William B Inabinett, Shiyu Wang, Paige M Estave, Emily G Peck, Sara R Jones, Rong Chen
Introduction: Chronic cocaine exposure results in changes in circulating steroid hormones, which is known to be associated with cocaine-seeking and taking behavior. However, whether cocaine also alters the brain content of these steroid hormones and cholesterol, a precursor to all steroid hormones, has yet to be extensively investigated. Thus, the goal of this study was to determine whether cocaine self-administration (SA) altered the content of cholesterol and steroid hormones (progesterone and testosterone) in both the plasma and the brain of animals.
Methods: Male Sprague-Dawley rats were allowed to self-administer cocaine (1.5 mg/kg/infusion) for a maximum 40 injections within 6 hours per day for 5 consecutive days followed by cue reactivity test and cocaine SA under the progressive ratio schedule as a measure of motivation to acquire cocaine. Eighteen hours after the last behavior test, the blood and brain tissue, including the prefrontal cortex (PFC) and dorsal striatum (CPu), were collected for biochemical assays.
Results: While cocaine SA did not alter the content of cholesterol and progesterone in the plasma, it reduced cholesterol content and almost completely abolished progesterone content in both the PFC and CPu. Further, testosterone levels were reduced in the CPu and plasma. Notably, plasma testosterone was positively correlated with its content in the PFC and CPu.
Conclusions: Cholesterol and progesterone in the brain are more sensitive to changes induced by cocaine SA than those in the plasma. Future studies should focus on understanding the functional consequence of altered brain steroids on neurotransmission and cocaine-seeking and taking behavior.
{"title":"Cocaine self-administration differentially modulates the content of cholesterol, progesterone and testosterone in the brain and plasma of male rats.","authors":"William B Inabinett, Shiyu Wang, Paige M Estave, Emily G Peck, Sara R Jones, Rong Chen","doi":"10.1159/000544983","DOIUrl":"https://doi.org/10.1159/000544983","url":null,"abstract":"<p><strong>Introduction: </strong>Chronic cocaine exposure results in changes in circulating steroid hormones, which is known to be associated with cocaine-seeking and taking behavior. However, whether cocaine also alters the brain content of these steroid hormones and cholesterol, a precursor to all steroid hormones, has yet to be extensively investigated. Thus, the goal of this study was to determine whether cocaine self-administration (SA) altered the content of cholesterol and steroid hormones (progesterone and testosterone) in both the plasma and the brain of animals.</p><p><strong>Methods: </strong>Male Sprague-Dawley rats were allowed to self-administer cocaine (1.5 mg/kg/infusion) for a maximum 40 injections within 6 hours per day for 5 consecutive days followed by cue reactivity test and cocaine SA under the progressive ratio schedule as a measure of motivation to acquire cocaine. Eighteen hours after the last behavior test, the blood and brain tissue, including the prefrontal cortex (PFC) and dorsal striatum (CPu), were collected for biochemical assays.</p><p><strong>Results: </strong>While cocaine SA did not alter the content of cholesterol and progesterone in the plasma, it reduced cholesterol content and almost completely abolished progesterone content in both the PFC and CPu. Further, testosterone levels were reduced in the CPu and plasma. Notably, plasma testosterone was positively correlated with its content in the PFC and CPu.</p><p><strong>Conclusions: </strong>Cholesterol and progesterone in the brain are more sensitive to changes induced by cocaine SA than those in the plasma. Future studies should focus on understanding the functional consequence of altered brain steroids on neurotransmission and cocaine-seeking and taking behavior.</p>","PeriodicalId":19117,"journal":{"name":"Neuroendocrinology","volume":" ","pages":"1-19"},"PeriodicalIF":3.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amanda Veiga Cheuiche, Letícia Guimarães da Silveira, Iara Regina Siqueira Lucena, Márcia Puñales, Fabiola Costenaro, Cristiane Kopacek, Gustavo Monteiro Escott, Sandra Pinho Silveiro, Leila Cristina Pedroso de Paula
Introduction: Pelvic ultrasound has been studied for the follow-up of girls with precocious puberty during gonadotropin-releasing hormone agonists (GnRHa) therapy. The addition of Doppler evaluation of uterine arteries needs to be further investigated. We aimed to evaluate the accuracy of the uterine artery pulsatility index (PI) for monitoring GnRHa therapy in girls with precocious puberty.
Methods: This is a retrospective cohort study of girls with central precocious puberty (CPP) and early and fast puberty (EFP) treated with GnRHa. We included girls who underwent pelvic ultrasound and Doppler imaging of the uterine arteries before and during therapy. Analyses included uterine artery PI and uterine, endometrial, and ovarian measurements. Receiver operating characteristic (ROC) curves with cutoffs determined by the Youden index were used for data analysis.
Results: In total, 28 pairs of PI measurements (54% of girls with CPP, 46% with EFP) before and during GnRHa therapy were included in the paired-sample analysis. The median duration of treatment at the time of ultrasound was 11.5 (7; 19) months. The mean PI was significantly higher during GnRHa therapy than at baseline (6.5 ± 1.8 vs. 4.0 ± 1.6, respectively, P < 0.001). A total of three girls met clinical and laboratory criteria for treatment failure. ROC curve analysis showed that the PI was able to identify an effective GnRHa therapy with a mean area under the curve (AUC) of 0.967 ± 0.04 (P < 0.001), and the PI cutoff point of 5.4 held a sensitivity of 84%, specificity of 100%, and accuracy of 86%.
Conclusion: We found a significant increase in the PI during GnRHa therapy, which reflects higher resistance in the blood flow to the uterus, indicating effective pubertal hormone suppression.
{"title":"Doppler Assessment of the Uterine Arteries is a Valuable Adjunct Tool for the Evaluation of Efficacy of Gonadotropin-Releasing Hormone Agonist Therapy in Girls with Central Precocious Puberty.","authors":"Amanda Veiga Cheuiche, Letícia Guimarães da Silveira, Iara Regina Siqueira Lucena, Márcia Puñales, Fabiola Costenaro, Cristiane Kopacek, Gustavo Monteiro Escott, Sandra Pinho Silveiro, Leila Cristina Pedroso de Paula","doi":"10.1159/000544985","DOIUrl":"https://doi.org/10.1159/000544985","url":null,"abstract":"<p><strong>Introduction: </strong>Pelvic ultrasound has been studied for the follow-up of girls with precocious puberty during gonadotropin-releasing hormone agonists (GnRHa) therapy. The addition of Doppler evaluation of uterine arteries needs to be further investigated. We aimed to evaluate the accuracy of the uterine artery pulsatility index (PI) for monitoring GnRHa therapy in girls with precocious puberty.</p><p><strong>Methods: </strong>This is a retrospective cohort study of girls with central precocious puberty (CPP) and early and fast puberty (EFP) treated with GnRHa. We included girls who underwent pelvic ultrasound and Doppler imaging of the uterine arteries before and during therapy. Analyses included uterine artery PI and uterine, endometrial, and ovarian measurements. Receiver operating characteristic (ROC) curves with cutoffs determined by the Youden index were used for data analysis.</p><p><strong>Results: </strong>In total, 28 pairs of PI measurements (54% of girls with CPP, 46% with EFP) before and during GnRHa therapy were included in the paired-sample analysis. The median duration of treatment at the time of ultrasound was 11.5 (7; 19) months. The mean PI was significantly higher during GnRHa therapy than at baseline (6.5 ± 1.8 vs. 4.0 ± 1.6, respectively, P < 0.001). A total of three girls met clinical and laboratory criteria for treatment failure. ROC curve analysis showed that the PI was able to identify an effective GnRHa therapy with a mean area under the curve (AUC) of 0.967 ± 0.04 (P < 0.001), and the PI cutoff point of 5.4 held a sensitivity of 84%, specificity of 100%, and accuracy of 86%.</p><p><strong>Conclusion: </strong>We found a significant increase in the PI during GnRHa therapy, which reflects higher resistance in the blood flow to the uterus, indicating effective pubertal hormone suppression.</p>","PeriodicalId":19117,"journal":{"name":"Neuroendocrinology","volume":" ","pages":"1-19"},"PeriodicalIF":3.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: Chronic social isolation (CSI) stress leads to numerous maladaptive changes in physiology and psychology, however, very little is known about the effects of longer time-scale CSI and there are divergent views regarding the underlying mechanisms. This study aimed to elucidate the common neuroendocrine mechanisms underlying the maladaptive changes caused by 14-week (14wk-) and 20-week (20wk-) CSI.
Methods: We investigated the impacts of 14wk- and 20wk- CSI on anxiety/depression-like behaviors in male C57BL/6N mice with classical behavioral tests, and the immunofluorescence method was used for quantification of the arginine vasopressin (AVP)/Oxytocin (OT) positive neurons in the PVN and screening out the differential activation brain regions (DABrs) on exposure of tail suspension. The expression of Avpr1a and Oxtr in the lateral septum dorsal (LSD) was assessed by quantitative RT-PCR (qPCR), and the function of LSD Avpr1a+/+ neurons in emotion regulation was verified with pharmacological approaches. The concentration of AVP/OT in plasma was examined with the Enzyme-linked immunosorbent assay (ELISA).
Results: 14wk- and 20wk- CSI increased anxiety/depression-like behaviors and altered levels of exploratory locomotion in opposite directions, which are likely due to an imbalance of the AVP/OT system within the PVN and peripheral plasma, differential activation of LSD and thalamic brain regions, and abnormal expression of Avpr1a in LSD. Pharmacological results demonstrated that Avpr1a receptor in the LSD were involved in emotion regulation.
Conclusion: This study suggests that the imbalance of the AVP/OT system and the dysfunction of Avpr1a+/+ neurons in the LSD were engaged in common neuroendocrinology mechanisms for anxiety/depression induced by long-term CSI.
{"title":"Involvement of the AVP/OT system and lateral septum in the modulation of anxiety/depression caused by 14-week and 20-week social isolation.","authors":"Jing Liu, Weizheng Zhang, Yuting Bai, Rui Fu, Miao Lin, Jialong Li, Liangteng Nie, Xiaohui Dang, Qiao Wang, Yunmeng Zhu, Lu Li, Xing Guo, Lizi Zhang, Yishan Qu, Kaizhe Huang, Xiao Han, Shufeng Shang, Jiayu Xiao, Yin Li, Caihong Huang, Rui Jia, Zhixiong He, Fadao Tai","doi":"10.1159/000544839","DOIUrl":"https://doi.org/10.1159/000544839","url":null,"abstract":"<p><strong>Introduction: </strong>Chronic social isolation (CSI) stress leads to numerous maladaptive changes in physiology and psychology, however, very little is known about the effects of longer time-scale CSI and there are divergent views regarding the underlying mechanisms. This study aimed to elucidate the common neuroendocrine mechanisms underlying the maladaptive changes caused by 14-week (14wk-) and 20-week (20wk-) CSI.</p><p><strong>Methods: </strong>We investigated the impacts of 14wk- and 20wk- CSI on anxiety/depression-like behaviors in male C57BL/6N mice with classical behavioral tests, and the immunofluorescence method was used for quantification of the arginine vasopressin (AVP)/Oxytocin (OT) positive neurons in the PVN and screening out the differential activation brain regions (DABrs) on exposure of tail suspension. The expression of Avpr1a and Oxtr in the lateral septum dorsal (LSD) was assessed by quantitative RT-PCR (qPCR), and the function of LSD Avpr1a+/+ neurons in emotion regulation was verified with pharmacological approaches. The concentration of AVP/OT in plasma was examined with the Enzyme-linked immunosorbent assay (ELISA).</p><p><strong>Results: </strong>14wk- and 20wk- CSI increased anxiety/depression-like behaviors and altered levels of exploratory locomotion in opposite directions, which are likely due to an imbalance of the AVP/OT system within the PVN and peripheral plasma, differential activation of LSD and thalamic brain regions, and abnormal expression of Avpr1a in LSD. Pharmacological results demonstrated that Avpr1a receptor in the LSD were involved in emotion regulation.</p><p><strong>Conclusion: </strong>This study suggests that the imbalance of the AVP/OT system and the dysfunction of Avpr1a+/+ neurons in the LSD were engaged in common neuroendocrinology mechanisms for anxiety/depression induced by long-term CSI.</p>","PeriodicalId":19117,"journal":{"name":"Neuroendocrinology","volume":" ","pages":"1-32"},"PeriodicalIF":3.2,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) are essential regulators of cortisol production within the hypothalamic-pituitary-adrenal (HPA) axis. Elevated cortisol levels, resulting from excessive ACTH, can lead to Cushing's syndrome, a condition with significant morbidity. Neuroendocrine tumors (NETs) can ectopically produce both ACTH and CRH, contributing to this syndrome. This review discusses the pathophysiology, types, clinical presentation, diagnosis, and management of these tumors. Emphasis is placed on the importance of identifying dual CRH/ACTH secretion, which complicates diagnosis and necessitates tailored therapeutic strategies. Furthermore, the review highlights the prognosis, common complications, and future directions for research in this area. We report the case of a 53-year-old female patient who presented with severe Cushing's syndrome and was diagnosed with ectopic ACTH syndrome. Despite initial indications pointing towards pituitary-dependent hypercortisolism, further investigations revealed the presence of a highly differentiated atypically located tumor in the upper lobe of the left lung, adjacent to the mediastinum. Immunohistochemistry of the tumor tissue demonstrated not only ACTH but also CRH and CRH-R1 expression. The simultaneous expression of these molecules supports the hypothesis of the presence of a positive endocrine feedback loop within the NET, in which the release of CRH stimulates the expression of ACTH via binding to CRH-R1. This case report highlights the challenges in diagnosing and managing ectopic ACTH syndrome, emphasizing the importance of a comprehensive diagnostic approach to identify secondary factors impacting cortisol production, such as CRH production and other contributing neuroendocrine mechanisms.
{"title":"Ectopic CRH/ACTH-Co-Secreting Neuroendocrine Tumors Leading to Cushing's Disease - A Case Presentation and Literature Review.","authors":"Jasmin Ewert, Maximilian Seidl, Jann Achim Hommen, Matthias Schott, Norbert Gattermann","doi":"10.1159/000544727","DOIUrl":"https://doi.org/10.1159/000544727","url":null,"abstract":"<p><p>Adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) are essential regulators of cortisol production within the hypothalamic-pituitary-adrenal (HPA) axis. Elevated cortisol levels, resulting from excessive ACTH, can lead to Cushing's syndrome, a condition with significant morbidity. Neuroendocrine tumors (NETs) can ectopically produce both ACTH and CRH, contributing to this syndrome. This review discusses the pathophysiology, types, clinical presentation, diagnosis, and management of these tumors. Emphasis is placed on the importance of identifying dual CRH/ACTH secretion, which complicates diagnosis and necessitates tailored therapeutic strategies. Furthermore, the review highlights the prognosis, common complications, and future directions for research in this area. We report the case of a 53-year-old female patient who presented with severe Cushing's syndrome and was diagnosed with ectopic ACTH syndrome. Despite initial indications pointing towards pituitary-dependent hypercortisolism, further investigations revealed the presence of a highly differentiated atypically located tumor in the upper lobe of the left lung, adjacent to the mediastinum. Immunohistochemistry of the tumor tissue demonstrated not only ACTH but also CRH and CRH-R1 expression. The simultaneous expression of these molecules supports the hypothesis of the presence of a positive endocrine feedback loop within the NET, in which the release of CRH stimulates the expression of ACTH via binding to CRH-R1. This case report highlights the challenges in diagnosing and managing ectopic ACTH syndrome, emphasizing the importance of a comprehensive diagnostic approach to identify secondary factors impacting cortisol production, such as CRH production and other contributing neuroendocrine mechanisms.</p>","PeriodicalId":19117,"journal":{"name":"Neuroendocrinology","volume":" ","pages":"1-29"},"PeriodicalIF":3.2,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Neuroendocrine neoplasms (NENs) are comparatively rare tumours. However, prevalence is increasing steeply, related to rising incidence, earlier detection, and prolonged survival in many cases of metastatic NENs; with implications on health care resources.
Summary: This commentary/narrative review extracts the relatively scare, available literature related to costs of NEN cancer care, which is mainly based on studies performed in the Unites States. Key, now implemented or evolving NEN related treatment options over the last 15 years are summarised. The commentary further highlights in part preventable aspects that can further contribute to cost pressure in NEN cancer care, including issues related to inappropriate use of available diagnostic tools; and not considering differential diagnoses when assessing people with suspected carcinoid syndrome - with these risks being minimised with access to centres with multi-specialty expertise in the management of people with NENs. Issues observed in people with exocrine and/or endocrine pancreatic deficiencies caused by a NEN or treatment of the NEN are mentioned, as well as some specific aspects related to diagnostics involving 68Ga PET-CT scans and treatment with Lutetium peptide-receptor radionuclide therapy (Lu-PRRT).
Key messages: This commentary summarises factors influencing cost of NEN cancer care, and highlights in part preventable issues mostly related to delayed involvement of a NEN multidisciplinary team, observed in a UK NEN referral centre (ENETS Centre of Excellence certified since 2015) over the last 15 years; resulting in sub-optimal management of people with NENs and ultimately adding to cost pressure.
{"title":"Factors influencing costs of cancer care for patients with neuroendocrine neoplasms.","authors":"Martin O Weickert","doi":"10.1159/000544050","DOIUrl":"https://doi.org/10.1159/000544050","url":null,"abstract":"<p><strong>Background: </strong>Neuroendocrine neoplasms (NENs) are comparatively rare tumours. However, prevalence is increasing steeply, related to rising incidence, earlier detection, and prolonged survival in many cases of metastatic NENs; with implications on health care resources.</p><p><strong>Summary: </strong>This commentary/narrative review extracts the relatively scare, available literature related to costs of NEN cancer care, which is mainly based on studies performed in the Unites States. Key, now implemented or evolving NEN related treatment options over the last 15 years are summarised. The commentary further highlights in part preventable aspects that can further contribute to cost pressure in NEN cancer care, including issues related to inappropriate use of available diagnostic tools; and not considering differential diagnoses when assessing people with suspected carcinoid syndrome - with these risks being minimised with access to centres with multi-specialty expertise in the management of people with NENs. Issues observed in people with exocrine and/or endocrine pancreatic deficiencies caused by a NEN or treatment of the NEN are mentioned, as well as some specific aspects related to diagnostics involving 68Ga PET-CT scans and treatment with Lutetium peptide-receptor radionuclide therapy (Lu-PRRT).</p><p><strong>Key messages: </strong>This commentary summarises factors influencing cost of NEN cancer care, and highlights in part preventable issues mostly related to delayed involvement of a NEN multidisciplinary team, observed in a UK NEN referral centre (ENETS Centre of Excellence certified since 2015) over the last 15 years; resulting in sub-optimal management of people with NENs and ultimately adding to cost pressure.</p>","PeriodicalId":19117,"journal":{"name":"Neuroendocrinology","volume":" ","pages":"1-26"},"PeriodicalIF":3.2,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143409434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The French Neuroendocrinology Is Enriched by Its Diversity.","authors":"David Vaudry","doi":"10.1159/000543954","DOIUrl":"10.1159/000543954","url":null,"abstract":"","PeriodicalId":19117,"journal":{"name":"Neuroendocrinology","volume":" ","pages":"1-2"},"PeriodicalIF":3.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Giovanni Vitale, Ilona Rybinska, Giulia Arrivi, Vincenzo Marotta, Gianfranco Di Iasi, Alessia Filice, Christopher Nardi, Annamaria Colao, Antongiulio Faggiano
Background: Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from neuroendocrine cells, exhibiting a wide range of behaviors from indolent to highly aggressive forms. Treatment options remain limited, particularly for progressive cases. Cabozantinib, a multitarget tyrosine kinase inhibitor, has demonstrated potential in targeting key pathways related to tumor growth, angiogenesis, and metastasis.
Summary: This review provides a comprehensive analysis of cabozantinib's therapeutic role across various NEN subtypes, including gastroenteropancreatic NENs, lung NENs, pheochromocytomas/paragangliomas, Merkel cell carcinoma, presacral NENs, pituitary neuroendocrine tumors, and neuroendocrine prostate cancer.
Key messages: The paper discusses several preclinical and clinical studies that demonstrate the efficacy of cabozantinib in slowing tumor progression and improving progression-free survival, particularly in patients with progressive, well-differentiated NENs. However, cabozantinib's complex toxicity profile limits its broad application, necessitating further research to optimize dosing, particularly in syndromic NENs. Ongoing trials are investigating cabozantinib in combination with somatostatin analogs, peptide receptor radionuclide therapy, temozolomide, and immunotherapies in order to overcome treatment resistance and expanding therapeutic strategies for advanced NENs.
{"title":"Cabozantinib in the Treatment of Neuroendocrine Neoplasms: Insights across Different Tumor Origins.","authors":"Giovanni Vitale, Ilona Rybinska, Giulia Arrivi, Vincenzo Marotta, Gianfranco Di Iasi, Alessia Filice, Christopher Nardi, Annamaria Colao, Antongiulio Faggiano","doi":"10.1159/000543953","DOIUrl":"10.1159/000543953","url":null,"abstract":"<p><strong>Background: </strong>Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors arising from neuroendocrine cells, exhibiting a wide range of behaviors from indolent to highly aggressive forms. Treatment options remain limited, particularly for progressive cases. Cabozantinib, a multitarget tyrosine kinase inhibitor, has demonstrated potential in targeting key pathways related to tumor growth, angiogenesis, and metastasis.</p><p><strong>Summary: </strong>This review provides a comprehensive analysis of cabozantinib's therapeutic role across various NEN subtypes, including gastroenteropancreatic NENs, lung NENs, pheochromocytomas/paragangliomas, Merkel cell carcinoma, presacral NENs, pituitary neuroendocrine tumors, and neuroendocrine prostate cancer.</p><p><strong>Key messages: </strong>The paper discusses several preclinical and clinical studies that demonstrate the efficacy of cabozantinib in slowing tumor progression and improving progression-free survival, particularly in patients with progressive, well-differentiated NENs. However, cabozantinib's complex toxicity profile limits its broad application, necessitating further research to optimize dosing, particularly in syndromic NENs. Ongoing trials are investigating cabozantinib in combination with somatostatin analogs, peptide receptor radionuclide therapy, temozolomide, and immunotherapies in order to overcome treatment resistance and expanding therapeutic strategies for advanced NENs.</p>","PeriodicalId":19117,"journal":{"name":"Neuroendocrinology","volume":" ","pages":"1-20"},"PeriodicalIF":3.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"The Hypothalamus and Pituitary Gland Regulate Reproduction and Are Involved in the Development of Polycystic Ovary Syndrome.","authors":"Bin-Yang Long, Xipeng Liao, Xin Liang","doi":"10.1159/000543877","DOIUrl":"10.1159/000543877","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Summary: </strong>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.</p><p><strong>Key messages: </strong>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.</p>","PeriodicalId":19117,"journal":{"name":"Neuroendocrinology","volume":" ","pages":"1-20"},"PeriodicalIF":3.2,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Camilla Mancini, Giulia Pecora, Gerardo Salerno, Luana Lionetto, Donatella De Bernardini, Giuseppe Costanzi, Saverio Gabrielli, Domenico Veroli, Vincenzo Visco, Maurizio Simmaco, Virginia Zamponi, Rossella Mazzilli, Antongiulio Faggiano
Introduction: Indoleamine 2,3-dioxygenase (IDO) converts L-tryptophan (T) to L-kynurenine (K) resulting in an immunosuppressive microenvironment. The aim of the current study was to evaluate in patients with neuroendocrine tumor (NET) (1) T and K concentrations; (2) correlation with clinical outcome; (3) relationship between IDO activity and inflammatory cytokines.
Methods: A cross-sectional study was performed to investigate the IDO pathway in patients in follow-up for NET. Clinicopathological features, serum levels of K and T through liquid chromatography, and serum assay of cytokines (IL-6, IL-10, IL-17A, IL-22, IL-23, TNF-α) through MAGPIX were evaluated.
Results: Seventy-eight NET patients were enrolled (66 lung, 12 pancreatic): 69.2% were in postoperative remission, 14.1% in stable disease, and 16.7% in disease progression. T was significantly lower in patients older than 65 years (p = 0.003). K and T were significantly lower in patients with progression (p = 0.03, p = 0.004, respectively). T was an independent predictor factor of progression in multivariable analysis (p = 0.041). A cutoff of 7.74 μg/mL significantly differentiates patients with progression and those with stable disease. IL-6 and IL-10 were significantly associated with tumor progression in univariate analysis (p = 0.005, p = 0.001, respectively) but not in the multivariable analysis. A statistically significant negative correlation was found between T and IL-10 (r = -0.366, p value = 0.04).
Conclusion: The K/T pathway may play a role as a potential predictor of tumor progression in NET. These findings need to be validated in large prospective studies investigating its metabolites as both prognostic and predictive factors for treatment response.
{"title":"Impact of Indoleamine 2,3-Dioxygenase Enzyme Activity in Neuroendocrine Tumors.","authors":"Camilla Mancini, Giulia Pecora, Gerardo Salerno, Luana Lionetto, Donatella De Bernardini, Giuseppe Costanzi, Saverio Gabrielli, Domenico Veroli, Vincenzo Visco, Maurizio Simmaco, Virginia Zamponi, Rossella Mazzilli, Antongiulio Faggiano","doi":"10.1159/000543658","DOIUrl":"10.1159/000543658","url":null,"abstract":"<p><strong>Introduction: </strong>Indoleamine 2,3-dioxygenase (IDO) converts L-tryptophan (T) to L-kynurenine (K) resulting in an immunosuppressive microenvironment. The aim of the current study was to evaluate in patients with neuroendocrine tumor (NET) (1) T and K concentrations; (2) correlation with clinical outcome; (3) relationship between IDO activity and inflammatory cytokines.</p><p><strong>Methods: </strong>A cross-sectional study was performed to investigate the IDO pathway in patients in follow-up for NET. Clinicopathological features, serum levels of K and T through liquid chromatography, and serum assay of cytokines (IL-6, IL-10, IL-17A, IL-22, IL-23, TNF-α) through MAGPIX were evaluated.</p><p><strong>Results: </strong>Seventy-eight NET patients were enrolled (66 lung, 12 pancreatic): 69.2% were in postoperative remission, 14.1% in stable disease, and 16.7% in disease progression. T was significantly lower in patients older than 65 years (p = 0.003). K and T were significantly lower in patients with progression (p = 0.03, p = 0.004, respectively). T was an independent predictor factor of progression in multivariable analysis (p = 0.041). A cutoff of 7.74 μg/mL significantly differentiates patients with progression and those with stable disease. IL-6 and IL-10 were significantly associated with tumor progression in univariate analysis (p = 0.005, p = 0.001, respectively) but not in the multivariable analysis. A statistically significant negative correlation was found between T and IL-10 (r = -0.366, p value = 0.04).</p><p><strong>Conclusion: </strong>The K/T pathway may play a role as a potential predictor of tumor progression in NET. These findings need to be validated in large prospective studies investigating its metabolites as both prognostic and predictive factors for treatment response.</p>","PeriodicalId":19117,"journal":{"name":"Neuroendocrinology","volume":" ","pages":"1-11"},"PeriodicalIF":3.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: Obesity may lead to cognitive impairment and neuropsychiatric disorders, which are associated with changes in the brain cortical structure, particularly in cortical thickness. However, the exact genetic association between obesity and brain cortical thickness remains inconclusive. We aimed to identify the relationship between obesity-related traits [body mass index (BMI), waist-hip ratio (WHR), and waist-hip ratio adjusted for BMI (WHRadjBMI)] and brain cortical thickness.
Methods: Leveraging summary statistics of large-scale GWAS(s) conducted in European-ancestry populations on BMI(N=806,834), WHR(N=697,734), WHRadjBMI (N=694,649), and brain cortex thickness (N=33,709), we performed GWAS combining genetic correlation, multi-trait meta-analysis and Mendelian randomization analysis.
Results: Our findings revealed a strong genetic correlation between BMI and brain cortical thickness(rg=-0.0542, P=0.0435), and a significant result was also observed for WHR and brain thickness (rg=-0.0744, P=0.009). In addition, we identified three loci between obesity-related traits. MR analysis supported the causal role of BMI (IVW beta=-0.006, 95% CI=-0.011- -3.85E-04;weighted median beta=-0.006, 95% CI=-0.013- -0.002), WHR (IVW beta=-0.011, 95% CI=-0.018- -0.005; weighted median beta=-0.008, 95% CI=-0.018- -0.003) and WHRadjBMI (IVW beta =0.011 95% CI=-0.018- -0.005; weighted median beta=-0.008, 95% CI=-0.018- -0.002) in brain cortical thickness.
Conclusion: This study has shown that genetically predicted obesity-related traits have a causal relationship with reduced cortical thickness. These findings provide genetic evidence for a link between obesity and structural changes in the brain, and suggest that obesity may be associated with neuropsychiatric disorders by affecting brain structure, particularly cortical thickness.
{"title":"Genetic associations between obesity and brain cortical thickness: combined genetic correlation, multi-trait meta- analysis and Mendelian randomization.","authors":"Jiankun Chen, Simin Pan, Yingfei Tan, Yuan Wu, Taoliang Huang, Bin Huang, Changcai Xie, Shubin Cai, Jiqiang Li, Yue Lu, Yu Chen","doi":"10.1159/000543574","DOIUrl":"https://doi.org/10.1159/000543574","url":null,"abstract":"<p><strong>Introduction: </strong>Obesity may lead to cognitive impairment and neuropsychiatric disorders, which are associated with changes in the brain cortical structure, particularly in cortical thickness. However, the exact genetic association between obesity and brain cortical thickness remains inconclusive. We aimed to identify the relationship between obesity-related traits [body mass index (BMI), waist-hip ratio (WHR), and waist-hip ratio adjusted for BMI (WHRadjBMI)] and brain cortical thickness.</p><p><strong>Methods: </strong>Leveraging summary statistics of large-scale GWAS(s) conducted in European-ancestry populations on BMI(N=806,834), WHR(N=697,734), WHRadjBMI (N=694,649), and brain cortex thickness (N=33,709), we performed GWAS combining genetic correlation, multi-trait meta-analysis and Mendelian randomization analysis.</p><p><strong>Results: </strong>Our findings revealed a strong genetic correlation between BMI and brain cortical thickness(rg=-0.0542, P=0.0435), and a significant result was also observed for WHR and brain thickness (rg=-0.0744, P=0.009). In addition, we identified three loci between obesity-related traits. MR analysis supported the causal role of BMI (IVW beta=-0.006, 95% CI=-0.011- -3.85E-04;weighted median beta=-0.006, 95% CI=-0.013- -0.002), WHR (IVW beta=-0.011, 95% CI=-0.018- -0.005; weighted median beta=-0.008, 95% CI=-0.018- -0.003) and WHRadjBMI (IVW beta =0.011 95% CI=-0.018- -0.005; weighted median beta=-0.008, 95% CI=-0.018- -0.002) in brain cortical thickness.</p><p><strong>Conclusion: </strong>This study has shown that genetically predicted obesity-related traits have a causal relationship with reduced cortical thickness. These findings provide genetic evidence for a link between obesity and structural changes in the brain, and suggest that obesity may be associated with neuropsychiatric disorders by affecting brain structure, particularly cortical thickness.</p>","PeriodicalId":19117,"journal":{"name":"Neuroendocrinology","volume":" ","pages":"1-11"},"PeriodicalIF":3.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}