Journal Of Neuroendocrinology[JOURNAL]
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200 papers
Effects of wintering under methylmercury exposure on spring reproductive onset in song sparrows (Melospiza melodia).
Bottini CLJ, Henry CJ, MacDougall-Shackleton SA
J Neuroendocrinol · 2025 Jun · PMID 40258682 · Full text
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 winte...
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.
Proteomic analysis of plasma proteins during fentanyl withdrawal in ovariectomized female rats with and without estradiol.
Sinclair P, Dhanjal NS, Towers EB … +2 more , Lynch WJ, Kabbani N
J Neuroendocrinol · 2025 Aug · PMID 40254411 · Full text
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 cr...
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.
Neuroendocrine mechanisms responsible for elevated gonadotrophin-releasing hormone and luteinising hormone pulses in polycystic ovary syndrome.
Moore AM
J Neuroendocrinol · 2025 Aug · PMID 40251138 · Full text
Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in premenopausal individuals with ovaries worldwide. Despite the diagnostic features of anovulation, ovarian cysts, and hyperandrogenemia,...
Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in premenopausal individuals with ovaries worldwide. Despite the diagnostic features of anovulation, ovarian cysts, and hyperandrogenemia, which indicate that ovary dysfunction is the cause of the syndrome, changes in central neuroendocrine circuits are a significant cause of PCOS pathology. Specifically, cells in the hypothalamus have a diminished ability to transmit negative feedback signals from gonadal sex steroid hormones to gonadotropin-releasing hormone (GnRH) neurons. This results in an elevated frequency of pulsatile hypothalamic GnRH and pituitary luteinizing hormone (LH) secretion, leading to ovarian hyperandrogenism and ovulatory dysfunction. In recent years, preclinical research in animal models has rapidly advanced our understanding of the neural mechanisms underlying GnRH pulse generation with the identification of KNDy cells-a unique cell population in the hypothalamus expressing the neuropeptides kisspeptin, neurokinin B and dynorphin. As a result, therapeutics targeting KNDy cell signaling have emerged as a promising avenue for treating GnRH/LH hypersecretion in PCOS patients. However, the precise central changes underpinning impaired negative feedback regulation of GnRH pulse generation in PCOS patients are still unclear. Evidence from both the clinic and animal models suggests that changes in the regulation of KNDy cells may be directly responsible for elevated GnRH and LH pulse frequency in PCOS. However, other cell populations regulating GnRH secretion may also be involved. This review provides an overview of our current understanding of the aetiology and contribution of neuroendocrine dysfunction in PCOS pathology. It also examines the evidence for neural mechanisms underlying GnRH/LH hypersecretion, which may serve as central targets in developing novel treatments. Finally, this review highlights key knowledge gaps that are hindering the development of preventive and curative interventions.
Increase of astrocyte apposition on GnRH neurons in early puberty onset induced by high fat diet.
Rodrigues-Santos I, Dos-Santos RC, de Jesus A … +6 more , Flores RA, Rosales RRC, Caliman IF, Anselmo-Franci JA, Antunes-Rodrigues J, Elias LLK
J Neuroendocrinol · 2025 Aug · PMID 40235166 · Full text
Puberty onset is driven by the activation of GnRH-secreting neurons and can be advanced by obesity. Astrocytes are dynamic cells that react to changes in the central nervous system environment and participate in the regu...
Puberty onset is driven by the activation of GnRH-secreting neurons and can be advanced by obesity. Astrocytes are dynamic cells that react to changes in the central nervous system environment and participate in the regulation of energy balance and reproduction. To assess the interaction of GnRH neurons and hypothalamic astrocytes during the puberty transition in HFD-treated mice, female and male mice were divided into three groups according to the diet offered at weaning: 42% high-fat diet (HFD42%), 60% high-fat diet (HFD60%), or regular diet (CHOW). The effects of HFD on reproductive tissue and fat content during the prepubertal and pubertal transition were assessed. The impact of HFD on astrocyte interaction with GnRH neurons in the medial preoptic area (MPOA) and arcuate/median eminence (ARC/ME) was assessed. HFD anticipated the first signs of puberty in both male and female mice. Furthermore, there was an increase in adipose and reproductive tissue content in early pubertal animals. Remarkably, the anticipation of puberty onset in females treated with HFD was associated with an increase in the astrocyte apposition on GnRH neurons in the MPOA. Also, there was an increase in astrocyte apposition on GnRH neurons and their fiber projections in the ARC/ME. This study suggests that the HFD-induced anticipation of puberty seems to be, at least partially, mediated by an increase in the morphological association between astrocytes and GnRH neurons in both the MPOA and ARC/EM, which may increase the excitability of GnRH neurons.
Prognostic value of clinical parameters and exosomal lncRNA NEAT1_1 in MEN1-related non-functioning pancreatic neuroendocrine tumors.
Manoharan J, Albers M, Khizanishvili N … +10 more , Krasser-Gercke N, Schmitt M, Mintziras I, Wächter S, Rinke A, Gao Y, Bartsch JW, Jesinghaus M, Di Fazio P, Bartsch DK
J Neuroendocrinol · 2025 Aug · PMID 40170567 · Full text
Non-functioning pancreatic neuroendocrine tumors (NF-pNETs) significantly contribute to the premature death of multiple endocrine neoplasia type 1 (MEN1) patients. Reliable prognostic markers are not yet available. Micro...
Non-functioning pancreatic neuroendocrine tumors (NF-pNETs) significantly contribute to the premature death of multiple endocrine neoplasia type 1 (MEN1) patients. Reliable prognostic markers are not yet available. MicroRNAs (miRNA) and long-non-coding (lnc) RNAs, transported by extracellular vesicles, are emerging as new prognostic tools. This study aimed to analyze the clinical characteristics, the exosomal-miRNA 451 (exo-miR451) and the lnc-RNA nuclear paraspeckle assembly transcript 1 (NEAT1_1, 3.7 kB) in the mild and aggressive courses of MEN1-NFpNET disease. Patient characteristics were assessed regarding an aggressive course of disease. In addition, exo-miR451 and exo-lnc-NEAT1_1 expression levels were quantified in serum by RT-qPCR and correlated with clinical data. Immunohistochemistry results of STAT3 (signal transducer and activator of transcription 3), regulated by NEAT1, were performed in NF-pNET tissue and correlated with exo-lnc-NEAT1_1 expression. Among 66 MEN1 patients with NF-pNETs, 13 (20%) had an aggressive disease course. No significant differences in patient characteristics were observed between those with aggressive (n = 13) and mild (n = 53) disease (all p > .5). Exosomal miRNA-451 was dysregulated in 55% (n = 23) of cases, showing a trend toward higher upregulation in the aggressive group (36% vs. 19%), although this difference was not statistically significant (p = .215). Exo-NEAT1_1 was overexpressed in 42% (16/38) of patients, without significant differences between groups (p = .0523). However, exo-NEAT1_1 expression strongly correlated with STAT3 immunohistochemical staining (p = .001). Although no prognostic marker could be identified, we show for the first time that the STAT3-NEAT1 pathway plays a role in MEN1-associated NF-pNET tumorigenesis.
Correction to abstract title "Efficacy and safety of [177Lu]Lu-edotreotide vs. everolimus in patients with grade 1 or grade 2 gastroenteropancreatic neuroendocrine tumours: COMPETE phase 3 trial".
J Neuroendocrinol · 2025 Aug · PMID 40170566 · Publisher ↗
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Role of membrane estrogen receptor alpha on the negative feedback of estrogens on luteinizing hormone secretion.
Faure MC, Corona R, Vandries L … +5 more , Deconinck C, Lenfant F, Gérard C, Foidart JM, Cornil CA
J Neuroendocrinol · 2025 Aug · PMID 40147496 · Publisher ↗
Estrogen receptor alpha (ERα) is critical for reproduction, but the relative contributions of its nuclear and membrane signaling are unclear.The present study investigated the role of membrane ERα (mERα) using two comple...
Estrogen receptor alpha (ERα) is critical for reproduction, but the relative contributions of its nuclear and membrane signaling are unclear.The present study investigated the role of membrane ERα (mERα) using two complementary approaches: a mouse model lacking mERα signaling (C451A-ERα mice) and estetrol (E), a natural estrogen described to prevent membrane ERα activation in different cell types. While ovariectomy (OVX) induced a comparable luteinizing hormone (LH) increase in both wild-type and C451A-ERα females, C451A-ERα females failed to respond to chronic estradiol (E) (1 μg) exposure, indicating dysregulated negative feedback. This lack of LH regulation in C451A-ERα females was mirrored by an absence of change in the number of neurons immunoreactive (ir) for kisspeptin (Kp) in both the rostral periventricular area of the third ventricle (RP3V) and the arcuate nucleus (ARC), for progesterone receptor (PR)-ir nuclei in the preoptic area and hypothalamus, and for neurokinin 3 receptor (NKR) in the ARC. Interestingly, increasing the dose of E to 5 μg restored normal negative feedback and normal numbers of Kp-ir neurons and PR-ir nuclei, but not the surface covered by Kp-ir fibers and the number of NKR-ir neurons in the ARC. By contrast, E mimicked the negative feedback of E on circulating LH in OVX WT females following both acute and chronic treatment and potentiated rather than blocked the effects of E when administered along with it. E also mimicked the stimulatory effects of E on the number of PR-ir nuclei in several preoptic and hypothalamic regions and the percentage of area covered by Kp-ir material in the ARC, as well as its inhibitory action on the number of Kp-ir neurons in the ARC. Therefore, the C451A-ERα mutation interferes with the control of the negative feedback through distinct mechanisms differing by their dose-dependency to E. By contrast, E mimicked all effects of E on the negative feedback and the associated neural circuits, indicating that E acts as a weak ERα agonist in this context. Together, these results suggest that C451A-ERα modifies the sensitivity to E, impacting the negative feedback of E on LH regulation.
The effects of feminization hormone therapy on the brain of transgender women: A hypothesis.
Zubiaurre-Elorza L, Uribe C, Marcos A … +5 more , Fernández R, Pásaro E, Del Cerro MCR, Burke SM, Guillamon A
J Neuroendocrinol · 2025 Jul · PMID 40145530 · Publisher ↗
Gender-affirming hormone therapy (GAHT) is a medical treatment used to help transgender individuals align their physical appearance with their gender identity. GAHT in transgender women (TW) has been found to lead to a r...
Gender-affirming hormone therapy (GAHT) is a medical treatment used to help transgender individuals align their physical appearance with their gender identity. GAHT in transgender women (TW) has been found to lead to a reduction in brain tissue with an expansion of the ventricles. We discuss an animal model studying the effects of GAHT that suggests dehydration of brain tissue and an alteration in the relative concentration of brain metabolites. We hypothesize that estradiol, acting on astrocytes, alters cerebral blood flow, water metabolism, and metabolite concentration and argue that these changes could explain the higher risk of stroke observed in GAHT-treated TW compared to untreated cisgender men. Future studies should clarify the mechanisms underlying the brain tissue changes induced by GAHT.
Early testosterone exposure during development advances myelination and affects neurogenesis of the vocal control motor path in male zebra finches (Taeniopygia guttata).
Diez A, Young KG, MacDougall-Shackleton SA
J Neuroendocrinol · 2025 Jun · PMID 40122144 · Full text
Birdsong learning and production is mediated through a vocal control circuit that exhibits ubiquitous and profound sex differences. In zebra finches (Taeniopygia guttata) only males sing, and sex differences in both neur...
Birdsong learning and production is mediated through a vocal control circuit that exhibits ubiquitous and profound sex differences. In zebra finches (Taeniopygia guttata) only males sing, and sex differences in both neuroanatomy and myelination of this circuit emerge during the first 3 months of life as song learning is taking place. Song crystallization occurs at the onset of sexual maturity, at a time when neuron recruitment to the vocal control region HVC is reduced and the myelination of the projection from HVC to the motor nucleus RA (robust nucleus of arcopallium) rapidly develops. Prior work demonstrated that experimental testosterone treatment early in song development disrupted song learning, potentially by leading to premature song crystallization, but the effects of testosterone on neurogenesis and myelination of the vocal control system are little studied. We implanted male zebra finches with blank or testosterone pellets around Day 35 at the onset of the sensorimotor phase of song development. We examined the effects of early testosterone treatment on song development, myelination, and neurogenesis (doublecortin labeled cells) of the motor path of the vocal control circuit (HVC to RA). We also quantified singing consistency at two ages in adulthood. Testosterone treatment accelerated changes in myelin within HVC and in the projection from HVC to RA and accelerated age-related changes in doublecortin-labeled cells in HVC. Song and syllable stereotypy increased with age, but we did not detect an effect of hormone treatment. These results are consistent with the hypothesis that the testosterone exposure during development initiates processes that normally occur at sexual maturity, including changes in neurogenesis and myelination of the motor control path of the vocal control system.
Seasonal regulation of Tsh-β, Dio2, Dio3, and GnRH-I mRNA expressions in Eurasian tree sparrow (Passer montanus) under natural conditions.
Kataki B, Dixit AS
J Neuroendocrinol · 2025 Jun · PMID 40108871 · Publisher ↗
Seasonal transitions in avian reproductive cycles are governed by neuroendocrine adaptability. The molecular mechanisms behind seasonal regulation are still not fully understood in many species and remain an important ar...
Seasonal transitions in avian reproductive cycles are governed by neuroendocrine adaptability. The molecular mechanisms behind seasonal regulation are still not fully understood in many species and remain an important area of ongoing research. Despite recognizing the importance of regulatory genes, gaps persist in comprehending the exact molecular processes that control the transitions between different reproductive phases. We investigated the expression patterns of Tsh-β (Thyroid-stimulating hormone subunit beta), Dio2 (Iodothyronine deiodinase 2), Dio3 (Iodothyronine deiodinase 3), and GnRH-I (Gonadotropin-releasing hormone I) mRNAs in regulating reproduction in both sexes of the Eurasian tree sparrow (Passer montanus). Adult tree sparrows (n = 4 for each sex) were procured from the wild, and mRNA expression of Tsh-β, Dio2, Dio3, and GnRH-I, along with gonadal size and body weight, was examined on a monthly basis for 1 year. Results revealed distinct annual cycles of Tsh-β, Dio2, Dio3, and GnRH-I mRNA expression and gonadal size in both sexes. Significantly higher expressions of Tsh-β, Dio2, and GnRH-I mRNA were observed during the breeding phase (April-May), while Dio3 expression was reported higher during the non-breeding phase. The synchronization in the pattern of increase in the Tsh-β, Dio2, and GnRH-I during the breeding phase is associated with gonadal growth, suggesting their potential involvement in regulating seasonal reproduction in tree sparrows. Thus, the control of the reproductive cycle in tree sparrows involves the actions of Tsh-β and Dio2/Dio3 leading to the activation and deactivation of GnRH-I via the HPG (hypothalamic-pituitary-gonadal) axis.
Corticosteroid-regulated gene transcription in SH-SY5Y-derived neurons: Insights into the mineralocorticoid and glucocorticoid receptor-mediated response.
Lugenbühl JF, Snijders C, Pernia CD … +3 more , Estruch MS, Kenis G, Daskalakis NP
J Neuroendocrinol · 2025 Jul · PMID 40108866 · Publisher ↗
Post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) are debilitating stress-related psychiatric disorders that can develop following exposure to traumatic events or chronic stress in some individual...
Post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) are debilitating stress-related psychiatric disorders that can develop following exposure to traumatic events or chronic stress in some individuals. The neurobiological processes leading to disease remain largely unknown. Among others, these disorders are characterized by a dysregulated hypothalamic-pituitary-adrenal axis, which is regulated by the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). This leads to altered downstream corticosteroid-induced gene expression. In vitro models are promising tools to investigate specific neurobiological underpinnings of the stress response in the brain. Here, we investigated the suitability of SH-SY5Y-derived neurons as a cost-efficient system to study the role of GR and MR in the neuronal stress response. SH-SY5Y-derived neurons were characterized, exposed to corticosteroids, and analyzed on transcriptomic and proteomic levels. We show that (i) these neurons express sufficient and seemingly functional GR and MR to allow the study of corticosteroid-induced transcription, (ii) three corticosteroids cortisol, dexamethasone, and aldosterone, induced similar transcriptomic effects, (iii) the antagonist spironolactone mildly attenuated the effects of dexamethasone in FKBP5, DUSP1, and SUPV3L1. Mifepristone did not significantly alter the effect of aldosterone. (iv) Integrating transcriptomic alterations of these corticosteroid-exposed neurons with those of iPSC-derived neurons exposed to dexamethasone showed concordant corticosteroid-induced effects in the two in vitro systems. To determine translational validity, we compared the gene expression in these neurons with the transcriptome of postmortem brain samples from individuals with PTSD and MDD, yielding stronger negative correlations of corticosteroid effects in SH-SY5Y-derived neurons with PTSD signatures than with MDD signatures. Upon further refinement and validation, SH-SY5Y-derived neurons may serve as a simplistic tool to study neuronal corticosteroid-induced gene expression and the implicated molecular networks around GR and MR. Strengthening our insight into these receptors' functions improves our understanding of the hypothalamic-pituitary-adrenal axis, which is commonly altered in stress-related psychiatric disorders such as PTSD and MDD.
Comprehensive chemoanatomical mapping, and the gonadal regulation, of seven kisspeptin neuronal populations in the mouse brain.
Hernández VS, Zetter MA, Hernández-Pérez OR … +5 more , Hernández-González R, Camacho-Arroyo I, Millar RP, Eiden LE, Zhang L
J Neuroendocrinol · 2025 May · PMID 40102056 · Full text
Kisspeptinergic signaling is well-established as crucial for the regulation of reproduction, but its potential broader role in brain function is less understood. This study investigates the distribution and chemotyping o...
Kisspeptinergic signaling is well-established as crucial for the regulation of reproduction, but its potential broader role in brain function is less understood. This study investigates the distribution and chemotyping of kisspeptin-expressing neurons within the mouse brain. RNAscope single, dual, and multiplex in situ hybridization methods were used to assess kisspeptin mRNA (Kiss1) expression and its co-expression with other neuropeptides, excitatory and inhibitory neurotransmitter markers, and sex steroid receptors in wild-type intact and gonadectomized young adult mice. Seven distinct kisspeptin neuronal chemotypes were characterized, including two novel kisspeptin-expressing groups described for the first time, that is, the Kiss1 population in the ventral premammillary nucleus and the nucleus of the solitary tract. Kiss1 mRNA was also observed to localize in both somatic and dendritic compartments of hypothalamic neurons. High androgen receptor expression and changes in medial amygdala and septo-hypothalamic Kiss1 expression following GDX in males, but not in females, suggest a role for androgen receptors in regulating kisspeptin signaling. This study provides a detailed chemoanatomical map of kisspeptin-expressing neurons, highlighting their potential functional diversity. The discovery of a new kisspeptin-expressing group and gonadectomy-induced changes in Kiss1 expression patterns suggest broader roles for kisspeptin in brain functions beyond those of reproduction.
Hypotheses in light detection by vertebrate ancient opsin in the bird brain.
Stevenson TJ, Liddle TA, Meddle SL … +4 more , Pérez JH, Peirson SN, Foster RG, Majumdar G
J Neuroendocrinol · 2025 Jun · PMID 40090886 · Full text
Extra-retinal photoreception is common across fish and avian species. In birds, the hypothalamus contains non-visual photoreceptors that detect light and regulate multiple endocrine systems. To date, light-dependent cont...
Extra-retinal photoreception is common across fish and avian species. In birds, the hypothalamus contains non-visual photoreceptors that detect light and regulate multiple endocrine systems. To date, light-dependent control of seasonal reproduction is one of the most well-studied systems that require deep brain photoreception. However, the precise photoreceptor(s) that detect light and the neuroendocrine connection between opsin-expressing cells and the gonadotropin-releasing hormone-1 (GnRH1) system remain poorly defined. In the past couple of decades, two opsin molecules have been proposed to link light detection with seasonal reproduction in birds: neuropsin (Opn5) and vertebrate ancient opsin (VA opsin). Only VA opsin is expressed in GnRH1 cells and has an absorption spectrum that matches the action spectrum of the avian photoperiodic reproductive response. This perspective describes how the annual change in daylength, referred to as photoperiod, regulates the neuroendocrine control of seasonal reproduction. The opsin genes are then outlined, and the cellular phototransduction cascade is described, highlighting the common feature of hyperpolarization in response to light stimulation. We then discuss the latest evidence using short-hairpin RNA to temporarily knock down VA opsin and Opn5 on transcripts involved in the neuroendocrine regulation of reproduction. Based on emerging data, we outline three theoretical scenarios in which VA opsin might regulate GnRH1 synthesis and release in birds. The models proposed provide a series of testable hypotheses that can be used to improve our understanding of avian light detection by VA opsin or other opsin-expressing cells in the brain.
Kisspeptin fiber and receptor distribution analysis suggests its potential role in central sensorial processing and behavioral state control.
Zhang L, Hernández VS, Zetter MA … +5 more , Hernández-Pérez OR, Hernández-González R, Camacho-Arroyo I, Eiden LE, Millar RP
J Neuroendocrinol · 2025 May · PMID 40065551 · Full text
Kisspeptin (KP) signaling in the brain is defined by the anatomical distribution of KP-producing neurons, their fibers, receptors, and connectivity. Technological advances have prompted a re-evaluation of these chemoanat...
Kisspeptin (KP) signaling in the brain is defined by the anatomical distribution of KP-producing neurons, their fibers, receptors, and connectivity. Technological advances have prompted a re-evaluation of these chemoanatomical aspects, originally studied in the early years after the discovery of KP and its receptor Kiss1r. Previously, we characterized (Hernández et al. bioRxiv 2024) seven KP neuronal populations in the mouse brain at the mRNA level, including two novel populations, and examined their response to gonadectomy. In this study, we mapped KP fiber distribution in rats and mice using immunohistochemistry under intact as well as short- and long-term post-gonadectomy conditions. Kiss1r mRNA expression was examined via RNAscope, in relation to vesicular GABA transporter (Slc32a1) in whole mouse brain, and to KP and vesicular glutamate transporter 2 (Slc17a6), Kiss1, and Slc32a1 in hypothalamic RP3V and arcuate regions. We identified KP fibers in 118 brain regions, primarily in extra-hypothalamic areas associated with sensorial processing and behavioral state control. KP-immunoreactive fiber density and distribution were largely unchanged by gonadectomy. Kiss1r was expressed prominently in sensorial and state control regions such as the septal nuclei, the suprachiasmatic nucleus, locus coeruleus, hippocampal layers, thalamic nuclei, and cerebellar structures. Co-expression of Kiss1r and Kiss1 was observed in hypothalamic neurons, suggesting both autocrine and paracrine KP signaling mechanisms. These findings enhance our understanding of KP signaling beyond reproductive functions, particularly in sensorial processing and behavioral state regulation. This study opens new avenues for investigating KP's role in controlling complex physiological processes, including those unrelated to reproduction.
Peptide receptor radionuclide therapy with somatostatin analogs beyond gastroenteropancreatic neuroendocrine tumors.
Santo G, di Santo G, Cicone F … +1 more , Virgolini I
J Neuroendocrinol · 2025 Mar · PMID 40064181 · Full text
First isolated by Brazeau et al. in 1972, somatostatin (SST) is a neuropeptide known for regulating various signaling pathways through its specific cell surface receptors. Somatostatin receptors (SSTRs) comprise a family...
First isolated by Brazeau et al. in 1972, somatostatin (SST) is a neuropeptide known for regulating various signaling pathways through its specific cell surface receptors. Somatostatin receptors (SSTRs) comprise a family of five G protein-coupled receptors that are widely distributed across the human body and are expressed by various tumor types. The growing understanding of their clinical potential led to the introduction of both cold and radiolabeled somatostatin analogs (SSAs), which have revolutionized the management of several cancers, especially neuroendocrine tumors. As a direct consequence, advances in peptide receptor radionuclide therapy (PRRT) over the last 30 years led to the approval of Lu-DOTATATE for the treatment of gastroenteropancreatic neuroendocrine tumors (GEPNETs). Theoretically, any cancer patients whose tumors express SSTR, as demonstrated in vivo through SSTR-based molecular imaging, could be candidates for PRRT, especially those with limited treatment options. However, evidence on the efficacy of PRRT in non-GEPNET SSTR-expressing tumors is limited, and mainly derived from small retrospective studies. Given the limited therapeutic options for advanced/metastatic patients, there is a clear need for randomized trials to formally approve PRRT with SSAs for patients who may benefit from this treatment, particularly in certain types of neuroendocrine neoplasms such as lung carcinoids, paragangliomas, and meningiomas, where high rates of disease control (up to 80%) can be achieved. In addition, emerging evidence supports the potential of combination therapies, alpha emitters, and non-SSTR-based radionuclide therapy in tumors beyond GEPNET. This review aims to provide a comprehensive overview of PRRT's role in cancers beyond GEPNET, exploring new possibilities and future directions for most SSTR highly expressing tumors.
Prostaglandin synthesis mediates the suppression of arcuate Kiss1 neuron activation and pulsatile luteinizing hormone secretion during immune/inflammatory stress in female mice.
Carrasco RA, Jang J, Jung J … +3 more , McCosh RB, Kreisman MJ, Breen KM
J Neuroendocrinol · 2025 May · PMID 40058772 · Full text
Stress induces a series of compensatory mechanisms with the objective of restoration or adaptation of physiological function. A common casualty of the response to stress is impaired reproduction via the inhibition of pul...
Stress induces a series of compensatory mechanisms with the objective of restoration or adaptation of physiological function. A common casualty of the response to stress is impaired reproduction via the inhibition of pulsatile luteinizing hormone (LH) secretion; however, how stressors convey LH inhibition remains unclear and may be dependent on stress type. Immune/inflammatory stress, modeled with peripheral lipopolysaccharide (LPS) exposure, induces a systemic inflammatory response which may contrast with the neural mechanisms employed by psychosocial stressors. We examined the suppressive effect of LPS versus psychosocial stress, modeled with restraint, on pulsatile LH secretion and investigated the neural mechanisms underlying LPS-induced LH suppression in ovariectomized (OVX) female mice. We observed that both LPS and restraint significantly suppressed mean LH concentrations; however, the dynamics of pulse suppression displayed stress-type dependency. LPS induced a reduction in both LH pulse frequency and amplitude, whereas restraint suppressed LH pulse frequency without compromising pulse amplitude. Next, we investigated the mediatory role of immune/inflammatory signaling for LPS to impair LH secretion and upstream arcuate Kiss1 cell function. Peripheral administration of flurbiprofen, a prostaglandin synthesis inhibitor, blocked the suppressive effect of LPS on LH pulse frequency and amplitude. Interestingly, flurbiprofen only partially prevented the suppressive effect of LPS on arcuate Kiss1 cell activity, as measured by c-Fos expression. These data demonstrate that immune/inflammatory stress inhibits the activity of the LH pulse generator, in part, via a prostaglandin-dependent pathway and supports the role of differential neural mechanisms mediating LH pulse suppression during stress.
Selective changes in vasopressin neurons and astrocytes in the suprachiasmatic nucleus of Prader-Willi syndrome subjects.
Correa-da-Silva F, Berkhout JB, Schouten P … +11 more , Sinnema M, Stumpel CTRM, Curfs LMG, Höybye C, Mahfouz A, Meijer OC, Pereira AM, Fliers E, Swaab DF, Kalsbeek A, Yi CX
J Neuroendocrinol · 2025 May · PMID 40055943 · Full text
The hypothalamic suprachiasmatic nucleus (SCN) hosts the central circadian pacemaker and regulates daily rhythms in physiology and behavior. The SCN is composed of peptidergic neuron populations expressing arginine vasop...
The hypothalamic suprachiasmatic nucleus (SCN) hosts the central circadian pacemaker and regulates daily rhythms in physiology and behavior. The SCN is composed of peptidergic neuron populations expressing arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP), as well as glial cells. Patients with Prader-Willi Syndrome (PWS) commonly experience circadian disturbances, which are particularly evident in their sleep/wake patterns. Using publicly available single-cell RNA sequencing data, we assessed the cell-type specificity of PWS-causative genes in murine SCN, which revealed the differential presence of PWS-related genes in glial and neural subpopulations. We then investigated neurons and glial cells in the SCN using immunohistochemistry in the postmortem hypothalami of PWS subjects and matched controls. We profiled neural populations characterized by AVP and VIP, astroglia characterized by glial fibrillary acid protein (GFAP), and microglia marked by ionized calcium-binding adapter molecule 1 (Iba1) and NADPH oxidase 2 (NOX2). Our analysis revealed an increased total number, neuronal density, and relative staining intensity of AVP-containing neurons in the PWS compared to controls while VIP-containing cells were unaltered. In contrast, GFAP-expressing astroglial cells were significantly lower in PWS subjects. Moreover, we did not detect any differences in microglia between PWS subjects and controls. Collectively, our findings show that PWS selectively affects AVP-containing neurons and GFAP-expressing astrocytes in the SCN. As each of these cell populations can affect the daily rhythmicity of the SCN biological clock machinery, the disruption of these cells may contribute to the circadian disturbances in patients with PWS.
Nuclear medicine and perspective thoughts in the diagnosis and treatment of pheochromocytoma and paraganglioma.
Harbi E, Aschner M
J Neuroendocrinol · 2025 Aug · PMID 40042101 · Publisher ↗
Pheochromocytoma and paraganglioma (PPGL) are rare and life-threatening tumors of the adrenal medulla and extra-adrenal paraganglia, respectively. Management of PPGL depends on accurate diagnosis and treatment. This revi...
Pheochromocytoma and paraganglioma (PPGL) are rare and life-threatening tumors of the adrenal medulla and extra-adrenal paraganglia, respectively. Management of PPGL depends on accurate diagnosis and treatment. This review provides a very comprehensive overview of nuclear medicine in PPGL with some of our perspective views on diagnostic challenges and pitfalls, treatment, and new phase studies. It describes nuclear medicine techniques including Cu/Ga-DOTA-SSA, F-FDOPA, F-FDG, I-MIBG, and some emerging molecular imaging agents and PRRT therapies, such as Pb VMT-α-NET and Pb VMT-α-NET targeted alpha therapy (TAT). It also provides insight into the use of proliferating cell nuclear antigen (PCNA) inhibitors in combination with therapeutics in aggressive/metastatic PPGL. Through a comprehensive review of the latest developments and clinical practice, this review aims to guide healthcare professionals in improving the diagnostic accuracy and therapeutic efficacy of PPGL.
22nd Annual ENETs Conference, 5th-7th March 2025.
J Neuroendocrinol · 2025 Mar · PMID 40040252 · Publisher ↗
Abstract loading — click title to view on PubMed.
A glucocorticoid receptor antagonist affects corticosterone but not neophobia in wild-caught house sparrows (Passer domesticus).
Henry MS, Kimball MG, Cochran EB … +6 more , Dusang BA, Frazier WJ, Stansberry KR, Kelly TR, Stelling EG, Lattin CR
J Neuroendocrinol · 2025 Jun · PMID 40035155 · Publisher ↗
Avoidance of novel stimuli (neophobia) affects how wild animals interact with their environment and may partly determine whether animals persist in human-altered landscapes. The neuroendocrine mediators of neophobia are...
Avoidance of novel stimuli (neophobia) affects how wild animals interact with their environment and may partly determine whether animals persist in human-altered landscapes. The neuroendocrine mediators of neophobia are poorly understood, although past work demonstrated that experimentally reducing circulating corticosterone in wild-caught house sparrows (Passer domesticus) decreased neophobia toward novel objects placed near the food dish. In this experiment, we directly tested the role of one of the two types of corticosterone receptors, the glucocorticoid receptor (GR), in mediating neophobia in house sparrows by administering a GR antagonist (RU486, n = 10) or a vehicle control (peanut oil, n = 10) over 5 consecutive days and measuring responses to novel objects both pre- and post-treatment. We also measured baseline and stress-induced corticosterone in all sparrows on the final day of behavior trials. To better understand the effects of RU486 on corticosterone over time, in a separate group of sparrows (n = 12) we administered RU486 or vehicle over 5 days and took multiple blood samples to assess baseline and stress-induced corticosterone. Overall, we did not detect an effect of subcutaneous RU486 injections on neophobia behavior. However, we did find that RU486 injections significantly decreased stress-induced corticosterone levels starting 1 day post-injection and baseline corticosterone levels starting 6 days post-injection, compared to vehicle-injected controls. Our results suggest that GR is not involved in mediating neophobia behavior in house sparrows.
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