Journal of Neuroendocrinology最新文献

Early detection of metastases and timely surgical intervention play a crucial role in the management of neuroendocrine tumors. In large-sized pheochromocytomas and sympathetic paragangliomas (PPGL), functional imaging with positron emission tomography (PET) is recommended, as it improves the detection of metastases, which may go undetected on conventional radiologic imaging. ¹¹C-hydroxyephedrine binds to the norepinephrine transporter receptor and is detected by PET/CT (HED-PET/CT). It has previously demonstrated high accuracy in detecting primary and metastatic PPGL; however, its impact on preoperative staging is unclear. In this study, we retrospectively analyzed a selected cohort of 44 patients with large PPGL to evaluate whether HED-PET/CT influences preoperative clinical decision-making. All patients who underwent HED-PET/CT at Uppsala University Hospital between 2004 and 2024 were screened for inclusion. In total, 44 patients with pheochromocytomas >5 cm and paragangliomas >4 cm were included. HED-PET/CT results were compared with CT/MR findings, and a final consensus was reached on whether preoperative HED-PET/CT would have altered clinical decision-making. HED-PET/CT identified previously undetected metastatic disease in three patients (6.8%), which had not been visualized on CT/MR. Additionally, two patients had discordant findings, where HED-PET/CT revealed additional metastases. In one case, a liver metastasis was identified postoperatively with HED-PET/CT, leading to a metastasectomy that could have potentially been avoided. These findings suggest that HED-PET/CT is highly accurate in detecting metastases; however, its routine preoperative use may be limited and appears to provide significant clinical benefit only in selected patients.

Miscarriage, defined as spontaneous pregnancy loss before 20 weeks of gestation, affects 10–15% of pregnancies in women under 30, rising to over 50% in women over 45. Implantation failure and early placental dysfunction are major contributors, yet the precise mechanisms remain incompletely understood. Kisspeptin, encoded by KISS1, is a critical regulator of the reproductive axis and is highly expressed in the placenta, where it modulates trophoblast proliferation, migration, invasion, and vascular remodelling. Human studies indicate that reduced placental kisspeptin is associated with recurrent pregnancy loss, while circulating kisspeptin levels increase dramatically throughout gestation and may serve as a biomarker for pregnancy viability. Mouse models, including CBA/J × DBA/2 matings and Kiss1/Kiss1r knockout lines, have provided mechanistic insights, showing that loss of kisspeptin signalling impairs decidualization, trophoblast invasion, and embryo implantation. These studies also highlight kisspeptin's role in modulating maternal immune responses and in coordinating hormonal cues, including progesterone, oestrogen, and prolactin, necessary for uterine receptivity. Despite shared features of placentation signal and endocrine regulation, significant species-specific differences exist (e.g. mice lack hCG, exhibit embryo-dependent decidualization, have less invasive trophoblasts) limiting direct extrapolation to human pregnancy. This review synthesizes current evidence on kisspeptin's paracrine and endocrine roles during early gestation, emphasizing the insights gained from murine models while highlighting the translational challenges in applying these findings to human miscarriage research.

Cardiac fibrosis is characterized by an excessive accumulation of extracellular matrix proteins and occurs in a variety of cardiac diseases, such as the highly prevalent syndrome heart failure with preserved ejection fraction (HFpEF) and other cardiac disorders. Interstitial fibrosis has been identified as a central pathophysiological factor induced and maintained by metabolic stress and chronic inflammation. Considering the limited treatment options for cardiac fibrosis, new therapeutic targets are urgently needed. Mounting evidence for the cardioprotective effects of the neuropeptide pituitary adenylate cyclase-activating peptide (PACAP) provides a rationale to elucidate its role and that of its receptor PAC1 in metabolic stress-mediated cardiac fibrosis. Metabolic stress was induced by feeding a cholesterol-enriched diet (CED) to PACAP^−/−/ApoE^−/−, PAC1^−/−/ApoE^−/− and ApoE^−/− mice and cardiac tissue subjected to analyses of fibrosis. Under CED feeding, a statistically significant (p < .001) increase in myocardial fibrosis was observed in PACAP^−/−/ApoE^−/− and PAC1^−/−/ApoE^−/− compared to ApoE^−/− mice. These findings suggest a role for PACAP signaling in the mitigation of metabolically induced cardiac fibrosis. The antifibrotic effect of PACAP is dependent on the expression of the PAC1 receptor and only emerges under metabolic stress conditions. PAC1 receptor agonists may have the potential to attenuate metabolically triggered cardiac fibrosis arising after a chronic high-fat diet.

Bone metastases (BMs) were reported in <15% of cases of neuroendocrine neoplasms (NENs). Their clinical behavior is various and clinical management is still undefined. This study aimed to describe the clinical practical management and survival outcome of neuroendocrine neoplasm patients with BMs. This is a retrospective, observational, multicenter, nationwide study, in which clinical-pathological characteristics, diagnostic tools, skeletal-related events (SREs), bone targeted agents (BTAs) and their correlation with clinical outcome were collected. Data from 320 patients from 18 Italian centers diagnosed with bone metastases during 2000–2013 were captured. Most patients had a well/moderately differentiated NEN, with synchronous distant metastases, mostly hepatic, the majority of which originated from a gastroenteropancreatic primary site. Bone was the first metastatic site in 41% of patients. After a median follow-up of 27 months 122 patients died. The median overall survival (OS) was 62 months. In 22% of patients (n = 72), SREs were observed, and 31% of patients received a BTA. At multivariable analysis of factors associated with OS after the development of BMs, primary lung site, Ki-67 ≥55% versus ≤20%, >10 BMs, mixed pattern (osteoblastic/osteolytic) versus osteoblastic, prior lung metastases and SREs were found to be significant poor prognosis factors. At multivariable analysis Ki-67 ≥55% versus ≤20% remains significantly associated with the development of SREs. Our study represents a real-life nationwide scenario of a large series of NEN patients with BMs handled at dedicated centers. Several hypotheses generated by this study are warranted to be tested in future homogeneous studies, including objective criteria for the use of BTAs.

The neuroendocrine control of growth is mediated by the hypothalamic–pituitary–somatic (HPS) axis. This involves the hypothalamic release of growth hormone-releasing hormone (GHRH), which stimulates the pituitary secretion of growth hormone (GH). GH subsequently promotes growth both directly and indirectly by stimulating insulin-like growth factor 1 (IGF1) release from the liver. While extensive research has focused on the actions and mechanisms of GH and IGF1, comparatively little attention has been given to how GHRH neurons themselves are regulated. This review aims to provide insight into how GHRH neurons are controlled, emphasizing their intrinsic electrophysiological properties and the broader brain circuitry involved in detecting physiological signals such as hormonal and metabolic status. Central to this regulation is the balance of excitatory and inhibitory inputs that generate the pulsatile secretion pattern essential for growth regulation. Somatostatin (SST) provides critical inhibitory control over both GH secretion and GHRH neuronal activity. Feedback from peripheral hormones and integration of environmental and metabolic cues can further shape GHRH neuron function. Developmental, sex-dependent, and species-specific variations in GHRH neuron regulation are also discussed, highlighting important avenues for future research. This review offers a neuroendocrine perspective on growth regulation, with important implications for understanding the brain's role in regulating growth and development.

How neuropeptides act within the neural circuits that control social behavior is not well understood. While the prevailing view is that neuropeptides act through synaptic release and then activation of their canonical receptors on postsynaptic membranes, we investigated the role of a very different form of neuropeptide action in a neural circuit regulating social communication. Specifically, we tested the hypothesis that non-synaptically released oxytocin (OT) can act via the non-canonical receptors vasopressin V1a receptors (V1aR) to regulate social communication in Syrian hamsters. Scent marking, a key form of hamster social communication, can be enhanced by the α-melanocortin stimulating hormone (α-MSH), which stimulates OT but not arginine-vasopressin (AVP) release. Here, we employed hypothalamic injections of α-MSH and the α-MSH MC4R receptor antagonist MCL-0020 to determine the role of α-MSH in the expression of flank marking. To determine if these effects were intracellular calcium (iCa²⁺) dependent, hamsters were injected with AVP to induce flank marking and with the iCa²⁺ antagonist TMB-8 to test whether it was possible to block this behavioral effect. Further, a highly selective AVP V1a receptor (V1aR) antagonist and an OT receptor (OTR) antagonist were injected into the hypothalamus to investigate the receptor responsible for activating flank marking. Finally, we employed an in vitro hypothalamic slice preparation using “Sniffer cells” biosensors to confirm that α-MSH induced the release of OT but not AVP. First, we found that the in vivo hypothalamic injection of α-MSH increased odor-stimulated scent marking, whereas blockade of its receptor with MCL-0020 reduced this behavior. Hypothalamic infusion of the iCa²⁺ antagonist TMB-8 significantly reduced both AVP-induced and α-MSH-induced flank marking. Moreover, only the V1aR antagonist, and not the OTR antagonist, significantly decreased scent marking in response to hypothalamic infusion of α-MSH. Finally, biosensor recordings from hypothalamic slices confirmed that α-MSH stimulates OT, but not AVP, release. Together, these results demonstrate that α-MSH triggers non-synaptic OT release that regulates scent marking via V1aR activation, revealing a novel mechanism by which neuropeptides modulate social behavior.

Hypothalamic neuroendocrine neurons control diverse homeostatic functions that are essential for survival. While the cell bodies of these neurons are widely distributed, the nerve terminals converge on one specialised area of the brain called the median eminence. It is here that releasing hormones are secreted into the blood to control the function of the anterior pituitary gland. This current review summarises studies which demonstrate that nerve terminals in the median eminence can undergo unique forms of plasticity under different physiological states. This includes changes in the types of neuropeptides produced, changes in morphology and changes in glial coverage. In addition, median eminence nerve terminals can also act as independent sites of integration of both synaptic and hormonal signals to control the output of the neuroendocrine axis. Together these mechanisms allow for regulation of neurosecretion in response to different physiological demands.

Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in several solid malignancies but are associated with endocrine immune-related adverse events (irAEs), particularly hypophysitis. This retrospective real-world data study aimed to assess the magnetic resonance imaging (MRI) findings in cases with immune-related (ir) hypophysitis. Sixty-six cancer patients treated with ICIs at Laikon General Hospital between January 2016 and September 2024, presenting with anterior pituitary hormone deficiencies, were included. All patients underwent baseline pituitary MRI at the time of ir-hypophysitis diagnosis (median time: 2 weeks post-diagnosis). A follow-up MRI was also available in 37 patients (median time: 1.6 years post-diagnosis). All scans were centrally reviewed by radiologists blinded to clinical data. Baseline MRI abnormalities demonstrated pituitary enlargement (25%), reduced enhancement (10%), empty sella (8.3%), heterogeneous enhancement (5%), reduced size (3.3%), and stalk deviation (1.7%). Among 31 patients with both baseline and follow-up MRIs, 45% showed imaging changes (partially empty sella, size alterations). No specific ICI regimen was associated with characteristic imaging patterns. Patients with multiple hormonal axis deficiencies had more frequent MRI abnormalities than those with isolated ACTH deficiency (68.4% vs. 46.3% initially; 71.3% vs. 56.4% at follow-up). Pituitary MRI abnormalities are present in approximately half of patients with ir-hypophysitis, with dynamic changes observed in follow-up imaging. However, the absence of findings in a substantial proportion highlights the limited sensitivity of MRI in this irAE and underscores the importance of clinical and biochemical evaluation.

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