Journal Of Neuroendocrinology[JOURNAL]
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200 papers
Prolactin-adjusted inferior petrosal sinus sampling: Pituitary and ectopic adrenocorticotropic hormone-dependent Cushing syndrome.
Sprenkeler VE, van Herwaarden AE, van de Ven AC … +4 more , Kusters B, Jenniskens SFM, Netea-Maier RT, de Laat JM
J Neuroendocrinol · 2025 Sep · PMID 40765079 · Full text
Inferior petrosal sinus sampling (IPSS) is a diagnostic procedure used to differentiate between ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome (EAS) and pituitary ACTH-dependent Cushing syndrome (C...
Inferior petrosal sinus sampling (IPSS) is a diagnostic procedure used to differentiate between ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome (EAS) and pituitary ACTH-dependent Cushing syndrome (CD). This study investigated the diagnostic value of IPSS, focusing on the use of prolactin adjustments and different calculation methods. We retrospectively analyzed data from patients with ACTH-dependent Cushing syndrome and inconclusive pituitary-MRI who underwent IPSS with corticotropin-releasing hormone (CRH) stimulation between 2015 and 2025. The cohort included 19 patients (16 CD, 3 EAS), with diagnoses confirmed by pathology examination and/or biochemical remission 1 year post-surgery. A pituitary source was confirmed in all patients with CD (n = 16) through pathology and/or biochemical remission. An ectopic source was confirmed by pathology in two of three patients with EAS. Using unadjusted ACTH ratios and previously established cut-off values resulted in three incorrect diagnoses out of 20 procedures. In contrast, prolactin-adjusted peak ACTH ratios provided a more distinct separation between CD and EAS, enabling correct diagnosis in all cases. Optimal cut-off values determined by receiver operating characteristic curve analysis were 1.0 for basal and 1.7 for concurrent prolactin-adjusted peak ACTH ratios, yielding 100% sensitivity and specificity. Basal prolactin-adjusted peak ACTH ratios were >1.5 in all patients with CD and <0.6 in all patients with EAS, while concurrent ratios were >1.1 in all patients with CD and <0.3 in all patients with EAS. Prolactin-adjusted peak ACTH ratios improve the diagnostic accuracy of IPSS and can effectively differentiate between ectopic and pituitary sources of ACTH. This study enhances the diagnostic accuracy of inferior petrosal sinus sampling (IPSS) for differentiating pituitary from ectopic ACTH-dependent Cushing syndrome by incorporating prolactin measurements and exploring various calculation methods. The findings contribute to advancing diagnostic techniques and improving clinical management of endocrine disorders. By enabling more accurate identification of the underlying cause of ACTH-dependent Cushing syndrome, this work supports clinicians in selecting optimal treatment strategies.
Profile of opioid peptide receptors in GnRH and kisspeptin neurons of female mice and rats.
Campideli-Santana AC, Coolen LM, Lehman MN … +1 more , Szawka RE
J Neuroendocrinol · 2025 Oct · PMID 40765036 · Publisher ↗
Kisspeptin neurons play a critical role in the estradiol feedback effects on gonadotropin-releasing hormone (GnRH) neurons and luteinizing hormone (LH) secretion. Endogenous opioid peptides regulate LH secretion, but the...
Kisspeptin neurons play a critical role in the estradiol feedback effects on gonadotropin-releasing hormone (GnRH) neurons and luteinizing hormone (LH) secretion. Endogenous opioid peptides regulate LH secretion, but the neuroendocrine mechanisms involved remain elusive. We used RNAscope to characterize the expression of kappa (Oprk1)-, mu (Oprm1)-, and delta (Oprd1)-opioid receptors in GnRH (Gnrh1) neurons and kisspeptin neurons of the rostral periventricular area of the third ventricle (Kiss1) and arcuate nucleus (Kiss1) in cycling mice and rats with physiological low (metestrus) and high (proestrus) levels of ovarian steroids. In mice, all opioid receptors were colocalized with Gnrh1, with increased coexpression of Oprk1 on proestrus compared with metestrus. Most Kiss1 neurons expressed Oprk1, Oprm1, or Oprd1, with no changes seen during the estrous cycle. The three opioid receptors were also expressed in Kiss1 neurons, and the expression of Oprk1 in Kiss1 neurons was reduced on proestrus compared with metestrus. When investigated in cycling rats, Kiss1 neurons displayed the same pattern of Oprk1 variation as in mice. However, whereas the mouse Kiss1 neurons displayed a predominance of Oprk1 expression, all three opioid receptors were similarly expressed in the rat. Our results show that Oprk1 is the main opioid receptor present in Kiss1 neurons of mice but not rats, whereas Oprk1, Oprm1, and Oprd1 are abundantly expressed in mouse Kiss1 and GnRH neurons. Fluctuations in ovarian steroids are likely to modulate Oprk1 levels in GnRH and Kiss1 neurons during the ovarian cycle, implicating this opioid receptor in the feedback control of LH secretion in female rodents.
Challenges in diagnosing paraneoplastic isolated adrenocorticotropic hormone deficiency: Insights from cancer histology and human leukocyte antigen analysis.
Urai S, Fujita Y, Bando H … +6 more , Kanzawa M, Yamamoto M, Fukuoka H, Iguchi G, Ogawa W, Takahashi Y
J Neuroendocrinol · 2025 Oct · PMID 40745446 · Publisher ↗
The specific human leukocyte antigen (HLA) alleles in individuals with tumors that ectopically express adrenocorticotropic hormone (ACTH), resulting in paraneoplastic isolated ACTH deficiency (IAD), remain elusive, prima...
The specific human leukocyte antigen (HLA) alleles in individuals with tumors that ectopically express adrenocorticotropic hormone (ACTH), resulting in paraneoplastic isolated ACTH deficiency (IAD), remain elusive, primarily because of the scarcity of reported cases. In this study, we endeavored to elucidate the pathogenic mechanisms underlying paraneoplastic IAD, a novel subtype of autoimmune hypophysitis. We specifically examined the histological characteristics of ACTH-expressing cells in cancer tissues of one patient and investigated the prevalence of shared HLA alleles across three patients diagnosed with paraneoplastic IAD. We analyzed the histological features of prostate-cancer tissues, including ectopic ACTH expression, in a patient with paraneoplastic IAD. In addition, we investigated common HLA alleles and estimated haplotypes among this patient and two others with paraneoplastic IAD on which we previously reported. Immunohistochemical analyses revealed ACTH-positive cells in only one of four tissue samples. Ectopic ACTH expression was limited to areas of relatively high-grade prostate cancer, with cellular cords and cribriform glands that exhibited nuclear hyperchromatism. HLA typing revealed shared class II alleles and haplotypes, including DRB4*01:03, among the three cases. This study provides novel histological insights and highlights the commonality of HLA class II alleles in the diagnosis and pathogenesis of paraneoplastic IAD, potentially aiding the identification of new cases and our understanding of the underlying mechanisms of the disease.
White paper on best practices for translational research in neuroendocrine neoplasms.
Cros J, Casanovas O, Castaño JP … +8 more , Dayton T, Alvarez AG, Gibert B, Simbolo M, Vandamme T, Cives M, Marinoni I, ENETS Basic and Translational Research Group (BTRG)
J Neuroendocrinol · 2025 Oct · PMID 40717619 · Full text
Basic and translational investigations play a crucial role in advancing our understanding of neuroendocrine neoplasms (NENs). In this white paper by the Basic and Translational Research Group of the European Neuroendocri...
Basic and translational investigations play a crucial role in advancing our understanding of neuroendocrine neoplasms (NENs). In this white paper by the Basic and Translational Research Group of the European Neuroendocrine Tumor Society, we discuss the qualities and drawbacks of current disease models and propose good practices for integrating state-of-the-art technologies including bulk and single-cell genomics, transcriptomics, and proteomics in contemporary NEN research. We also provide insights on how to properly handle tissue samples (particularly when starting material is limited) and discuss technical hints of relevance when planning liquid biopsy or tumor immunology studies. Future translational studies of NENs will benefit from centralized biologic material biobanking, research design planning in the context of multi-expertise committees, as well as experimental protocol optimization and sharing across the NEN scientific community.
Predictive utility of placental hypothalamic-pituitary-adrenal axis biomarkers and infant neurodevelopment.
Bakhireva LN, Ma X, Wiesel A … +5 more , Lowe JR, Rai R, Solomon E, Weinberg J, Roberts MH
J Neuroendocrinol · 2025 Oct · PMID 40703036 · Publisher ↗
Alcohol use remains common in pregnancy with prenatal alcohol exposure (PAE) associated with a plethora of adverse outcomes, including impaired emotional regulation and stress reactivity. Prior preclinical studies and em...
Alcohol use remains common in pregnancy with prenatal alcohol exposure (PAE) associated with a plethora of adverse outcomes, including impaired emotional regulation and stress reactivity. Prior preclinical studies and emerging clinical evidence indicate that PAE affects the fetal hypothalamic-pituitary-adrenal (HPA) axis via the maternal-fetal interface in the placenta; however, little is known about the effect of these alterations on neurodevelopmental outcomes. We earlier reported on the effect of PAE and maternal stress on HPA axis biomarkers in placenta and umbilical cord (UC) blood; in the current study, we examined the effect of HPA axis biomarkers on infant neurodevelopmental outcomes at 6-9 months of term-equivalent age. Participants in the Ethanol, Neurodevelopment, Infant and Child Health (ENRICH-2) prospective cohort were followed from the second trimester of pregnancy until infants were 6-9 months of term-equivalent age. Maternal alcohol use was assessed through prospective interviews and a battery of ethanol biomarkers; maternal stress, by a Perceived Stress Scale (PSS). Placenta and UC blood specimens were collected shortly after birth, flash frozen, and analyzed for mRNA and protein expression of placental corticotropin-releasing hormone (pCRH), hydroxysteroid 11-beta dehydrogenase types 1 and 2 (HSD11B1, HSD11B2) and corresponding proteins (11β-HSD1 and 11β-HSD2), and Nuclear receptor subfamily 3 Group C Member 1-alpha (NR3C1-α) and corresponding glucocorticoid receptor alpha. UC plasma cortisol and cortisone levels were measured with ELISA. Bayley Scales of Infant Development, fourth edition (BSID-4; Motor, Language, Cognitive scores) and Infant Behavior Questionnaire Revised (IBQ-R; Surgency, Orienting/Regulation, Negative Affect) assessed neurodevelopment at 6-9 months of term-equivalent age. Pearson correlation was used to examine associations between placental HPA axis biomarkers and neurodevelopmental outcomes overall and after stratification by group (Alcohol/Control). Multivariable linear regression assessed the independent effect of placental biomarkers and Alcohol * biomarker interactions on infant outcomes after adjusting for Alcohol and maternal stress. Participants (32 Alcohol and 68 Controls) were comparable in sociodemographic characteristics. Activation of the placental HPA axis was correlated with a decrease in BSID-4 scores among Controls and an increase in IBQ-R scores (Surgency and Negative Affect) among Alcohol participants. In multivariable analyses, the HSD11B2/HSD11B1 ratio was associated with a decrease in Cognitive scores, and the Alcohol * pCRH interaction was associated with a decrease in Orienting/Regulation and an increase in Surgency and Negative Affect (all p's < .05), after adjusting for Alcohol and PSS. A significant independent effect of PSS was also observed on infant motor skills, Orienting/Regulation, and Negative Affect. This is the first clinical study to characterize the role of placental HPA axis biomarkers and maternal psychosocial stress in PAE-induced changes on infant neurodevelopment, highlighting the importance of a "placenta-brain axis". We demonstrated that the effects of mild-to-moderate PAE on infant neurobehavior were observed in participants with the highest quartile of pCRH expression, emphasizing the role of placental biomarkers in PAE-induced effects.
Exploring the link between dopamine dysregulation and eating disorders: A narrative review.
Tharwani ZH, Shaeen SK, Zahid K … +8 more , Ahmed S, Naqrashi R, Murtaza A, Mughal S, Hasanain M, Anjum MU, Eljack MMF, Zaidi SW
J Neuroendocrinol · 2025 Oct · PMID 40702788 · Publisher ↗
The prevalence of eating disorders (ED), such as anorexia, bulimia, and binge-eating disorders, is on the rise, and it is imperative to explore the pathophysiological aspects and associations of these disorders to provid...
The prevalence of eating disorders (ED), such as anorexia, bulimia, and binge-eating disorders, is on the rise, and it is imperative to explore the pathophysiological aspects and associations of these disorders to provide better and precise treatment. Dopamine is an essential hormone and a neurotransmitter involved in an array of processes and pathways. Disruption of any of the dopamine pathways can lead to diseases such as Parkinson's, Huntington's, schizophrenia, or anhedonia. The mesolimbic pathway of dopamine has a special association with the feeding behavior of a person, and disruption of this pathway has been shown to be associated with ED. In this article, we comprehensively assess the relation between dopamine and ED and discuss the clinical implications involving the pharmacological associations of drugs influencing dopamine levels and their impact on the treatment of ED.
Reproductive experience influences the effects of Lactocaseibacillus rhamnosus HN001 on gut microbiota and hippocampal plasticity in female rats.
Pawluski JL, Kacimi K, Zhang C … +4 more , Guillot L, Guidice AL, Charlier TD, Lonstein JS
J Neuroendocrinol · 2025 Dec · PMID 40696219 · Full text
There is increasing interest in the role of probiotics in supporting maternal well-being throughout female reproduction. However, it remains largely unknown whether the brain of a female with reproductive experience resp...
There is increasing interest in the role of probiotics in supporting maternal well-being throughout female reproduction. However, it remains largely unknown whether the brain of a female with reproductive experience responds differently to probiotics compared to females without reproductive experience. Reproduction involves remarkable neuroplasticity; therefore, we hypothesized that reproducing females are particularly susceptible to the effects of probiotic treatment. Groups of early pregnant or age-matched virgin female Long-Evans rats were administered the probiotic, Lactocaseibacillus rhamnosus HN001 (HN001), in their drinking water or given untreated water for 30 days. To measure changes in gut microbiota, fecal samples were taken regularly. Brains were analyzed at the end of treatment to quantify hippocampal cells containing the neurogenesis marker doublecortin, the synaptic marker synaptophysin, and the microglial activation marker Iba1. For dams, an offspring retrieval test was performed. Main findings show that HN001 administration lowers Bacteroidota abundance in the gut regardless of reproductive experience. In HN001-treated dams there was an increase in the number of times offspring were carried and this was negatively correlated with Bacteroidota abundance in the dam's gut. HN001-treated dams also had more immature neurons in the hippocampus and more thick-type microglial cells in the dorsal hippocampus compared to control dams. HN001-treated females, regardless of reproductive experience, had lower density of synaptophysin immunoreactivity in the CA1, and more thick-type microglia cells in the ventral hippocampus, compared to control females. These results indicate that the probiotic, HN001, alters female rat maternal behavior, plasticity in the hippocampus, and the gut microbiota abundance, with some effects being influenced by reproductive experience.
Stress alters hypothalamic gene expression in adolescent male Golden hamsters.
Moran KM, Milewski TM, Curley JP … +1 more , Delville Y
J Neuroendocrinol · 2025 Sep · PMID 40659452 · Full text
In Golden hamsters (Mesocricetus auratus), a two-week exposure to chronic social stress in adolescence causes acceleration of agonistic behavior, enhanced adult aggression, impaired waiting impulsivity, and higher food i...
In Golden hamsters (Mesocricetus auratus), a two-week exposure to chronic social stress in adolescence causes acceleration of agonistic behavior, enhanced adult aggression, impaired waiting impulsivity, and higher food intake, body fat, and long-term increased body weight. In adult rodents, stress is accompanied by widespread alterations in gene expression in the brain. As stress is a potent modulator of both gene expression and behavior, the present research investigated possible mechanistic-related transcriptomic changes in the lateral, dorsomedial, and arcuate nucleus of the hypothalamus caused by adolescent stress using RNA Tag-sequencing, as these areas are involved in the regulation of metabolic and motivated behaviors. In each region, there were approximately 250 genes with higher expression compared to controls and 250 genes with lower expression. Many of the most significantly affected genes have been associated with metabolism and sex hormone function. For example, in the lateral hypothalamus, melanocortin 3 receptor, growth hormone releasing factor, both involved in metabolic processes, and neuropeptide VF precursor, involved in growth hormone inhibitory hormone production, were among the most increased in expression in stressed subjects. In the dorsomedial hypothalamus, neuropeptide W, involved in feeding cessation, was significantly decreased in expression in stressed animals. Across both regions, G-protein coupled receptor 50, involved in thermoregulation, sleep, and sex-related mood disorders, was significantly altered, but in opposite directions. In the arcuate nucleus, a number of blood brain barrier- and inflammation-related genes were altered as well. Furthermore, there were consistent patterns of genetic ensembles identified through gene ontology analysis and weighted gene correlation network analysis that were altered across each region. Many of these involved roles in RNA processing, DNA methylation, myelination, and synaptic organization. These findings reinforce prior behavioral, hormonal, and metabolic changes observed in this developmental model, and help guide future directions of research related to the negative consequences of early life stress.
Disrupted circadian rhythms and opioid-mediated adverse effects: Bidirectional relationship and putative mechanisms.
Mehranfard N, Ghasemi M, Saboory E
J Neuroendocrinol · 2025 Sep · PMID 40619210 · Full text
Recent studies have shown a link between disrupted circadian rhythms and the development of chronic opioid-induced negative effects. Both animal and human studies show a significant bidirectional relationship between the...
Recent studies have shown a link between disrupted circadian rhythms and the development of chronic opioid-induced negative effects. Both animal and human studies show a significant bidirectional relationship between the circadian system and opioid effects. Opioids can perturb circadian rhythms, and perturbation of the circadian rhythms can aggravate opioid-mediated adverse effects. These bidirectional interactions may attenuate the outcomes of long-term opioid therapy when not considered. A better understanding of the potential mechanisms underlying these interactions may be essential for more effective management of opioid-induced adverse effects. This review highlights the association between circadian rhythms and opioid-induced hyperalgesia, dependence, and withdrawal, and the possible role of the dopaminergic, serotoninergic, and noradrenergic systems, redox state, and stress in this association. We also highlight the existence of an interaction between other rhythmic biological processes, including the sleep-wake cycle as well as melatonin and glucocorticoid rhythms on the circadian and opioid systems and their possible effects on opioid-related negative effects.
Endoscopic submucosal dissection for gastric neuroendocrine neoplasms: A multicenter retrospective study.
Lazaridis N, Rimondi A, Chacchi-Cahuin R … +23 more , Lemmers A, Costa D, Bucalau AM, Mandair D, Gupta S, Tantau M, Pioche M, Rivory J, Santos-Antunes J, Marques M, Ramos Zabala F, Barbaro F, Pimentel-Nunes P, Uchima H, Albeniz E, Dinis-Ribeiro M, Costamagna G, Spada C, Bourke M, Caplin M, Toumpanakis C, Despott EJ, Murino A
J Neuroendocrinol · 2025 Sep · PMID 40619128 · Publisher ↗
Endoscopic submucosal dissection (ESD) has been reported as a feasible and effective treatment for Gastric Neuroendocrine Tumors (G-NETs). However, most of the experience comes from retrospective tertiary centers in East...
Endoscopic submucosal dissection (ESD) has been reported as a feasible and effective treatment for Gastric Neuroendocrine Tumors (G-NETs). However, most of the experience comes from retrospective tertiary centers in Eastern Asia. Data coming from western centers are lacking. This is a retrospective study, including patients who underwent endoscopic resection of G-NETs by ESD between 2010 and 2020 in Western Centers. Important clinical variables such as demographic, size, type, presence of lymphovascular invasion or distant metastasis, completeness of the endoscopic resection, recurrence, and procedure-related complications were recorded. Seventy-three ESD procedures on G-NETs from 69 patients from 11 centers were included. Median G-NETs size on endoscopy was 12 mm (IQR 10-15). Case mix accounted for 83.6% type 1, 15.1% type 3, and 1.4% type 2. En-bloc resection was possible in 69 procedure 94.5%, R0 resection rate stood at 79.5%. Five patients (7.2%) were referred for additional surgical intervention. One case of perforation was reported (1.4%), treated endoscopically. Three patients (4.4%) had evidence of recurrence during follow-up. ESD is an effective and safe treatment for G-NETs in western centers.
Controversies in NEN: An ENETS position statement on nutritional support in neuroendocrine neoplasms.
Grozinsky-Glasberg S, Hofland J, Alband S … +12 more , de Lima YC, Croitoru A, Geilvoet W, Igaz P, Kos-Kudła B, Krejs GJ, Laviano A, Panzuto F, Sadanandam A, Santos AP, Welin S, Srirajaskanthan R
J Neuroendocrinol · 2025 Dec · PMID 40562412 · Full text
Neuroendocrine neoplasms (NEN) themselves and also their treatment may cause malnutrition, inducing changes in physiological behaviour and eventually leading to increased rates of morbidity and mortality. Malnutrition is...
Neuroendocrine neoplasms (NEN) themselves and also their treatment may cause malnutrition, inducing changes in physiological behaviour and eventually leading to increased rates of morbidity and mortality. Malnutrition is a common, under-recognised and under-treated condition in patients with NEN, and there are limited data available on the role of optimising nutrition in this setting. There are no formal evidence-based European Neuroendocrine Tumor Society (ENETS) guidelines on nutrition evaluation and management in patients with NEN to date. This manuscript was initiated during the 2024 ENETS Advisory Board meeting by using an expert panel consensus methodology and specific structured questions, which were identified and addressed through a structured review of the literature. The manuscript aims to identify the presence of specific nutrient deficits and define unmet needs and controversies regarding nutrition and NEN in a succinct manner, to promote collaborative and multidisciplinary research in the field, and to offer practical guidance in terms of how to assess malnutrition and dietary interventions by means of formulating a structured questionnaire.
Thyroid lesions of neuroendocrine origin? Thinking of a "polka-dotted" zebra! Case series from three Italian referral centers and review of the literature.
Feola T, Cozzolino A, Grillo F … +13 more , Birtolo MF, Aini I, Messina E, Minotta R, Filice A, Zanata I, Razzore P, Rubino M, Isidori AM, Colao A, Faggiano A, Giannetta E, NIKE group
J Neuroendocrinol · 2025 Sep · PMID 40542625 · Full text
BACKGROUND: Neuroendocrine neoplasms (NENs) may metastasize very rarely to the thyroid. The current paper aims at identifying peculiar thyroid nodule's features that could prompt their diagnosis and analyzing therapeutic...
BACKGROUND: Neuroendocrine neoplasms (NENs) may metastasize very rarely to the thyroid. The current paper aims at identifying peculiar thyroid nodule's features that could prompt their diagnosis and analyzing therapeutic approach and patient's outcome. MATERIALS AND METHODS: A case series of three patients have been collected from three Italian referral centers. Moreover, we performed a keyword based PUBMED search, using relevant keywords. RESULTS: We included in the review 27 papers and 33 cases have been identified. Patients' age ranged from 17 to 85 years (mean age: 55.8 ± 14.2 years), 14 males, 42.4%. The majority of cases (48.5%) originated from a thoracic NEN. Median time to diagnosis from the primary tumor was 48 months (range 1-252 months). At ultrasound, they were generally hypoechoic nodules with irregular margins. The diagnosis was made by fine-niddle aspiration in the majority of cases, followed by nuclear medicine imaging. At immunohistochemistry, chromogranin A and synaptophysin were expressed in almost all of them, with negative calcitonin and thyroid transcription factor-1. Surgery or systemic treatment were needed according to primary tumor, disease stage, and patients' general condition. Prognosis was variable, better if primary tumor origin was thoracic. CONCLUSIONS: Thyroid metastases from NENs should be considered in the diagnostic work-up of suspicious thyroid nodules in patients with a positive medical history of previous NEN, mainly of thoracic origin. Immunohistochemistry is the key diagnostic tool for their identification. A prompt and correct diagnosis is mandatory because of its crucial prognostic and therapeutic implications.
Clinical/pathological features and survival outcomes of extra-pulmonary neuroendocrine carcinomas: A retrospective single-center series.
Benini L, Gervaso L, Frassoni S … +10 more , Bagnardi V, Cella CA, Algeri L, Ciardiello D, Zampino MG, Winchler C, Boselli S, Tamayo D, Spada F, Fazio N
J Neuroendocrinol · 2025 Sep · PMID 40534241 · Full text
Poorly differentiated neuroendocrine carcinomas (NECs) are rare malignancies with a dismal prognosis, few therapeutic options, and a lack of predictive factors. We describe a large series of extra-pulmonary (EP) NEC pati...
Poorly differentiated neuroendocrine carcinomas (NECs) are rare malignancies with a dismal prognosis, few therapeutic options, and a lack of predictive factors. We describe a large series of extra-pulmonary (EP) NEC patients from a neuroendocrine neoplasm (NEN) referral center, aiming to improve the clinical management of these diseases. Medical records of patients with histological diagnosis of pure histology EP-NEC, discussed at the NEN-dedicated multidisciplinary team (MDT) between October 2018 and August 2022, were included. Demographic features, tumor characteristics, molecular profile, treatments, and responses to treatments were collected. Among 1594 NEN diagnoses discussed at the MDT during the study period, 377 were NECs; the final population consisted of 173 patients, mostly presenting with advanced disease and often with a gastroenteropancreatic tract primary tumor. Molecular profiling was available for 52 patients (30%). The most frequent alterations occurred in TP53 and KRAS. One of 25 patients tested for microsatellite instability was confirmed MSI-h; one of 52 patients tested had a high tumor mutational burden (TMB = 19). Median overall survival (OS) was 15.4 months (95% confidence interval [CI]: 13.2-18.5). Most patients with advanced disease received a first-line chemotherapy (136/153 [88.9%]), often platinum plus etoposide (111/136 patients [82%]). The overall response rate (ORR) to first-line was 40%. Median progression-free survival (PFS) was 5.7 months (95% CI: 4.4-6.4). Forty-two percent and 18% of patients received second- and third-line therapy, respectively. No significant difference was seen when stratifying OS and PFS by Ki-67 groups and tumor cell morphology, whereas performance status and presence of metastases were significantly related to OS. In this single-center retrospective large series of EP-NECs, almost half of the patients showed a tumor response to first-line chemotherapy. No relevant correlation was found with primary site, tumor cell morphology, or Ki-67. The proportion of patients receiving subsequent lines, along with the mOS, confirms the aggressiveness of this disease. Molecular profiling was performed only fragmentarily, with limited practical applicability. Efforts shall be made in the future to implement these investigations.
The 20 kDa isoform of the human growth hormone variant alters adipose and muscle gene expression differently than human growth hormone.
Young JA, Bogart J, Buchman M … +5 more , Duran-Ortiz S, Bell S, Kopchick JJ, Berryman DE, List EO
J Neuroendocrinol · 2025 Dec · PMID 40524488 · Full text
The 20 kDa isoform of human growth hormone variant (20K hGH-V) (derived from the GH2 gene) has previously been shown to promote growth but lacks the diabetogenic and lactogenic activities of human GH (derived from the GH...
The 20 kDa isoform of human growth hormone variant (20K hGH-V) (derived from the GH2 gene) has previously been shown to promote growth but lacks the diabetogenic and lactogenic activities of human GH (derived from the GH1 gene). That is, 20K hGH-V-treated mice have similar body size and composition to hGH-treated mice, as well as improved insulin sensitivity despite having similar adipose tissue mass. Furthermore, 20K hGH-V-treated prolactin receptor-positive cancer cells exhibited significantly less growth compared to hGH treatment. The aim of this study was to use transcriptomics to compare the effects of 20K hGH-V injection to that of hGH injection on adipose and muscle tissue. GH knockout (GHKO) mice, which do not produce endogenous GH, were injected with hGH or 20K hGH-V daily for 5 days and dissected 4 h after the final injection. RNA was extracted from inguinal subcutaneous adipose tissue and quadriceps muscle and subjected to RNA sequencing. When comparing hGH to 20K hGH-V, there were 73 genes that were significantly altered (q value <.05 and log fold change >1 or < -1) in adipose and 32 in muscle, with two genes (Cish and Sv2b) common to both tissues. Gene set enrichment analysis (GSEA) indicated that the adipose tissue of the 20K hGH-V-treated mice had decreased enrichment of genes associated with T and B lymphocytes compared to hGH-treated adipose tissue. Furthermore, 20K hGH-V treatment resulted in increased enrichment of genes associated with adipogenesis and carbon metabolism compared to hGH treatment. In muscle tissue, the electron transport chain and muscle contraction pathways were upregulated in 20K hGH-V-treatment, while cell cycle, extracellular matrix organization, and xenobiotic metabolism pathways were negatively enriched. While most genes and signalling pathways were similar between the two hormone treatments, the differentially expressed genes identified may help explain some of the phenotypic differences between 20K hGH-V and hGH treatment and also suggest additional novel differences, notably muscle fibre type, immune cell infiltration, and fibrosis.
Controversies in NEN: An ENETS position statement on the endoscopic management of localised gastric, duodenal and rectal neuroendocrine neoplasms.
Panzuto F, O'Toole D, Klöppel G … +5 more , Knigge UP, Krejs GJ, Tsoli M, Volante M, Luong TV
J Neuroendocrinol · 2025 Dec · PMID 40524475 · Full text
Gastric, duodenal and rectal neuroendocrine tumours (NETs) are increasingly detected due to advances in endoscopic imaging. While international guidelines provide criteria for endoscopic management, several aspects remai...
Gastric, duodenal and rectal neuroendocrine tumours (NETs) are increasingly detected due to advances in endoscopic imaging. While international guidelines provide criteria for endoscopic management, several aspects remain controversial due to limited high-quality evidence. This position paper, developed by an expert panel, aims to clarify these unresolved issues and provide consensus-based recommendations. The primary objective of this position paper is to critically analyse and address key controversies in the endoscopic management of gastro-duodenal-rectal NETs. These include the optimal selection of endoscopic resection techniques, the significance of R1 resections, pathological assessment and surveillance strategies. Special attention is given to site-specific challenges, including the role of Ki-67 in type 1 gastric NETs, the management of multiple gastric lesions, the feasibility of endoscopic resection for type 3 gastric NETs and the limitations of advanced endoscopic techniques in the duodenum. This position paper was developed using an Expert Panel Consensus methodology. Topics were identified during the 2024 ENETS Advisory Board meeting and addressed through a structured literature review. Evidence was critically appraised, and expert discussions were conducted to identify key points. By reviewing controversial aspects of endoscopic management, this position paper will provide practical guidance to optimise decision-making and improve outcomes for patients with gastro-duodenal-rectal NETs. Multidisciplinary evaluation remains crucial to tailoring treatment strategies based on tumour characteristics, patient factors and procedural risks.
Response to the letter to "New developments and concepts in the diagnosis and management of diabetes insipidus (AVP-deficiency and resistance)" of Meric Coskun.
Angelousi A
J Neuroendocrinol · 2025 Aug · PMID 40506837 · Publisher ↗
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Rodent chronic variable stress procedures: A disjunction between stress entity and impact on behaviour.
Romanò N, Menzies J
J Neuroendocrinol · 2025 Sep · PMID 40497530 · Full text
Chronic variable stress (CVS) procedures are widely used to model depression in laboratory mice and rats. In order to explore how study design might impact experimental outcomes, we systematically documented characterist...
Chronic variable stress (CVS) procedures are widely used to model depression in laboratory mice and rats. In order to explore how study design might impact experimental outcomes, we systematically documented characteristics of study design in a series of published rodent CVS studies and, in a subset of studies, measured effect sizes in the behavioural tests used to evaluate the effects of CVS. We hypothesised that CVS procedures that were longer or involved more stressors would be associated with larger effect sizes in five commonly used behavioural tests: the sucrose preference test (SPT), the tail suspension test (TST), the forced swim test (FST), the open field test (OFT) and the elevated plus maze (EPM). We also hypothesised that effect sizes would positively correlate between the behavioural tests that are believed to measure the same consequences of CVS. We searched PubMed for articles using CVS procedures with mice or rats and systematically documented the duration (the length of the CVS procedure), burden (the total number of stressors experienced by the animal) and diversity (the total number of different types of stressors used) of the CVS procedures used. We also systematically documented the design of the behavioural tests used to evaluate the effects of CVS in each study and calculated the effect sizes obtained in these tests. To ask whether effect sizes in these tests correlated with characteristics of the CVS procedure used, we used a linear model of the effect of duration, burden, and diversity on the effect size, then calculated the Euclidean distance between studies' characteristics and correlated those with the differences in effect size between studies. To explore whether effect sizes correlated between different behavioural tests, we calculated a pairwise Pearson correlation. We observed that most studies used a unique CVS procedure. In contrast to our hypothesis, the most evident impact of CVS procedure design was on FST effect sizes, where longer-duration CVS procedures with more diverse types of stressors were associated with a smaller effect size in behavioural tests. When exploring correlations between behavioural test effect sizes, we found a positive correlation between effect sizes in the TST and FST, and in the OFT and EPM, but the strongest positive correlations were between the EPM and TST, and between the EPM and FST. These data uncover complex relationships that are not necessarily in concordance with current understanding of what these tests measure. Accordingly, our data raise scientific questions around the design of CVS procedures used and the behavioural tests used to evaluate them.
Anorectic and anxiogenic actions of cocaine- and amphetamine-regulated transcript in the lateral septum.
Shankhatheertha A, Payant MA, Phy-Lim J … +1 more , Chee MJ
J Neuroendocrinol · 2025 Sep · PMID 40462258 · Full text
Cocaine- and amphetamine-regulated transcript (CART) is produced in several brain regions including the hypothalamus where it is made in cells that also produce melanin-concentrating hormone (MCH). CART-expressing MCH ce...
Cocaine- and amphetamine-regulated transcript (CART) is produced in several brain regions including the hypothalamus where it is made in cells that also produce melanin-concentrating hormone (MCH). CART-expressing MCH cells densely innervate the lateral septum (LS), which integrates food- and mood-related behaviours. However, while MCH typically promotes feeding and anxiolysis, CART suppresses feeding and promotes anxiogenesis. The LS is a target site of orexigenic MCH actions, but it is not known if the actions of CART converge or oppose that of MCH in the LS. We implanted a bilateral cannula over the lateral or medial LS of male and female wildtype mice and infused vehicle, CART, MCH, or CART + MCH. We then assessed the intake of a standard chow diet or palatable high sugar diet over 4 h, as well as anxiety-like behaviour via the open-field test. In both male and female mice, intra-LS CART infusion alone did not produce anorexigenic effects. However, CART infusion diminished MCH-mediated feeding, especially via the lateral LS. By contrast, intra-LS CART infusion reduced time spent in the centre of an open field in male but not female mice. Our findings indicated that CART elicited anorectic effects in the presence of MCH, but CART independently produced anxiogenic effects. These outcomes suggested that putative CART and MCH co-release from MCH neurons may provide biphasic regulation of feeding and anxiety.
Loss of choroid plexus-derived insulin-like growth factor 2 (IGF2) leads to hyposmia, while retaining post-partum mood resilience in mice.
Phillipps HR, Hackwell ECR, Sandovici I … +2 more , Constância M, Grattan DR
J Neuroendocrinol · 2025 Sep · PMID 40457890 · Full text
During the post-partum period, new mothers are vulnerable to mood disorders. In adults, impairments in neurogenesis commonly associate with anxiety and depressive behaviors. Insulin-like growth factor 2 (IGF2) is express...
During the post-partum period, new mothers are vulnerable to mood disorders. In adults, impairments in neurogenesis commonly associate with anxiety and depressive behaviors. Insulin-like growth factor 2 (IGF2) is expressed in the choroid plexus (CP) within the subventricular zone (SVZ) neurogenic niche, and global loss of IGF2 leads to increased anxiety. Previously, we have shown that Igf2 expression in CP tissue increases 6-fold during lactation but returns to baseline on suppression of prolactin present in lactation, suggesting it is induced by high levels of prolactin. To gain more insight into the role of prolactin-induced Igf2 expression in the CP, we have measured IGF2 levels in cerebrospinal fluid across reproductive states and developed mice in which Igf2 is conditionally removed from the CP. Using CP-derived IGF2 knockout mouse models, we have measured Prlr expression in CP tissue, SVZ mitogenesis, olfaction, and anxiety-like behavior using an elevated plus maze (EPM) and light/dark transition test (LDTT). Interestingly, we observed a reduction in Prlr expression in CP tissue in one of our Igf2 knockout mouse models, suggesting Igf2 may also act upstream to regulate Prlr expression in CP tissue. No changes were detected in SVZ proliferation rates between Igf2 knockout and controls. Using a buried food test (BFT), however, we show mice with conditional loss of Igf2 in the CP take longer to find a buried fruit loop as compared to controls, indicating olfaction deficits. Overall anxiety levels, however, were comparable between knockout and controls in the EPM and LDTT. Together, our findings reveal loss of CP-derived IGF2 leads to hyposmia in the absence of detectable changes to SVZ mitogenesis. We propose that CP-derived IGF2 may be acting directly in the olfactory bulb to elicit changes to improve olfaction, which may become particularly important during the post-partum period to facilitate mother-pup interactions.
Crosstalk between thyroid hormones and the central corticotropin-releasing factor system in Atlantic salmon.
Culbert BM, Jenkins E, Bernier NJ
J Neuroendocrinol · 2025 Sep · PMID 40457880 · Full text
The corticotropin-releasing factor (CRF) system is primarily known for its conserved role in regulating pituitary corticotrope activity, but it can also influence thyroid hormone (TH) production by stimulating thyroid-st...
The corticotropin-releasing factor (CRF) system is primarily known for its conserved role in regulating pituitary corticotrope activity, but it can also influence thyroid hormone (TH) production by stimulating thyroid-stimulating hormone (TSH) production in non-mammalian vertebrates. However, few studies have explored how THs regulate the CRF system in teleosts. Furthermore, while the CRF system regulates corticotrope activity via a CRF receptor 1 (CRFR1) mediated pathway, the signaling pathway by which CRF stimulates TSH production in teleost thyrotropes is unknown. To better understand interactions between THs and the CRF system, we performed a series of in vivo, in vitro, and in silico analyses using Atlantic salmon (Salmo salar). We found that chronic elevation of triiodothyronine (T3) levels elicited ligand- and paralog-specific effects on transcript levels of CRF peptides in the hypothalamic and preoptic regions of the brain. Additionally, elevated T3 increased transcription of pituitary CRF receptor 2 (crfr2b) but had no effect on CRFR1 transcription. Consistent with interactions between THs and CRFR2, we found that transcription of TSH (tshba) only increased in cultured pituitaries when CRFR2 was activated. In contrast, CRFR1 activation only increased the transcription of corticotrope-related genes. Lastly, we found that putative TH response elements were present in the promoter of most CRF system components, further supporting the relationship between THs and the CRF system in teleosts. Collectively, our data reveal several novel mechanisms underlying crosstalk between THs and the central CRF system in teleost fishes and provide insight into the evolution of interactions between these hormone systems.
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