopaminergic activity is implicated in the etiology of many of these disorders and therefore ma...
Sex differences have been noted in the prevalence and severity of several neurological and mental health disorders. Midbrain dopaminergic activity is implicated in the etiology of many of these disorders and therefore may also contribute to some commonly seen sex differences in presentation and treatment. The ability of the lateral habenula to inhibit midbrain dopamine firing activity is reduced in female rats, and we test here the hypothesis that circulating gonadal hormones contribute to this sex difference. In vivo, single unit, extracellular recordings of dopamine neurons were conducted in female and male rats that were intact, gonadectomized, or had hormone replacement. Both spontaneous and habenula-evoked activities were recorded. In accordance with previous findings, we found that habenular stimulation produces profound inhibition in dopamine neurons that is of longer duration in male rats than female rats. There was no effect of gonadectomy on duration of inhibition in either males or females. Although there was a trend toward stronger rebound excitation in control male rats, there was no significant effect of gonadectomy in either the male or female rats. Here we show that circulating gonadal hormones have no apparent effect on habenular evoked dopamine inhibition. We discuss the limitations of the current study, including the possibility that the influence of circulating gonadal hormones may be limited to sub-populations of midbrain dopamine neurons.
European Society of Neuroendocrine Tumors (ENETS) 2025 guidance paper for lung and thymic carcinoids.
Baudin E, Durand A, Buikhuisen W … +10 more , Capdevila J, Caplin M, Deroose CM, Dromain C, Faggiano A, Filosso PL, Kaltsas G, Volante M, Walter T, Garcia-Carbonero R
J Neuroendocrinol · 2026 Apr · PMID 41941890 · Full text
This ENETS guidance paper, developed by a multidisciplinary working group, provides up-to-date and practical advice on the diagnosis and management of lung and thymic carcinoids, based on recent developments and study re...
This ENETS guidance paper, developed by a multidisciplinary working group, provides up-to-date and practical advice on the diagnosis and management of lung and thymic carcinoids, based on recent developments and study results. These recommendations aim to provide practical recommendations for the diagnosis, treatment and follow-up of these tumours, and pave the road for more standardised care for our patients expecting improved outcomes. This paper is structured on a question-answer format in order to address common dilemmas encountered in clinical practice, including controversial issues and areas of uncertainty, based on the best available evidence and expert opinion when good quality evidence is not available. Each recommendation will provide a level of evidence and grade of recommendation as per the GRADE system (adapted from the Infectious Disease Society of United States Public Health Service grading system).
Patterns of response and survival in metastatic paragangliomas and pheochromocytomas: Experience from two Spanish neuroendocrine tumor centers.
Del Olmo-García MI, Contreras Saldarriaga JE, Hernandez-Rienda L … +9 more , Hernando-Cubero J, García Alvarez A, García-Burillo A, Casterás A, Segura-Huerta A, Prado S, Palasí R, Merino-Torres JF, Capdevila Castillón J
J Neuroendocrinol · 2026 Apr · PMID 41933280 · Publisher ↗
Metastatic pheochromocytomas and paragangliomas (mPPGLs) are uncommon, heterogeneous neuroendocrine tumors lacking standardized systemic treatment pathways. Evidence on treatment response predictors and outcome-based str...
Metastatic pheochromocytomas and paragangliomas (mPPGLs) are uncommon, heterogeneous neuroendocrine tumors lacking standardized systemic treatment pathways. Evidence on treatment response predictors and outcome-based stratification remains limited. We conducted a retrospective study of 49 patients with mPPGLs treated between 2010 and 2024 at two Spanish referral centers. We evaluated clinical characteristics, systemic treatment patterns, radiologic responses (per RECIST), and survival outcomes. Patients were stratified into five clinical evolution patterns based on treatment response and disease trajectory. The most common indications for initiating systemic therapy were radiologic progression (59.5%) and high tumor burden (31%). First-line treatments included somatostatin analogues (SSAs, 40.5%), radionuclide therapies (33.3%: Lu 9.5% and I-MIBG 23.8%), and chemotherapy (23.8%). Partial response rates were higher with chemotherapy, I-MIBG, and Lu compared with SSAs. Tumor burden at treatment initiation appeared to be more closely associated with radiologic response than radiologic progression. Progression-free survival (PFS) appeared to differ according to first-line treatment type, with longer PFS observed in patients receiving radionuclide therapies. The median overall survival from systemic treatment initiation was 48 months. Five clinical evolution patterns were identified, highlighting disease heterogeneity. Radiologic progression remains the main trigger for systemic treatment in mPPGLs; however, initial tumor burden appears to be a stronger predictor of treatment response. Our proposed five-pattern clinical classification may contribute to prognostication and therapeutic individualization. Prospective studies are a key unmet need to determine the optimal timing and sequencing of systemic therapies in mPPGL.
The lesser the better? A systematic review and meta-analysis of resection strategy in lung neuroendocrine tumors.
Aviel G, Hojerat R, Idais I … +7 more , Hirsh-Raccah B, Grozinsky-Glasberg S, Ange AB, Shapira OM, Korach A, Izhar U, Wald O
J Neuroendocrinol · 2026 Apr · PMID 41922295 · Full text
INTRODUCTION: Lung neuroendocrine tumors (LNETs) are rare, with surgical resection as the mainstay of treatment, although the optimal extent remains uncertain. Herein, we present the first meta-analysis to assess the eff...
INTRODUCTION: Lung neuroendocrine tumors (LNETs) are rare, with surgical resection as the mainstay of treatment, although the optimal extent remains uncertain. Herein, we present the first meta-analysis to assess the effect of resection extent (lobar vs. sub-lobar) on overall survival. METHODS: We conducted a systematic review of the literature to identify studies comparing overall survival following lobectomy versus sub-lobar resection in LNETs. An inverse-variance meta-analysis was performed, and a Cox regression model was applied to reconstructed time-to-event data estimated from published Kaplan-Meier curves to generate pooled survival estimates. RESULTS: Six studies encompassing 3,700 patients (lobectomy, n = 2,409; sub-lobar resection, n = 1,291) were included in the final analysis. The pooled 5-year overall survival for the entire cohort was 78.8% (95% CI, 76.6-81.1). No statistically significant difference in overall survival was observed between lobectomy and sub-lobar resection (HR = 1.21; 95% CI, 0.80-1.83; I = 0%). Segmentectomy and lobectomy demonstrated comparable survival (p = 0.38), whereas wedge resection was associated with higher mortality (HR = 2.02; 95% CI, 1.64-2.49; I = 0%). Sampling of >10 lymph nodes was more frequent in lobectomy than sub-lobar resection (29.1% [95% CI, 0.8-95.3] vs 7.4% [95% CI, 0.01-98], respectively), likely contributing to the higher rate of nodal pathologic upstaging observed in the lobectomy group (6.2% [95% CI, 0.2-64.9] vs 2.2% [95% CI, 0-99]). CONCLUSION: In this first meta-analysis of surgical resection for LNETs, sub-lobar resection and lobectomy showed no clear difference in overall survival. Adequate lymph node assessment remains essential, irrespective of the surgical approach.
Electrophysiological recording of hypothalamic brain regions in vivo using the transpharyngeal surgical approach in the rat.
Ludwig M, Leng G, Brown CH
J Neuroendocrinol · 2026 Apr · PMID 41922294 · Full text
Transpharyngeal (ventral) surgery in urethane-anaesthetised rats allows in vivo electrophysiological recording and/or imaging from superficial hypothalamic brain regions and from the pituitary gland. This surgical approa...
Transpharyngeal (ventral) surgery in urethane-anaesthetised rats allows in vivo electrophysiological recording and/or imaging from superficial hypothalamic brain regions and from the pituitary gland. This surgical approach leaves the whole brain intact, providing a stable platform to study single or multiple identified cells over several hours with all central and peripheral inputs intact and the endocrine system functioning, which allows repeated drug application and stimulation of afferent inputs, as has been done for the arcuate nucleus, organum vasculosum of the lamina terminalis (OVLT) and suprachiasmatic nucleus (SCN) inputs to the supraoptic nucleus (SON). Exposing the ventral surface of the brain also allows simultaneous microdialysis for drug administration directly into the SON and for the collection of dialysate samples for measurement of somatodendritic neuropeptide release without disruption of the brain parenchyma. The most recent development using transpharyngeal surgery is two-photon imaging from the vasculature of the ventral surface of the brain, which has given insight into how SON neuronal activity affects cerebral blood flow and has identified a previously unknown SCN to OVLT portal blood system. Here we provide a brief history of the development of transpharyngeal surgery in the rat, instructions to complete the surgery and suggestions for future studies, extrapolating from the most recent developments in its use.
GABA receptor modulation of arcuate kisspeptin neuron bursting and synchronization activity in female mice.
Eddleston T, Morris PG, Herbison AE
J Neuroendocrinol · 2026 Apr · PMID 41912143 · Full text
The arcuate nucleus kisspeptin (ARN) neurons intermittently synchronize their activity to operate as the GnRH pulse generator and drive pulsatile reproductive hormone secretion in mammals. Although ARN neurons are known...
The arcuate nucleus kisspeptin (ARN) neurons intermittently synchronize their activity to operate as the GnRH pulse generator and drive pulsatile reproductive hormone secretion in mammals. Although ARN neurons are known to receive various GABAergic inputs, the effects of GABA and GABA receptor modulation on their ability to synchronize remain unknown. We have used GCaMP6s to monitor the activity of multiple ARN neurons simultaneously in acute brain slices from diestrous female Kiss1-Cre1,Ai162D mice. The effects of modulating GABA and GABA receptors on calcium transients exhibited by individual ARN neurons, reflecting burst firing, and their ability to generate synchronous bursting events were examined. The application of GABA was found to robustly suppress the occurrence of individual calcium transients and population bursting. The GABA receptor agonist muscimol had a biphasic effect in which ARN neurons could initially respond with an increase in baseline calcium but then became inhibited with significantly reduced episodes of individual burst firing and population synchronization events. Baclofen, the GABA receptor agonist, also reduced the frequency of ARN neuron burst firing. The receptor antagonists bicuculline and CGP-35348 had no effects on individual bursting frequency or dynamics, or the synchronous activation of ARN neurons indicating a lack of ongoing GABA transmission in the acute brain slice. These observations show that while GABAergic activation may initially facilitate excitability through GABA receptor-mediated depolarization, sustained GABAergic input to ARN neurons suppresses their burst firing and ability to synchronize through both GABA and GABA receptors. As such, GABAergic inputs to ARN neurons appear to have considerable potential to modulate the frequency of pulse generator activity in female mice.
Efficacy of FOLFIRINOX in digestive neuroendocrine carcinoma.
Butt BP, Sorbye H, Ladekarl M … +9 more , Stokmo HL, Lothe IMB, Fawad H, Tabaksblat EM, Revheim ME, Dybdahl B, Couvelard A, Perren A, Hjortland GO
J Neuroendocrinol · 2026 Apr · PMID 41911950 · Publisher ↗
Digestive neuroendocrine carcinomas (NEC) are rare, aggressive, and treatment-resistant malignancies. Platinum and etoposide are recommended as first line treatment; however, with limited benefit in colorectal NEC and in...
Digestive neuroendocrine carcinomas (NEC) are rare, aggressive, and treatment-resistant malignancies. Platinum and etoposide are recommended as first line treatment; however, with limited benefit in colorectal NEC and in NEC with low Ki67 of 20%-55%. There is no firm evidence for second-line treatment. Being efficient in digestive adenocarcinomas, FOLFIRINOX is sometimes used also in patients with NEC. In this retrospective cohort study, patients with digestive NEC who received FOLFIRINOX and were diagnosed 2014-2021 were retrospectively identified at three Scandinavian centers. Histology was re-evaluated according to the 2019 WHO classification to exclude NET G3 tumors. Patient characteristics, treatment response, and survival outcomes were assessed. Fifty cases were identified; four of these were classified as mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN). The most common primary sites were colon (n = 17) and pancreas (n = 13). FOLFIRINOX was administrated predominantly in later lines (82%). Overall response rate (RR) was 44% (95% confidence interval (CI): 29%-58%) and disease control rate 72% (CI: 57%-83%), while median progression free survival was 5.6 months (CI: 4.3-6.9 months). Twenty-three patients with colorectal primary, 12 patients with Ki67 < 55%, and 33 patients previously exposed to platinum and etoposide as first line; the RR was 52%, 50%, and 39%, respectively. This study suggests a role for FOLFIRINOX in digestive NEC. High efficacy was observed, even in patients with hard-to-treat colorectal primaries, in those with Ki67 < 55%, and in patients previously exposed to platinum and etoposide.
Effect of metformin on pancreatic neuroendocrine tumors of multiple endocrine neoplasia type 1.
Kozlov SV, Agarwal SK, Guerin TM … +7 more , Lawrence WC, Bassel LL, Graf A, Jha S, Weinstein LS, Blau JE, Del Rivero J
J Neuroendocrinol · 2026 Apr · PMID 41883001 · Full text
Metformin is a widely prescribed medication in the management of type 2 diabetes mellitus, and numerous epidemiological studies have indicated an association between metformin use and a reduced risk of certain cancers in...
Metformin is a widely prescribed medication in the management of type 2 diabetes mellitus, and numerous epidemiological studies have indicated an association between metformin use and a reduced risk of certain cancers in diabetic populations. However, evidence supporting a role for metformin in cancer prevention remains inconclusive. Exploring tumor-preventive strategies may be particularly relevant for inherited cancer syndromes with high tumor penetrance such as pancreatic neuroendocrine tumors (PNETs) associated with multiple endocrine neoplasia type 1 (MEN1). MEN1 is caused by germline pathogenic variants in the tumor suppressor gene MEN1, and mouse models with Men1 gene loss also develop PNETs. To evaluate whether metformin is associated with altered PNET outcomes in MEN1, we performed a retrospective analysis of MEN1 patients with PNETs, incorporating detailed clinical exposure data and complemented this analysis with a preclinical study using pancreatic islet β-cell-specific Men1-knockout mice treated with metformin. In the clinical cohort, metformin exposure varied substantially with respect to timing and duration relative to PNET diagnosis. No statistically significant association between metformin use and overall survival or metastatic disease was detected in this limited cohort. In the mouse model, treatment with 2 mg/mL metformin in drinking water initiated post-weaning did not prevent PNET development, nor did it alter circulating insulin or glucose levels. These findings indicate that, under the dosing and exposure conditions examined, metformin was not associated with measurable tumor-protective or tumor-preventive effects in MEN1-related PNETs. The study highlights important methodological considerations, including exposure timing and statistical power, and supports the need for prospective studies initiating metformin prior to tumor development in genetically predisposed populations.
Endogenous oestrogens as neuroprotective modulators in the human retina: Evidence from transcriptomic profiling and aromatase inhibition.
Canto A, Valero-Ochando J, López-Pedrajas R … +4 more , Olivar T, Hernández-Rabaza V, Almansa I, Miranda M
J Neuroendocrinol · 2026 Apr · PMID 41877439 · Full text
Steroid hormones, particularly estrogens, modulate neuronal survival in the central nervous system and the retina; however, their specific cell-type-specific roles in the human retina remain incompletely characterized. W...
Steroid hormones, particularly estrogens, modulate neuronal survival in the central nervous system and the retina; however, their specific cell-type-specific roles in the human retina remain incompletely characterized. We analyzed the single-cell RNA sequencing dataset E-MTAB-7316 to profile genes from the KEGG steroid hormone biosynthesis and oestrogen signalling pathways. Functional relevance of local oestrogen synthesis was tested in mouse retinal explants treated with the aromatase inhibitor letrozole (20 μM). Over 50% of steroid hormone metabolism genes were expressed in retinal cells, with cell-type specificity. COMT, HSD17B12, and HSD11B1L were broadly distributed, while LRTOMT, HSD17B7, and SRD5A1 were enriched in rod photoreceptors. Among oestrogen signalling genes, 114/139 were detected, with HSP90AA1 as the most abundant. When oestrogen synthesis was blocked with letrozole, retinal explants showed increased cell death, particularly in the outer nuclear layer, without inducing macrogliosis but with significant microglial activation (IBA1+). Our data indicate that the human retina expresses multiple components of steroid hormone metabolism and oestrogen signalling. The results are consistent with a potential role of locally synthesized oestrogens in photoreceptor maintenance and immune regulation, which may warrant further investigation as a possible avenue for retinal protection.
Noradrenergic inhibition of definitive POMC neurons through direct and indirect mechanisms.
Lavoie O, Turmel A, Khouma A … +4 more , Minbashi Moeini M, Liu C, Michael NJ, Caron A
J Neuroendocrinol · 2026 Apr · PMID 41877438 · Full text
Norepinephrine is a key neuromodulator of hypothalamic circuits that regulate energy balance. Previous studies suggested that norepinephrine inhibits proopiomelanocortin (POMC) neurons of the arcuate nucleus via α2a-adre...
Norepinephrine is a key neuromodulator of hypothalamic circuits that regulate energy balance. Previous studies suggested that norepinephrine inhibits proopiomelanocortin (POMC) neurons of the arcuate nucleus via α2a-adrenoceptors (ADRA2A), but the underlying mechanisms and physiological relevance of this pathway were not assessed. We therefore investigated how ADRA2 activation regulates POMC neuron activity and whether Adra2a expressed in POMC neurons contributes to energy and glucose homeostasis in vivo. We used whole-cell patch clamp electrophysiology in male and female mice to evaluate the impact of norepinephrine and the ADRA2 agonist UK 14,304 on definitive POMC neurons in the arcuate nucleus. We also generated and validated a novel Adra2a-flox mouse line, which was crossed with Pomc-CreERT2 mice to produce inducible POMC-specific Adra2a knockout mice (POMC). These mice were used for both electrophysiological analyses and in vivo assessment of energy and glucose homeostasis. Multiplex RNAscope confirmed that Adra2a was highly expressed in ~50% of POMC neurons, with significantly higher expression in females. Norepinephrine and the selective ADRA2 agonist UK 14,304 robustly inhibited POMC neurons in hypothalamic slices, producing hyperpolarization, reduced firing, and decreased input resistance independent of sex. These effects were mediated in part by activation of multiple potassium conductances, as blockade of K and K channels attenuated the response. They were also partly indirect, as blockade of synaptic transmission reduced the proportion of neurons that were inhibited. Deletion of Adra2a in definitive POMC neurons had little effect on body weight, food intake, or adiposity, but modestly impaired glucose tolerance in males. Electrophysiological studies revealed that loss of Adra2a in POMC neurons prevented UK 14,304-induced inhibition in approximately half of POMC neurons, supporting the involvement of both direct and indirect effects of UK 14,304 on POMC neuron activity. In conclusion, ADRA2A robustly inhibits hypothalamic POMC neurons through both direct and indirect mechanisms. However, Adra2a expression in POMC neurons is largely dispensable for the regulation of energy balance. These findings suggest that noradrenergic inhibition of POMC neuron activity involves additional cellular targets or network-level pathways beyond POMC neurons themselves.
DNA methylation as a predictor of pituitary neuroendocrine tumour behaviour: A systematic review.
van der Groef R, Mulugeta E, Neggers S … +1 more , Refardt J
J Neuroendocrinol · 2026 Apr · PMID 41866138 · Full text
Pituitary neuroendocrine tumours (PitNETs) range from slow-growing to highly aggressive tumours; however, traditional prognostic markers often fail to predict clinical outcomes reliably. DNA methylation has recently emer...
Pituitary neuroendocrine tumours (PitNETs) range from slow-growing to highly aggressive tumours; however, traditional prognostic markers often fail to predict clinical outcomes reliably. DNA methylation has recently emerged as a promising biomarker for assessing tumour behaviour. This systematic review evaluates its predictive value in PitNETs. To systematically assess the clinical applicability of DNA methylation profiles in predicting behaviour of PitNETs. Systematic review. A comprehensive search was conducted in Medline, Embase, Web of Science, and Cochrane CENTRAL on December 13, 2024, with an update on October 17, 2025. The search included studies on adult PitNET patients, specifically examining tumour behaviour in relation to DNA methylation. Excluded were studies that focused on cell-free DNA, investigated a single gene with no established relevance to tumour behaviour, or assessed tumour size only. Data were extracted from 20 eligible studies by four independent reviewers. The risk of bias was assessed using the QUIPS tool. Due to methodological differences across studies, the findings were summarised narratively. Twelve studies investigated tumour invasiveness, two examined tumour aggressiveness and five examined PitNET regrowth, recurrence and re-intervention. The majority of studies concentrated on non-functioning PitNETs and used Illumina arrays or PCR-based methods. These analyses identified several differentially methylated genes linked to invasiveness (e.g., PHYHD1, WNT4, STAT6, CDH1, CDH13), aggressive behaviour (e.g., AIP, PDCD1, LINE-1), and tumour regrowth (e.g., TERT, FAM90A1, ING2). DNA methylation profiling shows potential for predicting PitNET behaviour, but methodological inconsistencies limit its clinical application. Standardized methods and prospective validation are needed for clinical integration.
Follow-up is not justified in patients with typical lung carcinoids without lymph node involvement treated with curative intent: A Danish Multi-ENETS Center of Excellence Study.
Lau TS, Soldath P, Rewitz KS … +6 more , Jepsen P, Knigge U, Langer SW, Petersen RH, Andreassen M, Dam G
J Neuroendocrinol · 2026 Mar · PMID 41856797 · Full text
Typical carcinoids (TC) are neuroendocrine malignancies of the lung with low risk of recurrence and a favorable prognosis. It is unclear whether lymph node status and tumor size affect the recurrence risk. Following radi...
Typical carcinoids (TC) are neuroendocrine malignancies of the lung with low risk of recurrence and a favorable prognosis. It is unclear whether lymph node status and tumor size affect the recurrence risk. Following radical surgery, current guidelines recommend comprehensive follow-up including regular computed tomography (CT) imaging. We aimed to estimate the risk of recurrence in curatively treated patients with TC and to discuss the justification of the current comprehensive follow-up program. We identified all patients diagnosed with TC from 2009 to 2020 at Aarhus University Hospital, Denmark and Copenhagen University Hospital, Rigshospitalet, Denmark. Patients without distant metastases (M0) who underwent radical surgery (R0) were included in the analysis. The risk of recurrence was estimated using the Aalen-Johansen method treating death as a competing risk. Fine-Gray models were used to evaluate the effect of lymph node status and tumor size. Three-hundred and thirty patients were included in the analysis, of whom 40 had lymph node involvement and 290 did not. During a total follow-up time of 2806 years across all patients, with an individual median of 8.1 years (IQR: 5.9-11.2), 10 patients had recurrence: four in the node-negative group and six in the node-positive group. The 10-year cumulative risk of recurrence for all patients was 3.4% (95% confidence interval (CI): 1.7-6.0), for patients without lymph node involvement 1.6% (95% CI: 0.5-3.8), and for patients with lymph node involvement 15.6% (95% CI: 6.3-28.8). Of the four recurrences in the node-negative group, one led to re-resection with curative intent. Patients with TC without lymph node involvement have a very low risk of recurrence. Thus, we recommend tailoring the follow-up program based on lymph node status, with node-negative patients being excluded from regular follow-up programs.
Alk-Fam150b (augmentor α) expression in the paraventricular nucleus of the mouse hypothalamus at molecular resolution, and its sensitivity to acute stress.
Gueissaz L, Sideromenos S, Tretiakov EO … +2 more , Schnell R, Harkany T
J Neuroendocrinol · 2026 Mar · PMID 41856795 · Full text
Augmentor α (Fam150b)-induced activation of the ALK receptor (Alk) has gained significance as a hypothalamic signaling pathway with relevance to the control of food intake and energy homeostasis. In contrast, much less i...
Augmentor α (Fam150b)-induced activation of the ALK receptor (Alk) has gained significance as a hypothalamic signaling pathway with relevance to the control of food intake and energy homeostasis. In contrast, much less is known about the sensitivity of Fam150b-Alk expression and signaling upon noxious challenges. In this regard, acute stress is of particular interest because augmentor α, released from afferents of the food intake circuit of the arcuate nucleus within the paraventricular hypothalamus (PVN), could link stress-induced changes in food consumption. Nevertheless, conflicting data exist on whether Fam150b mRNA is expressed in the PVN. Here, we combined single-cell RNA-seq and multiplexed in situ hybridization to demonstrate that both Fam150b and Alk are expressed in the PVN of adult mice, including corticotropin-releasing hormone (CRH)-containing neurons. As such, a dichotomy of CRH neurons is present through their mutually exclusive expression of either Fam150b or Scgn (secretagogin). Fam150b and Alk were not co-expressed. When inducing inflammation-associated stress, Fam150b but not Alk mRNA expression increased in a mifepristone-sensitive manner, implying regulation by peripheral glucocorticoid feedback. We suggest that augmentor α-ALK signaling could underpin, at least partly, stress-induced changes in feeding and the control of body weight.
Controversies in neuroendocrine neoplasms: An European Neuroendocrine Tumor Society position statement on the role of surgery of the primary tumour in metastatic small intestinal and pancreatic neuroendocrine tumours.
Partelli S, Bartsch DK, Falconi M … +10 more , Grossman A, Knigge U, Langer SW, Martin W, O'Toole D, Perren A, Schrader J, Stalberg P, Walter T, Janson ET
J Neuroendocrinol · 2026 Mar · PMID 41856794 · Publisher ↗
The role of primary tumour resection (PTR) in metastatic small intestinal (SiNETs) and pancreatic neuroendocrine tumours (PanNETs) remains debated. While retrospective studies suggest improved survival and possible reduc...
The role of primary tumour resection (PTR) in metastatic small intestinal (SiNETs) and pancreatic neuroendocrine tumours (PanNETs) remains debated. While retrospective studies suggest improved survival and possible reduction of local complications, the evidence is limited by heterogeneity, selection bias, and an absence of prospective validation. Under the auspices of the European Neuroendocrine Tumor Society (ENETS) Advisory Board, this position paper summarises current knowledge and expert consensus on the rationale, potential benefits, patient selection, timing, integration with systemic therapies, and future perspectives for PTR. PTR may be considered in selected patients with liver-limited or liver-dominant disease, indolent tumour biology, and good performance status, especially to prevent obstruction, bleeding, or ischaemia, to reduce symptomatic tumour burden, or to facilitate systemic and liver-directed therapies. However, the risks of major surgery, including intestinal and pancreatic resections, with long-term impact on digestion and nutrition, must be carefully considered. Decisions should be made in dedicated multidisciplinary tumour boards. Future directions include incorporation of molecular biomarkers, functional imaging, tumour growth rate, radiomics, and real-world data to refine patient selection. Quality of life and patient-reported outcomes remain underexplored and should be co-primary endpoints in prospective studies. PTR should not currently be regarded as standard of care for all cases but may have a role in carefully selected patients within integrated and individualised management strategies.
The role of accessory proteins and co-factors in regulation of melanocortin-4 receptor signalling: An update.
Jamaluddin A, McClellan A, Raffan E … +1 more , Gorvin CM
J Neuroendocrinol · 2026 Mar · PMID 41834719 · Full text
The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor with an essential role in appetite suppression and energy homeostasis. Genetic mutations in the receptor and components of its signalling pathway that ca...
The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor with an essential role in appetite suppression and energy homeostasis. Genetic mutations in the receptor and components of its signalling pathway that cause obesity in humans, dogs and rodent models have revealed important insights into how the receptor signals and what regulates its cell surface expression. Structural studies have identified calcium as a critical cofactor for agonist binding and receptor function, while several transmembrane proteins have been shown to modulate MC4R activity. Here, we describe recent developments in our understanding of how accessory proteins and cofactors, identified using genomic approaches and screens for protein interaction, modify MC4R trafficking and signalling. We discuss how signalling by G and G pathways may have differential effects on food intake, weight gain and cardiovascular function. We also summarise recent studies of MC4R expression at primary cilia, receptor oligomerisation, newly identified proteins that regulate MC4R cell surface expression, and briefly discuss novel endogenous agonists.
Acute and persistent neuroendocrine and behavioral alterations after social fear conditioning in adolescent male mice.
Bludau A, Kabas M, Menon R … +1 more , Neumann ID
J Neuroendocrinol · 2026 Mar · PMID 41834699 · Full text
Adolescence is a critical developmental period with heightened stress susceptibility. Traumatic experiences during this phase are highly predictive of future affective disorders, such as social anxiety disorder (SAD), wh...
Adolescence is a critical developmental period with heightened stress susceptibility. Traumatic experiences during this phase are highly predictive of future affective disorders, such as social anxiety disorder (SAD), which may manifest during early adolescence. Social avoidance, a major symptom of SAD, can be robustly generated in adult male and female mice using the social fear conditioning (SFC) paradigm. Using the SFC paradigm in adolescent mice, we analyze behavioral and neuroendocrine responses after adolescent social trauma. Here, we demonstrate that social fear elicited by SFC in early adolescent (EA) male mice (SFCEA/29d) persists until adulthood (SFCEA/57d). We further compared neuroendocrine responses to a heterotypic (elevated platform) or homotypic (exposure to a conspecific) stressor after SFC performed either in EA (SFCEA/29d, SFCEA/57d) or adulthood (SFCAD). While in non-conditioned SFCEA/29d mice plasma corticosterone concentrations remained unchanged after social exposure in adolescence, SFCEA/29d resulted in a hyper-response of the HPA axis to the social, but not heterotypic stressor, with a negative correlation of plasma corticosterone concentrations and social investigation times. This effect of SFCEA/29d on plasma corticosterone response was absent in SFCEA/57d and SFCAD mice indicating a higher sensitivity to social trauma in EA. We further revealed a rise in plasma oxytocin (OXT) levels in adult SFC mice in response to the social challenge, whereas the OXT system of SFCEA/29d mice still seems to be unresponsive to the social stimulus. Importantly, after SFC either in EA or AD, the OXT response to social exposure found in SFCAD controls was completely abolished, whereas in SFCEA/57d mice OXT levels positively correlated with social investigation times, indicating social trauma-induced acute and long-lasting dysfunctions of the OXT system. In summary, we show that exposure to social trauma (SFC) in early adolescence exerts both short-term as well as long-term effects on social behavior. We further reveal that SFCEA/29d prevents the corticosterone hypo-response to social stimuli characteristic for early adolescence. Moreover, SFC/AD and SFCEA/57d impair the plasma OXT response to a social, but not heterotypic, stressor.
Ovarian influence on circadian and infradian modulation of nicotine-seeking in female mice.
Rosas-Ovando Z, Aguirre G, Molina-Jiménez T … +7 more , Flores-Muñoz M, López-Franco Ó, Zepeda RC, Corona-Morales AA, Martínez AJ, Salgado-Delgado RC, Juárez-Portilla C
J Neuroendocrinol · 2026 Mar · PMID 41816847 · Full text
Sex differences in tobacco intake are closely associated with hormonal fluctuations during the menstrual cycle in women. Elevated estrogen levels have been associated with increased stress, which may lead to a higher lik...
Sex differences in tobacco intake are closely associated with hormonal fluctuations during the menstrual cycle in women. Elevated estrogen levels have been associated with increased stress, which may lead to a higher likelihood of seeking psychoactive substances. Additionally, tobacco use has been associated with negative effects on reproductive health. Preclinical studies suggested that the estrous cycle significantly influences addictive behaviors, emphasizing the role of ovarian hormones. Furthermore, psychoactive substances entrain circadian rhythms, with animals showing increased locomotor activity 1-2 h before drug administration time, known as anticipatory activity, reflecting seeking behavior. This study aims to evaluate the impact of ovarian hormones on nicotine-anticipatory behavior. A circadian model of forced administration of nicotine via nebulization was implemented in intact and ovariectomized female mice, exposing them to nicotine at a fixed time (ZT4) for 20 min daily over 14 days. The effects of nicotine intake on ovarian follicle morphology and maturation were also assessed. Daily nicotine exposure successfully entrained a clear anticipatory behavior in intact mice. Notably, this anticipatory activity was completely abolished in ovariectomized females, indicating a critical dependence on ovarian factors. Furthermore, nicotine exposure disrupted the estrous cycle and induced significant ovarian follicular damage in intact females. Our findings suggest that the hormonal state is a primary modulator of nicotine-anticipatory behavior. Moreover, the observed nicotine-induced ovarian damage highlights a significant risk to female reproductive health, suggesting a bidirectional relationship between nicotine use and the hypothalamic-pituitary-gonadal axis.
Effects of gonadectomy on brain sex hormone levels and amyloid pathology in male and female App and App mice.
Muñoz P, Ali HG, Demetriou A … +8 more , Latorre-Leal M, Shimozawa M, Delac L, Troncea-Sandu TF, Inzunza J, Nilsson P, Maioli S, Nalvarte I
J Neuroendocrinol · 2026 Mar · PMID 41808585 · Full text
More women than men are diagnosed with Alzheimer's disease (AD). Sex hormones have been ascribed neuroprotective properties, and their decline, particularly the reduction of estrogen during menopause, has been implicated...
More women than men are diagnosed with Alzheimer's disease (AD). Sex hormones have been ascribed neuroprotective properties, and their decline, particularly the reduction of estrogen during menopause, has been implicated in AD risk. In this study, we examined how loss of circulating sex hormones affects cognitive performance and amyloid pathology in two mouse models of AD, the aggressive App and the slower App models of brain amyloidosis. Bilateral gonadectomy was induced in both male and female App and App mice. Pathology was assessed using cognitive tests and histological evaluations of amyloid depositions and neuroinflammation. Serum and brain estrogen and testosterone levels were measured by ELISA, and the expression of key estrogenic signaling genes was evaluated using qPCR. We report that female gonadectomy had little impact on behavior or pathology in the App model, whereas male gonadectomy improved learning and reduced hippocampal amyloid depositions. In the App model, gonadectomy worsened amyloid pathology in both sexes. Hormone analysis revealed that significant levels of estrogen in females, but not testosterone in males, remain partly preserved in the brain after gonadectomy, and that low testosterone levels associate with increased insulin-like growth factor 1 (IGF-1) expression which may play a compensatory role in maintaining estrogenic signaling. Our study provides new insights into how the loss of circulating sex hormones influences brain sex hormone levels and AD pathology and contributes to a better understanding of the sex differences observed in this disease.
Profile of gonadotropin secretion in male and female rats determined in the tail-tip blood by ultrasensitive ELISA.
Araujo-Lopes R, Gomes AF, Viana M … +5 more , Santos MS, Campideli-Santana AC, Macari S, Reis AM, Szawka RE
J Neuroendocrinol · 2026 Mar · PMID 41806846 · Full text
There is a need for accurate and less invasive methods of hormonal measurements. Here, we longitudinally determined luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion measured in the tail-tip blood...
There is a need for accurate and less invasive methods of hormonal measurements. Here, we longitudinally determined luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion measured in the tail-tip blood of male and female rats by ultrasensitive enzyme-linked immunosorbent assay (ELISA). In males, the ELISAs detected a significant increase in LH and FSH secretion after orchiectomy compared with the gonad-intact condition. The subsequent treatment with testosterone in the orchiectomized condition returned LH concentrations to the basal levels, whereas FSH secretion was partially restored to the gonad-intact levels. During the rat estrous cycle, LH and FSH secretion fluctuated around basal levels on diestrus, and the preovulatory surges of both hormones occurred on the late afternoon of proestrus. On estrus, LH secretion was continually low, while FSH concentrations progressively declined from elevated concentrations in the morning to lower levels in the afternoon. After ovariectomy, secretion of both LH and FSH rose above the basal levels of the estrous cycle. Estradiol treatment in the ovariectomized condition reduced LH and FSH secretion towards gonad-intact levels in the morning, with a greater effect on FSH. In the afternoon, estradiol treatment prompted a sharp proestrus-like surge of LH alongside a slower, gradual increase in FSH levels. In the present study, we characterize LH and FSH secretion in rats of both sexes under different hormonal conditions, using longitudinal hormonal measurement in the tail-tip blood by ultrasensitive ELISA. These findings provide novel methodological and conceptual information about gonadotropin secretion in rats relevant to the knowledge in reproductive endocrinology.
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