Journal of Neuroendocrinology最新文献

Glucocorticoids are produced through activation of the hypothalamic–pituitary–adrenal (HPA) axis, initiated by the release of corticotropin-releasing factor (CRF) from the hypothalamus. CRF acts through two receptor subtypes, CRF1 and CRF2. However, the specific contributions of CRF₁ and CRF₂ receptors to age-related changes in brain glucocorticoid activity remain largely unexplored. In certain tissues, including the hippocampus, glucocorticoid signaling is further amplified by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates inactive glucocorticoid metabolites into their active form. Notably, prior research investigating the role of hippocampal 11β-HSD1 in aging has focused exclusively on male subjects. In this study, we used genetic mouse models lacking functional CRF₁ or CRF₂ receptors to investigate their respective roles in regulating hippocampal 11β-HSD1 activity and glucocorticoid levels across age and sex. Mice of both sexes at 6 and 18 months of age were analyzed. Hippocampal 11β-HSD1 activity was assessed by measuring the ratio of corticosterone to dehydrocorticosterone using mass spectrometry in tissue extracts from CRF₁ and CRF₂ wild-type (WT), heterozygous (HET), and knockout (KO) mice. Our results demonstrate that hippocampal 11β-HSD1 activity increases with age in female CRF₁ WT and HET mice but not in CRF₁ KO females. In contrast, aged males exhibit elevated 11β-HSD1 activity regardless of CRF₁ genotype. In CRF₁ males, the age-related increase in hippocampal 11β-HSD1 activity is associated with higher hippocampal corticosterone levels, whereas in CRF₁ females, it corresponds with a decrease in hippocampal dehydrocorticosterone. CRF₁ deficiency leads to reduced hippocampal levels of both corticosterone and dehydrocorticosterone in males and females at both ages. CRF₁ deficiency is also associated with decreased plasma corticosterone levels in both male and female mice. Male, but not female, CRF₂ mice show an age-dependent increase in hippocampal 11β-HSD1 activity, which is not altered by CRF₂ deficiency. Moreover, CRF₂ deficiency results in increased plasma corticosterone in female, but not in male, mice. Overall, our findings reveal that hippocampal 11β-HSD1 activity increases with age in both sexes. In females, this increase is dependent on the presence of functional CRF₁ receptors. In contrast, males exhibit age-related increases in 11β-HSD1 activity independent of CRF₁ function. These findings underscore the importance of considering sex as a biological variable when developing therapeutic strategies targeting 11β-HSD1 to mitigate age-related memory decline.

During development, there is a significant sex difference in the expression of progestin receptor (PR) in the medial preoptic nucleus (MPN) of rodents. Males express high levels of PR immunoreactivity (PR-ir) in the MPN beginning at embryonic day 19, whereas PR is virtually absent in females until the second postnatal week. This sex difference indicates a developmental window during which the male MPN is more sensitive to progestins than the female MPN. The two PR isoforms, full-length PRB and the truncated PRA, can differentially regulate the expression of specific genes. Yet, it is unknown how these isoforms contribute to the sex difference in PR expression. In the present study, we investigated the relative contributions of PRA and PRB expression in the MPN during development. PR-ir in neonatal male and female PRA knockout (PRAKO) or PRBKO mice were compared with their wildtype (WT) counterparts. In the MPN, levels of PR-ir were higher in WT males than in WT females consistent with previous results from our lab. Moreover, this sex difference was also detected in both PRAKO and PRBKO mice, suggesting that both isoforms contribute to PR expression in males. We also investigated the expression of PRA and PRB in the ventrolateral subdivision of the ventromedial nucleus of the hypothalamus (VMN) and arcuate nucleus (ARC), two additional brain regions implicated in progestin function in reproduction in which males expressed PR at higher levels than females. Interestingly, in the VMN and the ARC, PRA was the predominant isoform. These findings suggest that the differential expressions of PRA and PRB result in sex differences in PR in the brain regions associated with sexually dimorphic behaviors and neuroendocrine functions.

Oxytocin (OT) is a neuropeptide involved, among other functions, in the regulation of stress and inflammation. OT's impact on inflammatory and stress-related processes is particularly relevant in older adults, given that elevated levels of systemic inflammation typically associated with age can be amplified by stress. Methylation of the OT receptor gene (OXTRm) is an epigenetic process that reduces the availability of receptors to bind with OT. While acute stress has been shown to increase OXTRm levels in older adults, the interplay of OXTRm and stress on inflammation remains unexamined. This study collected blood samples from 116 generally healthy older adults (M_age = 71.2 years, SD = 7.51 years, range = 55-95 years) to quantify methylation OXTRm at CpG site -924 and tumor necrosis factor (TNF)-α as biomarkers of systemic inflammation, as well as assessed self-reported levels of stress. Moderated linear regression revealed that higher OXTRm methylation levels and greater perceived stress were associated with greater systemic inflammation (B = 0.24, p = 0.006). These findings highlight OXTRm as an epigenetic pathway linking stress and inflammation in aging.

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

Feeding and reproductive function are regulated by intricate systems that monitor food availability and energy stores, and on the basis of energy status, promote or put a brake on reproduction. This is particularly evident in the systems that regulate feeding and reproductive state in female mammals. Here we describe some of the systems that regulate feeding and reproductive state focusing on how metabolic hormones impact the onset of puberty as discussed in the panel session presented at the recent Panamerican Neuroendocrine Society meeting in Santos, Brazil. Indeed, hormones like leptin and insulin, which are released when levels of energy resources are increasing, may be critical signals that activate hypothalamic pathways related to ovulation in females to cause the onset of puberty. In adults, increasing levels of these hormones signal to the hypothalamus to reduce food intake and increase energy expenditure. In contrast, hormones like ghrelin impact hypothalamic and extrahypothalamic brain regions to drive hunger and the motivation to eat ultimately increasing feeding behavior and decreasing energy expenditure. Based on these actions, we describe some potential targets for the treatment of obesity and the mechanisms by which these targets work to improve human health.

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

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

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

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