Journal of Neuroendocrinology最新文献

Finasteride, an inhibitor of the enzyme 5alpha-reductase, prescribed for benign prostatic hyperplasia and androgenetic alopecia, induces a wide variety of side effects during treatment and upon withdrawal, like sexual dysfunction and cognitive and psychological disorders, inducing the so-called post-finasteride syndrome (PFS). Here, we explored the behavioral effects of this drug in adult male rats after subchronic finasteride treatment (20 days) and at drug discontinuation (1 month). We employed multiple behavioral paradigms, including the open field test and elevated plus maze to assess locomotor activity and anxiety, and a novelty-seeking test to evaluate exploratory behavior and approach-avoidance tendencies. Our results revealed a dichotomy between immediate and delayed finasteride effects. While effects after subchronic treatment were mild, significant behavioral alterations emerged at the withdrawal. In particular, pronounced hyperactivity, decreased center exploration in the open field, and marked avoidance of novel stimuli, collectively indicating an anxiety-like behavioral phenotype, were revealed. These results, showing a picture of increased vulnerability, are in agreement with clinical reports in PFS, highlighting the relevance of our model for this condition. Moreover, the data here described strengthen the importance of monitoring patients not only during treatment but also following discontinuation of finasteride therapy.

Prenatal exposures to air pollution and maternal psychosocial stress are each associated with increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD), and epidemiological work suggests that concurrent exposure to these risk factors may be particularly harmful. This is important given that the same populations often bear the brunt of both toxicant and psychosocial stress burdens. Social impairments are a defining symptom in ASD. Previous work modeling combined prenatal exposure to diesel exhaust particles (DEPs) and maternal stress (MS) in rodents has found male-biased social deficits in offspring, as well as changes to neuroimmune processes and the gut microbiome. However, the precise neural circuits on which these exposures converge to impact social behavior are unclear. Oxytocin (OXT) and vasopressin (AVP) are neuropeptides critical to the regulation of social behavior across species, signaling primarily at the oxytocin receptor (Oxtr) and vasopressin V1a receptor (V1aR) in the brain. Here, we hypothesized that OXT and/or AVP expression would be reduced in the brain following DEP/MS exposure. Following prenatal exposure to DEP/MS or the vehicle/control condition (VEH/CON), we measured maternal and offspring outcomes during the perinatal period, social and anxiety-like behavior during adolescence, OXT and AVP cell/fiber density, and Oxtr and Avpr1a mRNA expression in early adulthood in several brain regions in both males and females. We observed a decrease in interaction time in DEP/MS males as compared to VEH/CON in the sociability assay and a decrease in social novelty preference in DEP/MS females as compared to VEH/CON. No effects of sex or treatment were observed on OXT or AVP cell number or fiber density in the hypothalamic regions assessed. However, numerous sex differences were observed in Oxtr and Avpr1a mRNA. Moreover, Avpr1a mRNA was significantly increased following DEP/MS exposure in the nucleus accumbens in both sexes and trended towards increasing in the dorsal hippocampus. Together, these findings suggest that DEP/MS exposure has a stronger impact on female social behavior than previously observed. Moreover, while DEP/MS exposure does not appear to impact OXT or AVP expression in the brain, V1aR expression is modulated by DEP/MS exposure in the nucleus accumbens.

Testosterone and oestrogens play significant roles in female physiology, extending beyond reproductive functions to influence brain health, mood regulation, and behaviour. Testosterone low-dose therapy is increasingly considered for alleviating sexual dysfunction symptoms in postmenopausal women, and has been recently investigated as therapy for depressive symptoms, though the mechanisms and safety of this approach are not entirely clear. Specifically, the effects of testosterone use on brain oestrogen synthase (aromatase), which maintains the balance between androgens and oestrogens, remain unexplored. This study investigated the effects of short-term, low-dose testosterone administration on brain oestrogen synthase availability and associated mood and behavioural changes in healthy women. Healthy women were exposed to 1 week of low-dose testosterone (10 mg/day). Binding of oestrogen synthase was examined by [¹¹C]cetrozole positron emission tomography before and during testosterone exposure. Psychometric assessment of depression, anxiety, and aggression was performed at the same time. Peripheral testosterone levels were significantly increased (up to 33-fold) upon treatment, which had no significant effect on brain oestrogen synthase binding in the thalamus, as supported by Bayesian analyses, nor in the hypothalamus and amygdala. Psychometric measures of depression, anxiety, and aggression also remained unchanged by testosterone treatment. These findings suggest that short-term, clinically relevant testosterone administration has no major effects on the brain oestrogen synthase availability in healthy women, which may reassure patients with hypoactive sexual desire disorder considering this treatment. Larger, long-term studies are needed to confirm these results and explore effects in patients with clinical need for testosterone treatment.

The human brain is highly sensitive to early adversity, which can have long-term consequences for later mental health. It is also a time of rapid learning of social, motor and other skills, including language. It is proposed that pre-adrenarche, the only epoch in human development in which cortisol is not accompanied by dehydroepiandrosterone (DHEA) and its sulphated derivative (DHEAS), represents the sensitive period but this is subsequently moderated by the advent of adrenarche and the surge of DHEA(S) at 6-8 years. Cortisol enhances plasticity and the formation of new memories as well as personality traits such as emotionality. DHEA(S) is well known to oppose many of the actions of cortisol on the brain, including those on learning, memory and synaptic function, all reflecting altered plasticity; adrenarche is therefore a time of moderated cortisol activity. Several endocrine-dependent neural mechanisms respond to the neuroendocrine transition at adrenarche, including alterations in perineuronal nets, gene expression of growth factors, serotonin activity, cytokine release and synaptic adaptability. Adrenarche will reduce the detrimental impact of adverse events but stabilise memories and psychological traits acquired during the cortisol-dominated pre-adrenarche epoch. The transition from pre- to post-adrenarche is therefore a highly significant neuroendocrine event in early life, with both potentially beneficial and disadvantageous consequences. This suggests a primary role for adrenarche, for which no function has yet been established.

The role of primary tumour resection (PTR) in metastatic small intestinal (SiNETs) and pancreatic neuroendocrine tumours (PanNETs) remains debated. While retrospective studies suggest improved survival and possible reduction of local complications, the evidence is limited by heterogeneity, selection bias, and an absence of prospective validation. Under the auspices of the European Neuroendocrine Tumor Society (ENETS) Advisory Board, this position paper summarises current knowledge and expert consensus on the rationale, potential benefits, patient selection, timing, integration with systemic therapies, and future perspectives for PTR. PTR may be considered in selected patients with liver-limited or liver-dominant disease, indolent tumour biology, and good performance status, especially to prevent obstruction, bleeding, or ischaemia, to reduce symptomatic tumour burden, or to facilitate systemic and liver-directed therapies. However, the risks of major surgery, including intestinal and pancreatic resections, with long-term impact on digestion and nutrition, must be carefully considered. Decisions should be made in dedicated multidisciplinary tumour boards. Future directions include incorporation of molecular biomarkers, functional imaging, tumour growth rate, radiomics, and real-world data to refine patient selection. Quality of life and patient-reported outcomes remain underexplored and should be co-primary endpoints in prospective studies. PTR should not currently be regarded as standard of care for all cases but may have a role in carefully selected patients within integrated and individualised management strategies.

The hypothalamic melanocortin system, comprised of proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, regulates energy balance but studies in humans are limited by lack of biomarkers to assess brain melanocortin activity. Previous studies evaluated POMC concentrations in human CSF in relation to BMI and leptin and to weight loss, including pharmacotherapy with lorcaserin which targets POMC neurons, showing that lower baseline POMC predicted a better weight loss response to lorcaserin. We performed a retrospective analysis of baseline CSF POMC levels in 139 healthy weight-stable individuals without diabetes or neurologic disease who participated in previous studies, including a subgroup analysis of 70 subjects spread equally across the BMI spectrum (19.2-57.3) and in 97 subjects with obesity. POMC was measured in CSF and AgRP was measured in CSF and plasma by sensitive 2-site ELISAs. Mean CSF POMC was lower in individuals with elevated versus normal BMI (200 vs. 269 fmol/mL; p = .0003) and strong negative correlations between CSF POMC and both BMI and leptin were found in 70 subjects across the BMI spectrum (p < .0001); this remained significant in all 139 subjects but not in 97 with obesity. The cohort with obesity included some very low CSF POMC levels (bottom 10%) that do not overlap with non-obese subjects. Strong positive correlations were noted between CSF POMC and AgRP in both CSF and plasma in all groups, including the subgroup with obesity, providing evidence that activities of both sets of neurons may be linked independently of leptin and BMI. Importantly CSF POMC levels remained remarkably constant when nine weight-stable subjects were studied twice over several years. In summary, CSF POMC was lower in individuals with elevated BMI and correlated negatively with BMI and leptin across the BMI spectrum but not within a cohort with obesity. However, the cohort with obesity contained subjects with very low CSF POMC levels that may indicate POMC deficiency and predict treatment response to melanocortin agonists. It remains to be determined if alternative biomarkers associated with low CSF POMC can be identified for use in the clinical setting.

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor with an essential role in appetite suppression and energy homeostasis. Genetic mutations in the receptor and components of its signalling pathway that cause obesity in humans, dogs and rodent models have revealed important insights into how the receptor signals and what regulates its cell surface expression. Structural studies have identified calcium as a critical cofactor for agonist binding and receptor function, while several transmembrane proteins have been shown to modulate MC4R activity. Here, we describe recent developments in our understanding of how accessory proteins and cofactors, identified using genomic approaches and screens for protein interaction, modify MC4R trafficking and signalling. We discuss how signalling by G_s and G_q/11 pathways may have differential effects on food intake, weight gain and cardiovascular function. We also summarise recent studies of MC4R expression at primary cilia, receptor oligomerisation, newly identified proteins that regulate MC4R cell surface expression, and briefly discuss novel endogenous agonists.

Puberty is a critical developmental stage during which individuals acquire the capacity for sexual reproduction. This transition involves a series of complex biological events primarily orchestrated by the activation of the hypothalamo–pituitary–gonadal (HPG) axis. Central to this process are gonadotropin-releasing hormone (GnRH) neurons, which play a key role in regulating reproductive maturation and function throughout life. However, the precise mechanisms that trigger the pubertal increase in GnRH activity remain incompletely understood. Evidence from our laboratory indicates that a profound remodeling of the hypothalamus is crucial for sexual maturation. In this review, we discuss findings from our research utilizing a combination of RNA sequencing, conditional genetic manipulation with mouse models and viral vectors, and systems neuroscience approaches. Our results reveal that the pubertal transition involves changes in the chemical phenotype and site-specific innervation of key hypothalamic neurons. Among these neuronal populations, those expressing growth hormone-releasing hormone (GHRH), kisspeptin, or dopamine transporter (DAT) are the focus of this review. Building upon data from other laboratories, our findings offer new insights into the neural and molecular mechanisms by which the hypothalamus orchestrates sexual maturation.

Small intestinal neuroendocrine tumors (siNET) are rare malignancies, often diagnosed at advanced stages with metastatic spread. While surgery is the only curative treatment, medical therapies, including somatostatin analogues (SSA), peptide receptor radionuclide therapy (PRRT), and other systemic treatments, are essential for disease stabilization. The aim was to assess median progression free survival (mPFS), and prognostic factors for the most frequently used medical treatment modalities in patients with unresectable disease. It was a retrospective single-center cohort study, including 378 patients diagnosed with siNET between 2000 and 2020. The median overall survival (mOS) for the cohort was 97 (95% CI: 83–111) months. Median PFS for octreotide and lanreotide treatment/treated patients (n = 255) was 30 (95% CI: 24–36) months and 5 years PFS was 32%, with no significant difference between the two agents. Risk factors for disease progression included age, Ki-67 index, and gender (female as a protective factor). Median PFS for PRRT (n = 140) was 31 (95% CI: 25–37) months. Thirty-seven patients who had PFS > 18 months after the first 4 cycles received another 2 cycles of PRRT. Median PFS after the first 4 cycles was 37 (95% CI: 30–44) months versus 10 (95% CI: 6–14) months after the 2 additional PRRT cycles. Patients treated with everolimus had a median PFS of 5 (95% CI: 0.3–10) months, and chemotherapy with streptozocin and 5-fluorouracil resulted in a median PFS of 8 (95% CI: 5–11) months. In conclusion, SSA remains the cornerstone of first-line therapy for unresectable siNET, with PRRT offering a valuable alternative for patients with progression on SSA. Re-introduction of PRRT with 2 additional cycles had reduced efficacy compared with the initial treatment. PFS was short in non-somatostatin receptor-based therapies like everolimus and chemotherapy.