Neuroendocrinology最新文献

In the article "Epidemiology of Neuroendocrine Neoplasia Worldwide: A Review of the Literature (2012-2022)" [Neuroendocrinology. 2025; https://doi.org/10.1159/000548790] by Nwoguh et al., the third author's name should correctly read Ayanna Gadsden-Jeffers.The original online article has been updated to reflect this.

Introduction: The increased susceptibility to hypertension at menopause is characterized by alterations in brain circuits that regulate cardiovascular homeostasis; however, the mechanisms underlying this association are not well understood. Recent evidence using an accelerated ovarian failure (AOF) model of menopause demonstrates that hypertension is critically dependent on ionotropic glutamate receptor signaling in the hypothalamic paraventricular nucleus (PVN), a brain area critical for blood pressure regulation. There are various glutamate receptors (i.e., NMDA, AMPA) and functionally diverse PVN subregions (i.e., endocrine, autonomic), yet regional gene expression patterns of specific receptors during hypertension in AOF mice is lacking.

Methods: In situ hybridization was used to map gene expression of glutamate receptors in functionally distinct PVN subregions. Female mice were infused with slow-pressor angiotensin II (AngII) at a late stage of AOF comparable to postmenopause and were compared to age-matched male mice.

Results: Hypertension affected the expression of AMPA or NMDA receptor genes exclusively in males and only in mediocaudal PVN subregions that are known to project to brainstem and spinal regions implicated in autonomic processes (Gria1 and Grin2a, respectively) or the anterior pituitary region (Gria2).

Conclusion: These findings demonstrate that altered expression of key ionotropic glutamate receptor genes is limited to regions critically involved in modulating sympathetic and parasympathetic activity as well as neuroendocrine processes in males only.

Background: Acute mountain sickness (AMS) strikes people who travel too quickly to high altitude, outstripping their ability to acclimatize. Individual susceptibility to AMS remains unpredictable. The aim of study was to investigate the neuroendocrine mechanisms regulation of corticotropin-releasing hormone (CRH) and associated with AMS.

Methods: Volunteers performed exercise by cycling or by running, and the other was assigned to ascend from low to high altitude. CRH and cortisol levels were tested. AMS questionnaires were answered by volunteers. Rats were exposed in a hypobaric chamber for altitude hypoxia. CRH, Crhr1mRNA, and corticosterone levels were measured. LDH and O₂ saturation were evaluated.

Results: In rats, hypobaric hypoxia resulted in increased CRH release and mRNA expression in the paraventricular nucleus (PVN). Hypobaric hypoxia also upregulated Crhr1mRNA in the pituitary and PVN in a hypoxia exposure-dependent manner, along with activation of apoptotic gene mRNA and neuronal apoptosis in cortex. These effects were associated with activation of CRHR1. Hypoxia-enhanced plasma CRH levels were negatively correlated with brain CRH level but positively with plasma corticosterone in rats. In humans, exercise at low altitude increased CRH and cortisol levels in both plasma and saliva. The increased levels in plasma correlated with increased salivary CRH. Significantly, lowlanders with high plasma CRH at low altitude developed AMS after rapid ascent to the Tibet plateau. At high altitude, lowlanders with high AMS scores had high salivary and plasma CRH levels.

Conclusions: Hypobaric hypoxia is associated with high plasma CRH in rats. In humans, strong activation of CRH and CRHR1 is positively linked to AMS. CRH levels in saliva or plasma appear to predict individual responses to hypoxia.

Introduction: Gastrointestinal neuroendocrine neoplasms (GI-NENs) outside the appendix and pancreas are exceptionally rare in children and adolescents. Limited data on presentation, treatment, and outcomes hinder clinical decision-making.

Methods: We retrospectively analyzed 16 patients under 18 years with histologically confirmed NENs of gastrointestinal origin, enrolled in the German Malignant Endocrine Tumor (MET) Registry from 1997 to 2024. Neuroendocrine carcinomas were eligible for inclusion but were not observed. Findings were compared with a cohort (age 0-20 years) from the SEER database.

Results: Median age at diagnosis was 15.4 years; 62.5% were male. Primary tumor sites included the stomach (43.8%), colorectum (18.8%), duodenum and Meckel's diverticulum (12.5% each), and jejunum and omentum majus (6.3% each). Distant metastases were present in 31.3%, with no isolated lymph node involvement. All tumors were well-differentiated NETs: G1 (43.8%), G2 (37.5%), and G3 (6.3%). Hereditary syndromes were confirmed in 18.8% and suspected in 12.5%. Somatostatin receptor 2 (SSTR2) expression was seen in most tested tumors. At 30.1-month median follow-up, 3-year overall survival (OS) and event-free survival were 93.3% and 73.3%, respectively, both associated with tumor grade, stage, and resection. The SEER cohort (n = 83) primarily had rectal primaries, localized disease, and the 3-year OS was 95.2%.

Conclusion: Pediatric GI-NENs may present with advanced disease but have favorable outcomes following resection. Given the rarity and complexity, close evaluation by multidisciplinary tumor boards at each treatment step is strongly recommended to support individualized care.

Introduction: The pre-pubertal quiescence of pulsatile gonadotropin-releasing hormone secretion in mammals is considered due to repressed Kiss1 (encoding kisspeptin) expression in kisspeptin/neurokinin B/dynorphin A (KNDy) neurons. In this study, we aimed to investigate the effects of negative feedback levels of estradiol-17β (low E2) and energy balance on Kiss1, Tac3 (encoding neurokinin B), and Pdyn (encoding dynorphin A) expression in ovariectomized (OVX) pre- and post-pubertal rats, and the effects of central kisspeptin immunoneutralization on puberty onset in ovary-intact rats.

Methods: Kiss1, Tac3, and Pdyn expression in the hypothalamic arcuate nucleus was determined using in situ hybridization or quantitative RT-PCR. Vaginal opening and first estrus were examined as indices of puberty.

Results: Low E2 markedly reduced the number of Kiss1-expressing cells in OVX pre-pubertal rats under normal diet and food-restricted conditions but had no effect in post-pubertal rats. The number of Pdyn-expressing cells was significantly lower in pre-pubertal rats than in post-pubertal rats under both dietary conditions. The numbers of Tac3-expressing cells remained elevated in all models. Furthermore, central infusion of anti-kisspeptin antibody significantly delayed puberty onset in female rats.

Conclusion: These findings suggest that kisspeptin-dependent puberty onset in female rats is likely to be triggered by the coordinated upregulation of Kiss1 and Pdyn expression in KNDy neurons under conditions of reduced estrogen negative feedback and sufficient energy availability. In contrast, Tac3 likely plays a permissive role in puberty onset. Taken together, these results provide novel insights into how estrogen and metabolic signals converge in KNDy neurons to regulate puberty onset.

Background: "One for all, and all for one," the famous rallying cry of the Three Musketeers, in Alexandre Dumas's popular novel, certainly applies to the 20,000 cells composing the suprachiasmatic nuclei (SCN). These cells work together to form the central clock that coordinates body rhythms in tune with the day-night cycle. Like virtually every body cell, individual SCN cells exhibit autonomous circadian oscillations, but this rhythmicity only reaches a high level of precision and robustness when the cells are coupled with their neighbors. Therefore, understanding the functional network organization of SCN cells beyond their core rhythmicity is an important issue in circadian biology.

Summary: The present review summarizes the main results from our recent study demonstrating the feasibility of recording SCN cells in freely moving mice and the significance of variations in intracellular calcium over several timescales.

Key message: We discuss how in vivo imaging at the cell level will be pivotal to interrogate the mammalian master clock, in an integrated context that preserves the SCN network organization, with intact inputs and outputs.

Background: Polycystic ovary syndrome (PCOS) is a complex condition with unclear mechanisms, posing a challenge for prevention and treatment of PCOS. The role of the hypothalamus and pituitary gland in regulating female reproduction is critical. Abnormalities in the hypothalamus and pituitary can impair reproductive function. It is important to study hypothalamic and pituitary changes in patients with PCOS.

Summary: This article reviews articles on the hypothalamus and PCOS with the goal of summarizing what abnormalities of the hypothalamic-pituitary-ovarian axis are present in patients with PCOS and to clarify the pathogenesis of PCOS. We find that the mechanisms by which the hypothalamus and pituitary regulate reproduction in girls are complex and are associated with altered sex hormone levels, obesity, and insulin resistance. Different animal models of PCOS are characterized by different alterations in the hypothalamus and pituitary and respond differently to different treatments, which correspond to the complex pathogenesis of patients with PCOS.

Key messages: Arcuate nucleus (ARC) is associated with luteinizing hormone (LH) surges. Suprachiasmatic nucleus, ARC, and RP3V are associated with LH surges. Animal models of PCOS have different characteristics.

Background: Aging is the main risk factor for developing cognitive impairments and associated neurodegenerative diseases. However, environmental factors, including nutritional health, are likely to promote or reduce cognitive impairments and neurodegenerative pathologies. An intricate relationship exists between maternal nutrition and adult eating behavior, metabolic phenotype, and cognitive abilities.

Summary: The objective of the present review was to collect available data, suggesting a link between maternal overnutrition and the latter impairment of cognitive functions in the progeny, and to relate this relationship with Alzheimer's disease (AD). Indeed, cognitive impairments are major behavioral signs of AD. We first reviewed studies showing an association between unbalanced maternal diet and cognitive impairments in the progeny in humans and rodent models. Then we looked for cellular and molecular hallmarks which could constitute a breeding ground for AD in those models. With this end, we focused on synaptic dysfunction, altered neurogenesis, neuroinflammation, oxidative stress, and pathological protein aggregation. Finally, we proposed an indirect mechanism linking maternal unbalanced diet and progeny's vulnerability to cognitive impairments and neurodegeneration through promoting metabolic diseases. We also discussed the involvement of progeny's gut microbiota in the maternal diet-induced vulnerability to metabolic and neurodegenerative diseases.

Key messages: Further investigations are needed to fully decipher how maternal diet programs the fetus and infant brain. Addressing this knowledge gap would pave the way to precise nutrition and personalized medicine to better handle cognitive impairments in adulthood.

Introduction: This study investigates the circadian rhythm of melatonin in normal sleepers and delayed sleep-wake phase disorder (DSWPD) patients using quantitative pharmacology methods to better understand sleep disorders and their underlying mechanisms.

Methods: We developed an indirect effect model incorporating a surge function using data from 10 normal sleepers and 26 DSWPD patients. Model accuracy and stability were evaluated using diagnostic plots, visual predictive check, and bootstrap. Monte Carlo simulations (n = 1,000) quantitatively compared melatonin circadian rhythm characteristics between normal sleepers and DSWPD patients. Finally, Bayesian estimation utilizing external data from 3 normal sleepers and 3 DSWPD patients predicted melatonin concentration at different time points and the dim light melatonin onset (DLMO).

Results: An indirect effect model incorporating a surge function effectively described the circadian rhythm of endogenous melatonin. The model estimates a population typical value (relative standard error %) of amplitude, 7.95 (15.47%); peak time, 23:59 (4.13%); peak width, 4.12 (5.78%); elimination rate constant, 1.23 h-1 (21.82%); baseline melatonin concentration, 3.21 pg/mL (23.27%). Monte Carlo simulation revealed that DSWPD patients exhibited approximately 7-h delay in DLMO, similar melatonin elimination rate constants, and a significantly lower melatonin production rate constants compared to normal sleepers. Bayesian estimation of the melatonin circadian characteristics and DLMO in DSWPD patients closely matched actual data, with model-estimated DLMO exhibiting an error margin within ±10%.

Conclusion: Compared to normal sleepers, DSWPD patients exhibited a reduced rate of melatonin production, similar rate of melatonin elimination, and delayed DLMO, highlighting notable circadian melatonin profile alterations. The final model employed Bayesian feedback to estimate melatonin circadian rhythm characteristics and DLMO in DSWPD patients using sparsely sampled data.

Introduction: Among neuroendocrine lung cancers, lung carcinoids (LCs, further divided into typical [TC] and atypical [AC]) are rare, representing only the 2% of all bronchopulmonary malignancies, and lack prognostic classification and stratification.

Methods: We audited 2 international cohorts of patients with a confirmed diagnosis of LC for prognostic analysis. We used data from the Christie Hospital (Manchester, UK, N = 282) and validated our findings using the cohort of Vall d'Hebron Hospital patients (Barcelona, Spain, N = 80). We analysed patient data to identify a prognostic model for metastasis-free survival (MFS) and stage IV overall survival (OS).

Results: Serum lactate dehydrogenase concentration, stage, gender, and tumour Ki-67% were significant at multivariable analysis (stratified for stage) for MFS after surgery (C-index = 0.76, p < 0.001), while histological subtype (TC vs. AC) and other clinical variables were not. Independent prognostic factors for OS from onset of metastases included smoking history, along with known factors (patient age, proliferation index, FDG-PET maximum SUV). The model C-index was 0.77 (p < 0.001), with good concordance when applied to the external validation from Vall d'Hebron (C-index = 0.94). Previously undescribed, patients with smoking history lived shorter (median OS = 34 months vs. not reached, p < 0.0001), and the median OS could be shorter in current smokers (26.2 months) compared to ex-smokers (35.3 months).

Conclusion: We provide a novel prognostic tool to estimate patient risk, clinical trial stratification and assist clinical decisions in the rarest lung tumours. We also describe for the first time that smoking history is an independent prognostic factor for OS in stage IV.