Journal of Neuroendocrinology最新文献

{"title":"The curious case of the hypothalamic–pituitary–gonadal axis dysfunction in subordinate female naked mole-rats (Heterocephalus glaber): No apparent role of opioids and glucocorticoids","authors":"Daniel W. Hart,&nbsp;E. Roberts,&nbsp;M. J. O'Riain,&nbsp;R. P. Millar,&nbsp;N. C. Bennett","doi":"10.1111/jne.13444","DOIUrl":"10.1111/jne.13444","url":null,"abstract":"<p>The naked mole-rat (<i>Heterocephalus glaber</i>) is a unique model mammal in which to study socially induced inhibition of the hypothalamic–pituitary–gonadal (HPG) axis. Naked mole-rat groups exhibit a high degree of reproductive bias in which breeding is restricted to one female (the queen) and one male, with subordinate non-breeding colony members rarely, if ever, having the opportunity to reproduce due to a dysfunctional HPG axis. It is posited that aggression directed at subordinates by the queen suppresses reproduction in these subordinates, yet the underlying physiological mechanisms causing this dysfunction are unknown. This study aimed to investigate the possible factors contributing to the dysfunction of the HPG axis in subordinate female naked mole-rats with a specific focus on the role of ovarian feedback and stress-related factors such as circulating glucocorticoid and endogenous opioid peptides. The results showed that stress-related factors appear to not mediate the suppression of reproductive function in subordinate female naked mole rats. Indeed, in some cases, the activation of the stress axis may lead to reproductive activation instead of deactivation. At the same time, the role of ovarian sex steroid feedback in reproductive suppression is likely limited and not clearly delineated. This study highlights the need for detailed studies to elucidate the mechanism of reproductive suppression in this unique model mammalian species which may shed light on, and reveal novel mechanisms, in the social regulation of reproduction.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"36 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jne.13444","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world effectiveness of adjuvant octreotide therapy in patients with pancreatic neuroendocrine tumors at high recurrence risk: A multicenter retrospective cohort study","authors":"Shiwei Guo,&nbsp;Heshui Wu,&nbsp;Suizhi Gao,&nbsp;Weiyu Hu,&nbsp;Hui Jiang,&nbsp;Yun Bian,&nbsp;Yijie Zhang,&nbsp;Bo Li,&nbsp;Gang Li,&nbsp;Xuefeng Xu,&nbsp;Min Wang,&nbsp;Chenglin Zhu,&nbsp;Linlin Qu,&nbsp;Qiang Huang,&nbsp;Renyi Qin,&nbsp;Wenhui Lou,&nbsp;Gang Jin","doi":"10.1111/jne.13442","DOIUrl":"10.1111/jne.13442","url":null,"abstract":"<p>Adjuvant therapy for pancreatic neuroendocrine tumors (PanNETs) after radical resection lacks evidence-based data and remains controversial. This study aimed to validate whether long-acting octreotide is a potential candidate for adjuvant therapy in patients with G2 PanNETs at high recurrence risk by clustering real-world data. A retrospective review of patients with nonmetastatic grade 2 PanNETs who underwent radical resection at six research centers between 2008 and 2020 was conducted. Propensity score matching and inverse probability of treatment weight analysis were used to control confounding factors. Overall, 357 patients (octreotide group, <i>n</i> = 82; control group, <i>n</i> = 275) were analyzed. Kaplan–Meier survival analyses showed that the octreotide group had longer disease-free survival (DFS) compared with the control group (36 months: 93.3% vs. 79.0%, <i>p</i> = .0124; 60 months: 71% vs. 67.6%, <i>p</i> = .0596, respectively), as well as overall survival (OS) (60 months: 98% vs. 83.8%, <i>p</i> = .0117, respectively). Multivariate analyses indicated that octreotide long-acting repeatable (LAR) adjuvant therapy was associated with higher OS (<i>p</i> = .0270) at 60 months. Propensity score matching analysis showed that octreotide adjuvant therapy was associated with higher DFS (<i>p</i> = .0455) and OS (<i>p</i> = .0190) at 60 months. Similar results were obtained via inverse probability of treatment weight analysis. Subgroup analysis indicated that octreotide LAR was associated with a high DFS in patients with lymph node metastasis or Ki-67 &lt;10% PanNETs. Adjuvant therapy with long-acting octreotide following radical resection of nonmetastatic G2 PanNETs may be associated with improved DFS and OS in a real-world setting.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"36 12","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208507","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":"Lack of a genetic risk continuum between pubertal timing in the general population and idiopathic hypogonadotropic hypogonadism","authors":"Lacey Plummer,&nbsp;Ravikumar Balasubramanian,&nbsp;Maria Stamou,&nbsp;Mark Campbell,&nbsp;Pranav Dewan,&nbsp;Nora Bryant,&nbsp;Kathryn Salnikov,&nbsp;Margaret Lippincott,&nbsp;Stephanie Seminara","doi":"10.1111/jne.13445","DOIUrl":"10.1111/jne.13445","url":null,"abstract":"<p>Pubertal timing is a highly heritable trait in the general population. Recently, a large-scale exome-wide association study has implicated rare variants in six genes (<i>KDM4C</i>, <i>MC3R</i>, <i>MKRN3</i>, <i>PDE10A</i>, <i>TACR3</i>, and <i>ZNF483</i>) as genetic determinants of pubertal timing within the general population. Two of the genes (<i>TACR3</i>, <i>MKRN3</i>) are already implicated in extreme disorders of pubertal timing. This observation suggests that there may be a pervasive “genetic risk continuum” wherein genes that govern pubertal timing in the general population, by extension, may also be causal for rare Mendelian disorders of pubertal timing. Hence, we hypothesized that the four novel genes linked to pubertal timing in the population will also contribute to idiopathic hypogonadotropic hypogonadism (IHH), a genetic disorder characterized by absent puberty. Exome sequencing data from 1322 unrelated IHH probands were reviewed for rare sequence variants (RSVs) (minor allele frequency bins: &lt;1%; &lt;0.1%; &lt;0.01%) in the six genes linked to puberty in the general population. A gene-based rare variant association testing (RVAT) was performed between the IHH cohort and a reference public genomic sequences repository—the Genome Aggregation Database (gnomAD). As expected, RVAT analysis showed that RSVs in <i>TACR3</i>, a known IHH gene, were significantly enriched in the IHH cohort compared to gnomAD cohort across all three MAF bins. However, RVAT analysis of the remaining five genes failed to show any RSV enrichment in the IHH cohort across all MAF bins. Our findings argue strongly against a pervasive genetic risk continuum between pubertal timing in the general population and extreme pubertal phenotypes. The biologic basis of such distinct genetic architectures' merits further evaluation.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"36 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208510","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":"PTPRJ is a negative regulator of insulin signaling in neuronal cells, impacting protein biosynthesis, and neurite outgrowth","authors":"Jannis Ulke,&nbsp;Simran Chopra,&nbsp;Otsuware Linda-Josephine Kadiri,&nbsp;Peter Geserick,&nbsp;Vanessa Stein,&nbsp;Sahar Cheshmeh,&nbsp;André Kleinridders,&nbsp;Kai Kappert","doi":"10.1111/jne.13446","DOIUrl":"10.1111/jne.13446","url":null,"abstract":"<p>Central insulin resistance has been linked to the development of neurodegenerative diseases and mood disorders. Various proteins belonging to the enzyme family of protein tyrosine phosphatases (PTPs) act as inhibitors of insulin signaling. Protein tyrosine phosphatase receptor type J (PTPRJ) has been identified as a negative regulator in insulin signaling in the periphery. However, the impact of PTPRJ on insulin signaling and its functional role in neuronal cells is largely unknown. Therefore, we generated a <i>Ptprj</i> knockout (KO) cell model in the murine neuroblast cell line Neuro2a by CRISPR-Cas9 gene editing. <i>Ptprj</i> KO cells displayed enhanced insulin signaling, as shown by increased phosphorylation of the insulin receptor (INSR), IRS-1, AKT, and ERK1/2. Further, proximity ligation assays (PLA) revealed both direct interaction of PTPRJ with the INSR and recruitment of this phosphatase to the receptor upon insulin stimulation. By RNA sequencing gene expression analysis, we identified multiple gene clusters responsible for glucose uptake and metabolism, and genes involved in the synthesis of various lipids being mainly upregulated under PTPRJ deficiency. Furthermore, multiple Ca²⁺ transporters were differentially expressed along with decreased protein biosynthesis. This was accompanied by an increase in endoplasmic reticulum (ER) stress markers. On a functional level, PTPRJ deficiency compromised cell differentiation and neurite outgrowth, suggesting a role in nervous system development. Taken together, PTPRJ emerges as a negative regulator of central insulin signaling, impacting neuronal metabolism and neurite outgrowth.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"36 12","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jne.13446","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional diversity along the anteroposterior axis of the ventromedial hypothalamus","authors":"Nicolas Gutierrez‐Castellanos, Inês C. Dias, Basma F. A. Husain, Susana Lima","doi":"10.1111/jne.13447","DOIUrl":"https://doi.org/10.1111/jne.13447","url":null,"abstract":"Innate behaviors ensure animal survival and reproductive success. Defending their territory, escaping from predators or mating with a sexual partner, are fundamental behaviors determining the ecological fitness of individuals. Remarkably, all these behaviors share a common neural substrate, as they are under the control of the ventromedial hypothalamus (VMH). Decades of research have contributed to understanding the exquisite diversity of functional ensembles underlying the wide array of functions that the VMH carries out. These functional ensembles are usually distributed throughout the dorsoventral and mediolateral axes of this nucleus. However, increasing evidence is bringing to attention the functional diversity of the VMH across its anteroposterior axis. In this review, we will overview our current understanding of how different ensembles within the VMH control a wide array of animal behaviors, emphasizing the newly discovered roles for its anterior subdivision in the context of conspecific self‐defense.","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"254 1","pages":"e13447"},"PeriodicalIF":3.2,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208509","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 in high-grade digestive neuroendocrine neoplasms (NET G3 and NEC)","authors":"Halfdan Sorbye,&nbsp;Grace Kong,&nbsp;Simona Grozinsky-Glasberg,&nbsp;Jonathan Strosberg","doi":"10.1111/jne.13443","DOIUrl":"10.1111/jne.13443","url":null,"abstract":"<p>Peptide receptor radionuclide therapy (PRRT) has been primarily studied in low and intermediate-grade digestive neuroendocrine tumors (NET G1-G2). The documentation of a similar benefit for high-grade digestive neuroendocrine neoplasms (NEN) has been limited. This review evaluates the use of PRRT for high-grade digestive NEN (well-differentiated NET G3 and poorly differentiated neuroendocrine carcinomas [NEC]). We identified one phase III trial and seven retrospective studies reporting specifically on PRRT outcome of &gt;10 digestive high-grade NEN patients. The retrospective single-arm studies indicate a benefit for PRRT in NET G3. The randomized phase III NETTER-2 trial demonstrates major PFS superiority of PRRT versus somatostatin analog therapy as the first-line treatment for the NET G3 subgroup. PRRT can now be considered a potential first-line treatment for somatostatin receptor-positive NET G3 patients, but whether it should be the first-line standard of care for all NET G3 patients is still not clarified. For NEC, scarce data are available, and pathologic distinction between NEC and NET G3 can be difficult when Ki-67 is below 55%. PRRT could be considered as a treatment for refractory NEC in very selected cases when there is a high uptake on somatostatin receptor imaging, Ki-67 is below 55%, and there is no rapid tumor progression.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"37 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jne.13443","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gastric neuroendocrine tumors: 20-Year experience in a reference center","authors":"Davide Ravizza,&nbsp;Mariangela Giunta,&nbsp;Isabella Sala,&nbsp;Vincenzo Bagnardi,&nbsp;Darina Tamayo,&nbsp;Giuseppe de Roberto,&nbsp;Cristina Trovato,&nbsp;Ivana Bravi,&nbsp;Pietro Soru,&nbsp;Margherita Maregatti,&nbsp;Eleonora Pisa,&nbsp;Emilio Bertani,&nbsp;Guido Bonomo,&nbsp;Francesca Spada,&nbsp;Fazio Nicola","doi":"10.1111/jne.13440","DOIUrl":"10.1111/jne.13440","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Few studies have been published on the long-term outcomes of patients with gastric neuroendocrine tumors (gNETs). We analyzed their management over a two-decade period, focusing on endoscopic and clinical outcomes. Clinical, laboratory, endoscopic, surgical, and histopathological data from Types 1 and 3 gNETs histologically diagnosed between March 2000 and December 2021 at the European Institute of Oncology (IEO, Milan) were retrospectively collected. Sixty-nine patients were included (60 Type 1, 9 Type 3): 53 (77%) were treated endoscopically, 6 (9%) surgically, and 10 (14%) did not receive any treatment. Overall, 293 lesions were removed endoscopically: 74% by forceps, 20% by endoscopic mucosal resection (EMR), and 5% by endoscopic submucosal dissection (ESD). No differences were observed between EMR and ESD in terms of complete resection rate (<i>p</i> value = .50) and complications rate (<i>p</i> value = .084). The median follow-up period was 5.8 years (range: 0.3–20.5), during which no gNET-related deaths were observed. Metachronous gNETs developed in 60% of patients with Type 1 gNET. Six patients with lymph node metastases (LNM) were younger (<i>p</i> value = .006) and had larger lesions (<i>p</i> value &lt;.001) than patients without LNM. Most Type 1 gNETs were successfully excised using forceps, with EMR and ESD being equally effective. The presence of incomplete resection was not associated with a worse prognosis, which remains excellent in this highly recurrent disease. Younger age and a size ≥10 mm were associated with an increased risk of LNM.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Clinical Trial Registration</h3>\u0000 \u0000 <p>Project code UID 2854.</p>\u0000 </section>\u0000 </div>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"36 12","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080550","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":"Hypothalamic obesity: Epidemiology in rare sellar/suprasellar tumors—A German claims database analysis","authors":"Julian Witte,&nbsp;Bastian Surmann,&nbsp;Manuel Batram,&nbsp;Markus Weinert,&nbsp;Mathias Flume,&nbsp;Nicolas Touchot,&nbsp;Julia Beckhaus,&nbsp;Carsten Friedrich,&nbsp;Hermann L. Müller","doi":"10.1111/jne.13439","DOIUrl":"10.1111/jne.13439","url":null,"abstract":"<p>Hypothalamic obesity (HO) is defined as abnormal weight gain resulting in severe persistent obesity due to physical, tumor- and/or treatment-related damage to the hypothalamus. HO epidemiology is poorly understood. We developed a database algorithm supporting the standardized identification of tumor/treatment-related HO (TTR-HO) patients. The algorithm is used to estimate incidence rates of TTR-HO patients in the German healthcare context from a representative claims database (<i>n</i> = 5.42 million) covering 2010–2020. Patients were identified based on surgery/radiotherapy procedures and HO-associated tumor diagnoses (<i>n</i> = 3976). HO was defined by incident obesity and validated based on incident diabetes insipidus diagnoses and desmopressin prescription within a 12-month period after surgery/radiotherapy. Uncertainty due to algorithm definitions is explored in sensitivity analyses. Estimated annual incidence of TTR-HO in Germany is between 0.7 and 1.7 cases per 1,000,000 persons (2019 prevalence: <i>n</i> = 1262 patients). With observed cases in all age groups, two HO-incidence peaks are identified: children/young adults aged 10–24 years and adults aged 40–44 years. Most frequent HO-validated tumor diagnoses are benign sellar/suprasellar tumors (6.1/1,000,000 persons over 9 years), including tumors of the craniopharyngeal duct (1.3/1,000,000), neoplasms of the pituitary gland (4.1/1,000,000), and nonspecific brain tumors of endocrine glands (2.4/1,000,000). This is the first real-world database analysis of TTR-HO epidemiology, refining current estimates of HO epidemiology and early patient identification. A more comprehensive characterization of patients with HO as well as a better understanding of clinical implications will be crucial in developing optimal treatment strategies to improve patient outcomes.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"36 12","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jne.13439","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estrogenic regulation of hippocampal inhibitory system across lifespan.","authors":"Pablo Méndez, Rut de la Vega-Ruiz, Alberto Montes-Mellado","doi":"10.1111/jne.13441","DOIUrl":"https://doi.org/10.1111/jne.13441","url":null,"abstract":"<p><p>Estrogens produced in peripheral tissues and locally in the brain are potent neuromodulators. The function of the hippocampus, a brain region essential for episodic memory and spatial navigation, relies on the activity of ensembles of excitatory neurons whose activity is temporally and spatially coordinated by a wide diversity of inhibitory neurons (INs) types. Over the last years, we have accumulated evidence that indicates that estrogens regulate the function of hippocampal INs through different mechanisms, including transcriptional regulation and rapid nongenomic signaling. Here, we argue that the well-documented influence of estrogens on episodic memory may be related to the actions of local and peripheral estrogens on the heterogenous populations of hippocampal INs. We discuss how physiological changes in peripheral sex hormone levels throughout lifespan may interact with local brain sources to regulate IN function at different stages of life, from early hippocampal development to the aging brain. We conclude that considering INs as mediators of sex hormone actions in the hippocampus across the healthy life span will benefit our understanding of sex-biased neurodevelopmental disorders and physiological aging.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":" ","pages":"e13441"},"PeriodicalIF":3.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982561","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":"Understanding negative feedback: Changes in high-molecular-weight adrenocorticotropic hormone in adrenocorticotropic hormone-independent Cushing's syndrome","authors":"Yuto Ichinose,&nbsp;Mei Nakatsuji,&nbsp;Hironori Bando,&nbsp;Masaaki Yamamoto,&nbsp;Maki Kanzawa,&nbsp;Kei Yoshino,&nbsp;Hidenori Fukuoka,&nbsp;Wataru Ogawa","doi":"10.1111/jne.13438","DOIUrl":"10.1111/jne.13438","url":null,"abstract":"<p>Cushing's syndrome is characterized by chronic glucocorticoid oversecretion and diverse clinical manifestations. Distinguishing between adrenocorticotropic hormone (ACTH)-independent and ACTH-dependent forms is crucial for determining treatment options. Plasma ACTH levels aid in the differential diagnosis, with undetectable or low levels suggesting ACTH-independent hypercortisolemia. ACTH is derived from pro-opiomelanocortin, and its processing involves prohormone convertase 1/3. High-molecular-weight ACTH is generally found in ACTH-producing pituitary tumors and ectopic ACTH syndrome. The mechanism of negative feedback and the process of high-molecular-weight ACTH alternation during ACTH-independent Cushing's syndrome remain unclear. A 40-year-old woman with hypertension and multiple fractures developed symptoms suggestive of Cushing's syndrome. Computed tomography revealed a left adrenocortical tumor along with atrophy of the right adrenal gland. ACTH levels were undetectable at the previous clinic, indicating ACTH-independent Cushing's syndrome. However, subsequent measurements at our hospital revealed non-suppressed ACTH (18.1 pg/mL), prompting further investigation. Gel exclusion chromatography confirmed the presence of high-molecular-weight ACTH. Metyrapone treatment decreased the cortisol levels. In this situation, in which ACTH levels should be elevated, a decrease in high-molecular-weight ACTH levels was observed. Histological findings revealed cortisol-producing adenoma without ACTH expression. This case highlights the importance of assay differences in evaluating ACTH concentrations and introduces a novel finding of circulating high-molecular-weight ACTH. The observed decline in high-molecular-weight ACTH levels suggests a potential time lag in the negative feedback within the hypothalamic–pituitary–adrenal axis exhibited by glucocorticoids. This temporal aspect of the regulation of ACTH-related molecules warrants further exploration to enhance our understanding of the hypothalamic–pituitary–adrenal axis feedback mechanism.</p>","PeriodicalId":16535,"journal":{"name":"Journal of Neuroendocrinology","volume":"36 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971313","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}