Journal of Neuroendocrinology最新文献

{"title":"The impact of re-characterizing metastatic pancreatic neuroendocrine tumors: A prospective study.","authors":"Kazhan Mollazadegan, Johan Botling, Britt Skogseid, Barbro Eriksson, Lovisa Falkman, Liang Zhang, Ieva Lase, Staffan Welin, Anders Sundin, Joakim Crona","doi":"10.1111/jne.70040","DOIUrl":"https://doi.org/10.1111/jne.70040","url":null,"abstract":"<p><p>The biology of metastatic pancreatic neuroendocrine tumors (panNET) may alter over time. It remains to be defined if, how, and when this patient group should be recommended to re-evaluate the characteristics of their disease. This prospective single-center, longitudinal cohort study at Uppsala University Hospital, Sweden (NCT03130205), included metastatic panNET patients with progressive disease to participate in a standardized re-characterization protocol: clinical and biochemical analyses, core-needle biopsy, and dual-positron emission tomography/computed tomography (PET/CT) (¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) and Gallium-68 DOTATOC (⁶⁸Ga-DOTATOC)) with NETPET score assessments. At further disease progression, a second re-characterization was offered. The proportion of patients with a clinically significant change is reported and defined as information that could lead to a change in the therapeutic algorithm proposed in the European Neuroendocrine Tumor Society (ENETS) guidelines. Between 2017 and 2021, 21 patients with progressive metastatic panNETs were included. Before inclusion, 19 tumors were grade (G) 1 or 2, and two were G3. Sixteen patients underwent biopsy with collection of adequate tumor material, of whom 81.3% (n = 13/16) displayed an increase in the Ki-67 index, with transition from G2 to G3 in 50% (n = 8/16). Twelve and 15 patients were positive on ¹⁸F-FDG- and ⁶⁸Ga-DOTATOC-positron emission tomography (PET), respectively. This corresponded to NETPET grades P1 (n = 2), P2b (n = 12), and P3b (n = 1). A clinically significant change was noted among 62% (n = 13/21) of patients at first re-characterization, leading to therapy change in 7 positron emission tomography/computed tomography (PET/CT) patients. After the second re-characterization, a significant clinical change occurred in 43% (n = 3/7) with a shift in therapy for one patient. This study shows that a considerable number of progressive metastatic panNETs experience significant changes in their disease characteristics over time. This may result in a revised treatment plan and highlights the need to re-evaluate all relevant aspects of panNET disease. Such comprehensive re-characterization is particularly crucial in the context of clinical trial inclusion.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":" ","pages":"e70040"},"PeriodicalIF":3.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144040543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic variable mild stress alters the transcriptome and signaling properties of the anterodorsal bed nucleus of the stria terminalis in a sex-dependent manner.","authors":"Thomas J Degroat, Sarah E Paladino, Benjamin A Samuels, Troy A Roepke","doi":"10.1111/jne.70041","DOIUrl":"https://doi.org/10.1111/jne.70041","url":null,"abstract":"<p><p>Chronic stress is a physiological state marked by dysregulation of the hypothalamic-pituitary-adrenal axis and high circulating levels of stress hormones, such as corticosterone in mice or cortisol in humans. This dysregulated state may result in the development of mood disorders, but the process by which this occurs is still unknown. The bed nucleus of the stria terminalis (BNST) serves as an integration center for stress signaling and is therefore likely an important area for the development of mood disorders. This project utilized a chronic variable mild stress (CVMS) paradigm to persistently stress mice for 6 weeks, followed by RNA-Sequencing of the anterodorsal (ad) BNST and electrophysiology of corticotropin-releasing hormone-expressing cells in the adBNST. Our results show significant sex biases in the transcriptome of the adBNST as well as effects of CVMS on the transcriptome of the adBNST specifically in males. Female-biased genes are related to synaptic transmission, while male-biased genes are related to RNA processing. Stress-sensitive genes in males are related to synaptic transmission and synapse formation. Additionally, electrophysiology data showed that CVMS suppressed the M-current in males but not females. However, CVMS increased the strength of excitatory post-synaptic currents in females but not males. This suggests significant differences in how males and females process chronic stress. It also suggests that the BNST is more sensitive to chronic stress in males than in females.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":" ","pages":"e70041"},"PeriodicalIF":3.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overexpression of the short isoform of the dopamine D2 receptor causes diet-induced obesity and hyperglycemia in mice.","authors":"Hanna Gonzalez, Lei Cheng, Qing Chang, Paul E Gold, Diego Perez-Tilve, YanYan Wang","doi":"10.1111/jne.70042","DOIUrl":"https://doi.org/10.1111/jne.70042","url":null,"abstract":"<p><p>Dopamine and dopamine D2R receptors (D2R) are involved in regulating eating behavior and endocrine and metabolic functions. D2R exists in two D2R isoforms: D2L (long form) and D2S (short form). Little is known if the changes in the expression levels of D2S and D2L would cause metabolic alterations. Here, we examined the role of these two D2R isoforms in obesity and glucose homeostasis. Mice of two genotypes were fed a higher fat diet (HFD). Body weight and food intake were monitored chronically, and various fat pads were dissected. Glucose tolerance and insulin tolerance tests were conducted. Energy expenditure and respiratory exchange ratio were measured via indirect calorimetry. We found when feeding with HFD, dopamine D2L knockout (D2L KO) mice (expressing purely D2S) of both female and male gained significantly more body weight than wild-type (WT) mice (expressing predominantly D2L) of both sexes. In addition, when feeding HFD, D2L KO mice showed an increased food intake compared to WT mice. Furthermore, when feeding HFD, both female and male D2L KO mice displayed impaired glucose tolerance. There were no significant differences in energy expenditure, respiratory quotient, and insulin sensitivity between D2L KO and WT mice. These results suggest that an increased expression level of D2S to D2L makes mice prone to obesity and hyperglycemia. Our findings identify a new risk factor contributing to the development of metabolic syndrome and increase our understanding of pathophysiological mechanisms leading to weight gain and diabetes.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":" ","pages":"e70042"},"PeriodicalIF":3.3,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PRRT plus holmium-166-SIRT (HEPAR PLuS) versus PRRT-only in patients with metastatic neuroendocrine tumors: A propensity-score matched analysis.","authors":"W B Veldhuis, T Walter, D M V de Vries-Huizing, J Theysohn, S Barton, E D Ekkelenkamp, B Lachachi, R J G de Jong, L W van Golen, H Lanzafame, L Milot, H Lahner, M E G H Lam, M E T Tesselaar, A J A T Braat","doi":"10.1111/jne.70034","DOIUrl":"https://doi.org/10.1111/jne.70034","url":null,"abstract":"<p><p>Patients with bulky neuroendocrine liver metastases (NELM) undergoing PRRT with [¹⁷⁷Lu]Lu-DOTATATE have a worse survival than patients with limited liver metastases. Previously, the safety and efficacy of additional selective internal radiotherapy (SIRT), using holmium-166 (¹⁶⁶Ho)-microspheres, directly following PRRT in patients with NELM were confirmed in the prospective HEPAR PLuS study. The aim of the current study was to provide insight into the efficacy and survival benefit of PRRT + ¹⁶⁶Ho-SIRT over PRRT-only by means of a propensity score matched historical cohort. A multicenter retrospective data collection was performed to match patients treated with PRRT-only to the prospectively collected HEPAR PLuS study patients. Demographic, clinical, laboratory, and imaging data were collected. The primary endpoint was the proportion of patients with progression-free survival (PFS) at 2 years after the start of PRRT. Secondary endpoints included the proportion of patients with 2-year hepatic PFS (hPFS), general PFS and hPFS, objective response rates (ORR), and overall survival (OS). Twenty-four patients were 1:1 matched and included in the analysis. All key matching criteria were balanced between cohorts if feasible. The proportion of patients with PFS and hPFS at 2 years was 68% and 82% after PRRT + ¹⁶⁶Ho-SIRT versus 55% and 50% after PRRT only. Time to median PFS was comparable (31 vs. 30 months). An initial delay in hepatic progression or death of any cause was observed in PRRT + ¹⁶⁶Ho-SIRT mNET patients (75% probability of PFS at 27 vs. 22 months), most notably in intestinal tumors (75% probability of PFS at 26 vs. 15 months). Best ORR was 71% after PRRT + ¹⁶⁶Ho-SIRT versus 25% after PRRT only. This study showed that ¹⁶⁶Ho-SIRT after PRRT (vs. PRRT-only) had a positive effect on the liver disease progression in patients with NELM, increasing the 2-year hPFS rate and tumor response and delaying hepatic progression or death. However, this effect did not translate into improving general PFS and OS.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":" ","pages":"e70034"},"PeriodicalIF":3.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Photostimulation increases food intake, agouti-related protein (AGRP) and type II iodothyronine deiodinase (DIO2) gene expression in the medio-basal hypothalamus of Gambel's White-crowned Sparrow.","authors":"Timothy Boswell, Sarena K Olson, George E Bentley, Nicole Perfito, Marilyn Ramenofsky","doi":"10.1111/jne.70036","DOIUrl":"https://doi.org/10.1111/jne.70036","url":null,"abstract":"<p><p>Before migration, birds express hyperphagia leading to deposition of fuel in support of long-distance flight. Long days in spring stimulate a photoperiodic neuroendocrine cascade leading to heightened food intake. A major component of the response of the reproductive system to increased daylength in birds is the local conversion of thyroxine (T4) to triiodothyronine (T3) in the medial basal hypothalamus. However, mechanisms of photostimulation regulating hyperphagia in migratory birds have yet to be resolved. We report results from two studies of Gambel's White-crowned Sparrow (Zonotrichia leucophrys gambelii), a long-distance migrant. We used quantitative PCR to measure basal hypothalamic gene expression of several neuropeptides, glucocorticoid receptors, type II and type III iodothyronine deiodinase enzymes (DIO2 and DIO3), and α1 and α2 subunits of the cellular energy sensor AMP-activated protein kinase (AMPKα1 and AMPKα2). The first study involved birds on short days of 9L:15D exposed to 18 h food deprivation. In the second study, birds were photostimulated by one or two long days of 20L:4D. We observed no significant effects of food deprivation on hypothalamic gene expression. However, photostimulation significantly increased food intake on the first and second long days and was associated with significant increases in agouti-related protein (AGRP) and AMPKα2 mRNAs and in the ratio of DIO2/DIO3 expression. The pattern of increased DIO2 and decreased DIO3 gene expression is likely to have increased basal hypothalamic T3 content. This, in turn, may lead to altered local AMPK signaling to increase AGRP biosynthesis and thereby promote photostimulated hyperphagia.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":" ","pages":"e70036"},"PeriodicalIF":3.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropeptides and reproductive flexibility in songbirds: A mini review.","authors":"Vatsala Tripathi, Sanjay Kumar Bhardwaj, Vinod Kumar","doi":"10.1111/jne.70030","DOIUrl":"https://doi.org/10.1111/jne.70030","url":null,"abstract":"<p><p>Synchronization of physiological and behavioral activities associated with avian reproduction requires corresponding changes in the activity of the hypothalamus-pituitary-gonadal axis. This involves complex brain peptidergic pathways, which show spatial and temporal differences in their expression and distribution during the annual reproductive cycle. The well-studied pathways include gonadotropin-releasing and inhibiting hormones (GnRH, GnIH), neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART), vasoactive intestinal peptide (VIP) and other peptides like arginine vasotocin (VT), oxytocin (mesotocin), and spexin. Together, these peptides form a neurochemical framework for the integration of both internal and external (environmental) cues; this results in a neuroendocrine response. Conceivably, therefore, the neurochemical framework within which brain peptides possibly interact and perform reproductive regulatory roles might show species differences. Here, we aim to review briefly the roles of these neuropeptides in reproduction in both opportunistically and seasonally breeding birds. Much of the discussion will be based on our own research on the opportunistic breeding zebra finch and the seasonally breeding redheaded bunting, Indian weaverbird, and spotted munia. The summer breeding redheaded bunting and weaverbird are typical photosensitive long-day species, but they show qualitative differences in response to stimulatory photoperiods during the post-reproductive period of their annual cycle. Buntings exhibit absolute photorefractoriness, while weaverbirds exhibit relative photorefractoriness. The autumn breeding spotted munia, on the other hand, is an atypical photosensitive species. It responds to both short and long photoperiods and presumably lacks photorefractoriness.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":" ","pages":"e70030"},"PeriodicalIF":3.3,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of melatonin in physiological mitigation of sleep disruption in an unnatural temporal environment.","authors":"Amaan Buniyaadi, Abhilash Prabhat, Sanjay Kumar Bhardwaj, Vinod Kumar","doi":"10.1111/jne.70035","DOIUrl":"https://doi.org/10.1111/jne.70035","url":null,"abstract":"<p><p>Illuminated nights reduce melatonin peak and disrupt sleep. Using this as the basis of the present experimental paradigm, we investigated whether nocturnal melatonin levels were crucial for sleep regulation in a diurnal vertebrate. Acclimated Indian house crows (Corvus splendens) were randomly segregated into three groups of 12 each. For the next 10 days, one group was maintained on 12 L:12 D, as before (LD control); for the other two groups, the absolute darkness was replaced with dim light at night (dLAN; L = ~150 lux, D = ~6 lux). Under dLAN, half an hour before light off time, the LD control and one dLAN group received intraperitoneally 200 μL of vehicle (0.75% physiological saline), while the other dLAN group received a similar 200 μL vehicle but containing melatonin at a dose of 50 μg bird^-1 day^-1. Under dLAN, exogenous melatonin elevated nocturnal AANAT mRNA and plasma melatonin levels and induced changes in diurnal expressions of clock genes (PER2, CRY1, BMAL1, NPAS2, REVERB) in the pineal gland and hypothalamus, and of genes encoding melatonin receptors (MEL1a, MEL1b) and epigenetic modifiers (HAT1, HDAC2, HDAC4, DNMT3a) in the hypothalamus. Elevated nocturnal melatonin levels bettered sleep with positive effects on the hypothalamic expression of genes associated with nocturnal sleep (cytokine pathway: TLR4, TNFα, IL-1β, NOS1; calcium pathway: CAMK2, SIK3) and awake (ACHM3, EGR1, HOMER1a, OREXIN) states, and with neurogenesis and synaptic plasticity (BDNF, EGR1, CREB). These suggested the role of melatonin in mitigation of the dLAN-induced sleep disruption. Nocturnal melatonin peak levels are a crucial component of the regulatory transcriptional pathways underlying the daily wake-sleep pattern, with far-reaching implications for sleep-related issues in diurnal species including perhaps humans inhabiting an over-lit environment with pervasive light pollution.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":" ","pages":"e70035"},"PeriodicalIF":3.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Timing mismatches, carryover effects, and the role of neuroendocrine mechanisms in determining birds' responses to environmental change.","authors":"Thomas P Hahn, Jamie M Cornelius, Heather E Watts","doi":"10.1111/jne.70032","DOIUrl":"https://doi.org/10.1111/jne.70032","url":null,"abstract":"<p><p>The neuroendocrine system plays a critical role in the synchronization of life cycle stages with variation in the environment, and in the coordination of life cycle stages with one another. When humans modify environments, these neuroendocrine mechanisms may impact how different individuals, populations, species, and even communities are affected. Here we conceptualize how endocrine mechanisms may influence the likelihood of: (1) timing mismatches between life cycle stages and environmental conditions, and (2) carryover effects within annual cycles. Timing mismatches can occur when an individual fails to synchronize a particular life cycle stage to the appropriate environmental conditions. Carryover effects occur when activities of one stage (including its timing) affect the performance in one or more subsequent stages. We suggest that there is a trade-off between timing adjustments within and across stages such that neuroendocrine mechanisms that reduce timing mismatches in temporally changing environments (e.g., strong neuroendocrine responsiveness to short-term cues, with resultant increased temporal flexibility to fine-tune the current stage to local conditions) may inherently increase the likelihood of carryover effects (e.g., through delay of a transition between stages), and vice versa. We use two examples-flexibility of the onset of photorefractoriness mediated by responsiveness to short-term cues, and sensitivity of molt to sex steroids-to illustrate these ideas, and suggest that future work should investigate the impacts of variation in these and potentially other seasonal timing mechanisms on carryover effects. The conceptual framework presented here suggests that there may be no single best set of tactics for coping with the effects of climate change; species with neuroendocrine mechanisms facilitating temporal flexibility may avoid some timing mismatches but set themselves up for deleterious carryover effects as they make temporal adjustments to environmental conditions modified by climate change.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":" ","pages":"e70032"},"PeriodicalIF":3.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of wintering under methylmercury exposure on spring reproductive onset in song sparrows (Melospiza melodia).","authors":"Claire L J Bottini, Calista J Henry, Scott A MacDougall-Shackleton","doi":"10.1111/jne.70027","DOIUrl":"https://doi.org/10.1111/jne.70027","url":null,"abstract":"<p><p>Exposure to methylmercury (MeHg) on breeding grounds may have numerous deleterious effects on birds, including neurotoxicity, disruption of hormones, and impaired reproduction. But it is unknown if MeHg exposure on wintering grounds can carry over and produce negative effects on the following spring breeding seasonal transition. To evaluate this, we exposed male captive song sparrows (Melospiza melodia) to environmentally relevant levels of dietary MeHg for 3 months during winter. We then photostimulated the birds with a long-day photoperiod and observed them for 21 days post-exposure. Contrary to our predictions, we found no carry-over effects of MeHg on the timing of changes in spring reproductive physiology assessed by testes mass, syrinx mass, plasma androgen concentrations, number of GnRH neurosecretory cells, and body condition. However, following photostimulation, MeHg-exposed birds had smaller cloacal protuberances. Although we observed no obvious effects on the timing of reproductive onset, the results suggest that winter MeHg exposure could induce carry-over effects on secondary sexual traits that may affect birds' breeding performance. Overall, our findings indicate that songbirds can buffer against the main effects of prior winter MeHg exposure so as to not delay reproductive onset in spring, but more studies are required for long-term effects on breeding performance.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":" ","pages":"e70027"},"PeriodicalIF":3.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic analysis of plasma proteins during fentanyl withdrawal in ovariectomized female rats with and without estradiol.","authors":"Patricia Sinclair, Navdeep S Dhanjal, E Blair Towers, Wendy J Lynch, Nadine Kabbani","doi":"10.1111/jne.70033","DOIUrl":"https://doi.org/10.1111/jne.70033","url":null,"abstract":"<p><p>Evidence from both clinical and preclinical studies indicates that females experience a faster progression to drug addiction and more severe addiction-related health effects compared with males. Estradiol (E2) plays a critical role in these sex differences. Recently, we demonstrated that E2 significantly exacerbates adverse health effects, such as respiratory distress and weight loss, in ovariectomized (OVX) female rats during withdrawal from extended-access fentanyl self-administration. To uncover the mechanisms behind E2-enhanced toxicity, we investigated proteomic changes in the plasma of fentanyl-withdrawn OVX rats under both E2 and non-E2 presentation conditions.Plasma samples were collected following extended-access fentanyl self-administration during protracted withdrawal, when adverse health effects were most pronounced. Using liquid chromatography coupled with electrospray ionization tandem mass spectrometry (LC-ESI MS/MS) we conducted proteomic analysis in OVX rats comparing the effect of fentanyl withdrawal, with or without E2, to drug-naïve control rats.We found a significant effect of fentanyl withdrawal on plasma proteomes within OVX rats. Fentanyl withdrawal was associated with a significant change in 15 plasma proteins including B-factor, properdin (Cfb), apolipoprotein E (ApoE), complement 4, precursor (C4), C-reactive protein (Crp), zinc-alpha-2-glycoprotein precursor (Azgp1), and serine peptidase inhibitor 3L (Serinpa3l). The addition of E2 was associated with enhanced proteomic changes. Bioinformatic gene ontology enrichment analysis indicates that fentanyl withdrawal can disrupt the expression of proteins associated with immunity, lipid transport, and components of the extracellular matrix. We identify protein changes in plasma that may contribute to adverse health outcomes in females, with and without E2, during fentanyl withdrawal. These findings support the development of targeted strategies addressing health risks during opioid use disorder in women.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":" ","pages":"e70033"},"PeriodicalIF":3.3,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}