Neuroendocrine Dysfunction Research Articles

Neuroendocrine challenges and clinical outcomes in men with chronic traumatic brain injury: a cross-sectional study.

Marked changes in the hypothalamic-pituitary axis have been documented in patients with traumatic brain injury (TBI). These enduring endocrine challenges could significantly influence the physical and psychological outcomes thereby impacting overall recovery. This study aimed to determine the prevalence and types of endocrine dysfunction in men with chronic TBI and to determine the association of endocrine dysfunction with clinical outcomes. A cross-sectional study that included male participants of 25-45 years (N = 66) with moderate to severe TBI within 6-24 months of injury. Serum Cortisol, Free T4, TSH, Luteinizing hormone, Testosterone, ACTH, Prolactin and IGF-1 were assessed. Glasgow Outcome Scale Extended (GOS-E) and Modified Barthel Index (MBI) scores were also assessed in them. The study cohort comprised male patients with a mean ± age of 32.8 ± 5.7 years. Low IGF-1 levels were most commonly encountered, followed by hypogonadism. Hypopituitarism was present in 56.1%. The proportion of hypogonadism was significantly higher in the group with moderate-total dependence (13/26) as compared to the functionally independent (8/40) group (50% vs. 20%; P = 0.011). Univariate and multivariate logistic regression analysis was used to determine the factors associated with hypopituitarism, revealing that severity of injury (OR = 2.6;) and GOS-E (OR = 3.1) were significant (P < 0.10) on univariate analysis. This study emphasizes the need to screen TBI patients for neuroendocrine dysfunction during the chronic phases and to establish screening criteria.

Copeptin's role in traumatic brain injury: The promising quest for a new biomarker

ObjectiveTraumatic brain injury (TBI) necessitates reliable biomarkers to improve patient care. This study explored copeptin as a potential biomarker in TBI and its relation to vasopressin (ADH) in such patients. MethodsA cross-sectional study was conducted on 50 TBI patients. Exclusion criteria included specific medical conditions and recent traumatic events. Copeptin and ADH testing were performed within 30 days post-trauma. Patient data, Glasgow Coma Scale (GCS) scores, imaging results, and the need for surgical intervention were obtained from medical charts. ResultsCopeptin levels negatively correlated with GCS scores (ρ = − 0.313, p = 0.027), indicating a potential association with trauma severity. Copeptin levels (mean: 3.22 pmol/L, median 2.027 pmol/L, SD = 3.15) tended to be lower than those found in the normal population, suggesting possible neuroendocrine dysfunction post-TBI. ADH levels (mean: 67.93 pmol/L, median 56.474 pmol/L SD = 47.67) were higher than the normal range and associated with the need for surgery (p = 0.048). Surprisingly, copeptin and ADH levels negatively correlated (r = − 0.491; p < 0.001), potentially due to differences in degradation processes and physiological variations in TBI patients. ConclusionCopeptin shows potential as a predictive biomarker for assessing TBI severity and predicting patient outcome. However, its complex relationship with ADH in TBI requires further investigation. Careful interpretation is needed due to potential variations in excretion dynamics and metabolism. Larger studies on TBI patient cohorts are essential to validate copeptin as a reliable biomarker and improve patient care in TBI.

Effect of delayed diagnosis on neuroendocrine function in individuals with suprasellar germ cell tumors.

The impact of delayed diagnosis on tumor-related prognosis appears to be minimal in individuals with intracranial germ cell tumors (iGCTs). However, its effect on neuroendocrine functions remains unclear. We aimed to assess the effects of delayed diagnosis on neuroendocrine function in individuals with suprasellar GCTs. We conducted a retrospective cohort study of 459 individuals with suprasellar GCTs and categorized them into two groups based on disease duration: delayed diagnosis (> 6 months) and non-delayed diagnosis (≤ 6 months). We compared endocrinological symptoms, neuroendocrine dysfunction and its grading (categorized into 0-3 grades based on severity), and recovery from neuroendocrine dysfunction in both groups. Patients with delayed diagnosis exhibited higher incidences of amenorrhea, slow growth, fatigue, and polyuria/polydipsia. Neuroendocrine dysfunction, including central adrenal insufficiency (CAI), central hypothyroidism (CHT), arginine vasopressin deficiency (AVP-D), growth hormone deficiency, hypogonadism, and hyperprolactinemia, was more pronounced in the delayed diagnosis group at diagnosis, the end of treatment, and the last follow-up. Furthermore, individuals with delayed diagnosis showed higher grades of neuroendocrine dysfunction at diagnosis (OR=3.005, 95% CI 1.929-4.845, p<0.001), end of oncologic treatment (OR=4.802, 95% CI 2.878-8.004, p<0.001), and last follow-up(OR=2.335, 95% CI 1.307-4.170, p=0.005) after adjusting for confounders. Finally, less recovery, particularly in CAI, CHT, and AVP-D, was seen among the group with delayed diagnosis after treatment. Among individuals with suprasellar GCTs, delayed diagnosis is associated with increased, more severe, and less recovered neuroendocrine dysfunction, emphasizing the importance of early diagnosis and treatment to reduce neuroendocrine dysfunction.

Protocol-Based Standardized Endocrinological Evaluation of Children With Traumatic Brain Injury: A Quality Improvement Initiative.

Traumatic brain injury (TBI) can disrupt the hypothalamo-pituitary axis, causing neuroendocrine dysfunction. As a third of children can develop post-traumatic hypothalamo-pituitary axis dysfunction (HPAD), a longitudinal follow-up is required in children with TBI. The study comprised a pre-quality improvement (QI) phase (baseline phase) and a QI phase (post-intervention phase). Retrospective data were collected on children with TBI at our hospital during the pre-QI phase of the study to estimate the baseline data on HPAD prevalence and pediatric endocrine referral rate. Guidance protocol for standardizing the pediatric endocrine referral, evaluation, and follow-up of children with TBI was implemented. Prospective data were collected to estimate outcome measures (prevalence of HPAD, rate of initial endocrine consultation and outpatient follow-up) and process measures (protocol adherence rate). Twenty-seven children, aged ≤19 years, were admitted with TBI in the pre-QI phase. The median age was 9 years. Motor vehicle accidents predominated. Thirty percent had limited endocrine evaluation, and 4% had transient cranial diabetes insipidus (DI). The QI phase included 8 children. Demographic data were similar to those in the pre-QI phase. Both outcome and process measures increased to 75% from the pre-QI phase following the protocol implementation. A lower prevalence rate of HPAD in the current cohort may be owing to underevaluation and a smaller sample size. The QI initiative incorporating a guidance protocol-based endocrinological approach to children with TBI improved the pediatric endocrinology referral and follow-up rates.

Association of early life adversity with cardiovascular disease and its potential mechanisms: a narrative review.

Strong epidemiological evidence has shown that early life adversity (ELA) has a profound negative impact on health in adulthood, including an increased risk of cardiovascular disease, the leading cause of death worldwide. Here, we review cohort studies on the effects of ELA on cardiovascular outcomes and the possible underlying mechanisms. In addition, we summarize relevant studies in rodent models of ELA. This review reveals that the prevalence of ELA varies between regions, time periods, and sexes. ELA increases cardiovascular health risk behaviors, susceptibility to mental illnesses, and neuroendocrine and immune system dysfunction in humans. Rodent models of ELA have been developed and show similar cardiovascular outcomes to those in humans but cannot fully replicate all ELA subtypes. Therefore, combining cohort and rodent studies to further investigate the mechanisms underlying the association between ELA and cardiovascular diseases may be a feasible future research strategy.

Advancing Research and Treatment: An Overview of Clinical Trials in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Future Perspectives.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, debilitating, and multi-faceted illness. Heterogenous onset and clinical presentation with additional comorbidities make it difficult to diagnose, characterize, and successfully treat. Current treatment guidelines focus on symptom management, but with no clear target or causative mechanism, remission rates are low, and fewer than 5% of patients return to their pre-morbid activity levels. Therefore, there is an urgent need to undertake robust clinical trials to identify effective treatments. This review synthesizes insights from clinical trials exploring pharmacological interventions and dietary supplements targeting immunological, metabolic, gastrointestinal, neurological, and neuroendocrine dysfunction in ME/CFS patients which require further exploration. Additionally, the trialling of alternative interventions in ME/CFS based on reported efficacy in the treatment of illnesses with overlapping symptomology is also discussed. Finally, we provide important considerations and make recommendations, focusing on outcome measures, to ensure the execution of future high-quality clinical trials to establish clinical efficacy of evidence-based interventions that are needed for adoption in clinical practice.

A cross-sectional study exploring the relationship between symptoms of anxiety/depression and P50 sensory gating in adult patients diagnosed with chronic fatigue syndrome/myalgic encephalomyelitis.

Chronic fatigue syndrome (CFS) is a clinical disease that affects multiple body systems. It is characterized by persistent or recurring fatigue, which may be linked to immune, neuroendocrine, and energy metabolism dysfunctions. Individuals with CFS may experience pain, sleep disorders, anxiety, and depression. This research analyzed the fundamental characteristics of anxiety/depression symptoms in patients with CFS and investigated the association between these symptoms and the P50 SG (sensory gate) ratio. Two hundred and forty-nine subjects fulfilled the CDC-1994 criteria for CFS and were included in the study. The subjects successively completed the Symptom CheckList-90-Revised (SCL-90-R), Hamilton Anxiety Rating Scale-14 (HAMA-14), and Hamilton Depression Rating Scale-24 (HAMD-24). Auditory-evoked potential P50 were measured using the 128-lead-electroencephalograph. According to HAMA and HAMD, 17.3% (n = 43) of the patients did not exhibit anxiety/depression, with a threshold score of 7 and 7 for HAMA and HAMD. When the threshold score was 14 and 20 respectively, 43.3% (n = 108) of the patients did not exhibit anxiety/depression. The SCL-90-R results indicated that 69.5% (n = 173) of these individuals with the score arranging from 0 to 160 did not present mental problems. There was a correlation between somatization scores and P50 SG ratio in the overall sample and no anxiety or depression (NAOD) group delimited by 14 and 20, respectively, (p < 0.05). Regression analysis showed that anxiety and depression were risk factors associated with an abnormal P50 SG ratio. A significant correlation exists between the P50 SG ratio and clinical symptoms such as fatigue, anxiety, and depression. Abnormalities in brain function among patients with CFS may play a crucial role in the pathogenesis of the condition, leading to their classification as being prone to functional neurological disorders. The P50 SG ratio cannot be used as a diagnostic marker for CFS but show some significance on the mechanism, classification, treatment, and prognosis of CFS.

Angelica keiskei leaves extract attenuates psychosocial stress in overcrowding-subjected rats

Angelica keiskei is currently used as a popular functional food with various beneficial effects, including antioxidant, anti-obesity, anti-tumor, anti-diabetic, and anti-bacterial. A recent in vitro study reported that A. keiskei inhibits monoamine oxidases (MAOs), suggesting the antidepressant property of A. keiskei. However, in vivo studies on laboratory animals subjected to psychosocial stress have not been conducted. In this study, the effects of an A. keiskei leaf extract (AKE) on rats undergoing chronic social overcrowding stress were explored. Six-month-old male and female Wistar rats were housed in groups of three in 12 × 12 × 18 cm cages (overcrowding) for 28 days. Both male and female rats were divided into two groups (N = 10); the control group received oral distilled water, while the other group (treatment group) received 20 mg/kgBW/day of AKE supplementation. The results showed that AKE-treated rats exhibited lower anxiety- and depressive-related behaviors than that of control-stressed rats. AKE significantly decreased corticosterone and increased testosterone and estrogen levels in stressed rats. Additionally, brain tissue malondialdehyde and TNF-alpha levels were reduced, while brain neurotransmitter 5-hydroxytryptamine and antioxidant superoxide dismutase levels were elevated by the AKE. These findings suggest, for the first time, that AKE could alleviate overcrowding stress-induced behavioral, neuroendocrine, antioxidant, and inflammatory dysfunctions. AKE extract could potentially be used as an agonist to reduce stress and depression.

Reproductive neuroendocrine defects programmed by prenatal testosterone treatment between gestational days 60-90 are amplified by postnatal obesity in sheep.

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women of reproductive age, and obesity can increase the severity and development of the PCOS phenotype. Prenatal testosterone (T) treatment between gestational days 30-90 advanced puberty and disrupted the reproductive and metabolic phenotype in female sheep, recapitulating attributes of women with PCOS, with postnatal obesity amplifying its severity. On the other hand, prenatal T treatment from gestational days 60-90 led to a much milder phenotype. We hypothesized that reproductive neuroendocrine defects programmed by prenatal T treatment between gestational days 60-90 are amplified by postnatal obesity in sheep. Suffolk ewes received T propionate (T; 100mg) or corn oil (C; vehicle) twice weekly from gestational days 60-90. At 5months of age, T lambs were assigned to either a maintenance (100% of NRC requirements) or overfed (130% NRC) diet and C lambs were fed the maintenance diet. We compared the timing of puberty (n = 15/group) determined by twice weekly measurement of progesterone concentrations, estradiol positive feedback responsiveness (n = 8/group) determined by assessing LH secretion in response to exogenous estradiol, periovulatory LH dynamics during the second breeding season (n = 8/group) following synchronization with two injections of PGF2α, and progesterone negative feedback (n = 8/group) determined by characterizing LH pulses during the mid-luteal phase between C, T-maintenance and T-overfed groups. Our findings indicate that postnatal obesity: 1) exacerbated reproductive defects and further deteriorated reproductive cyclicity during the second breeding season (adulthood); 2) did not amplify the impairment in estradiol positive feedback in delaying the timing and amplitude of the LH surge, although it reduced the total amount of LH secreted during the preovulatory LH surge; 3) amplified the reduced responsiveness to progesterone negative feedback manifested as an increase in LH pulse amplitude and peak. These observations, in addition to supporting our previous findings that prenatal T treatment results in reproductive neuroendocrine dysfunction and periovulatory disruptions, provide evidence that these neuroendocrine defects programmed between gestational days 60-90 are amplified by postnatal obesity in female sheep.

Gordon Holmes Syndrome Model Mice Exhibit Alterations in Microglia, Age, and Sex-Specific Disruptions in Cognitive and Proprioceptive Function.

Gordon Holmes syndrome (GHS) is a neurological disorder associated with neuroendocrine, cognitive, and motor impairments with corresponding neurodegeneration. Mutations in the E3 ubiquitin ligase RNF216 are strongly linked to GHS. Previous studies show that deletion of Rnf216 in mice led to sex-specific neuroendocrine dysfunction due to disruptions in the hypothalamic-pituitary-gonadal axis. To address RNF216 action in cognitive and motor functions, we tested Rnf216 knock-out (KO) mice in a battery of motor and learning tasks for a duration of 1 year. Although male and female KO mice did not demonstrate prominent motor phenotypes, KO females displayed abnormal limb clasping. KO mice also showed age-dependent strategy and associative learning impairments with sex-dependent alterations of microglia in the hippocampus and cortex. Additionally, KO males but not females had more negative resting membrane potentials in the CA1 hippocampus without any changes in miniature excitatory postsynaptic current (mEPSC) frequencies or amplitudes. Our findings show that constitutive deletion of Rnf216 alters microglia and neuronal excitability, which may provide insights into the etiology of sex-specific impairments in GHS.

Intracranial germ cell tumors: a view of the endocrinologist.

Intracranial germ cell tumors (iGCTs) are rare malignant neoplasms that mainly affect children and adolescents. The incidence, clinical presentation, and prognosis of iGCTs exhibit high heterogeneity. Previous studies have primarily focused on eliminating tumors, reducing tumor recurrence, and improving survival rates, while neglecting the impact of the tumors and their treatment on neuroendocrine function. Throughout the entire course of the disease, neuroendocrine dysfunction may occur and is frequently overlooked by oncologists, neurosurgeons, and radiologists. Endocrinologists, however, are more interested in this issue and have varying priorities at different stages of the disease. From onset to the diagnostic phase, most patients with iGCTs may present with symptoms related to impaired neuroendocrine function, or even experience these symptoms as their first indication of the condition. Particularly, a minority of patients with sellar/suprasellar lesions may exhibit typical imaging features and elevated tumor markers long after the onset of initial symptoms. This can further complicate the diagnosis process. During the peritumor treatment phase, the neuroendocrine function shows dynamic changes and needs to be evaluated dynamically. Once diabetes insipidus and dysfunction of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes occur, hormone replacement therapy should be administered promptly to ensure successful tumor treatment for the patient. Subsequently, during the long-term management phase after the completion of tumor treatment, the evaluation of growth and development as well as corresponding hormone replacement therapy are the most concerning and complex issues. Thus, this paper reviews the interest of endocrinologists in iGCTs at different stages.

Overactivation of GnRH neurons is sufficient to trigger polycystic ovary syndrome-like traits in female mice

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder leading to anovulatory infertility. Abnormalities in the central neuroendocrine system governed by gonadotropin-releasing hormone (GnRH) neurons might be related to ovarian dysfunction in PCOS, although the link in this disordered brain-to-ovary communication remains unclear. Here, we manipulated GnRH neurons using chemogenetics in adult female mice to unveil whether chronic overaction of these neurons would trigger PCOS-like hormonal and reproductive impairments. We used adult Gnrh1cre female mice to selectively target and express the designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetic tool hM3D(Gq) in hypophysiotropic GnRH neurons. Chronic chemogenetic activation protocol was carried out with clozapine N-oxide (CNO) i.p. injections every 48h over a month. We evaluated the reproductive and hormonal profile before, during, and two months after chemogenetic manipulations. We discovered that the overactivation of GnRH neurons was sufficient to disrupt reproductive cycles, promote hyperandrogenism, and induce ovarian dysfunction. These PCOS features were detected with a long-lasting neuroendocrine dysfunction through abnormally high luteinizing hormone (LH) pulse secretion. Additionally, the GnRH-R blockade prevented the establishment of long-term neuroendocrine dysfunction and androgen excess in these animals. Taken together, our results show that hyperactivity of hypothalamic GnRH neurons is a major driver of reproductive and hormonal impairments in PCOS and suggest that antagonizing the aberrant GnRH signaling could be an efficient therapeutic venue for the treatment of PCOS. European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement n◦ 725149).

FRI278 Kisspeptin Neuron Projections And Expression Patterns Are Unaltered In Prenatally Androgenized Female Mice Modeling PCOS

Abstract Disclosure: M. Prescott: None. Y. Watanabe: None. A. Ruddenklau: None. L. Fisher: None. C.L. Jasoni: None. R.E. Campbell: Consulting Fee; Self; Bayer, Inc. Polycystic ovary syndrome (PCOS) is associated with impaired gonadal steroid hormone feedback and a hyperactive central reproductive axis, implicating the brain in PCOS pathophysiology. Excess prenatal androgen (PNA) exposure is linked with the development of PCOS, and preclinical evidence suggests that PNA can program altered connections within the gonadotropin-releasing hormone (GnRH) neuronal network. Kisspeptin neurons are critical upstream regulators of GnRH neurons, relaying hormone feedback and potently activating GnRH secretion, but their role in PCOS remains incompletely understood. This study tested the hypothesis that prenatal androgen excess programmes altered neuroanatomical connections between kisspeptin neurons and GnRH neurons and modified neuropeptide and steroid hormone receptor expression in kisspeptin neurons. To investigate this, we labelled, imaged and assessed kisspeptin fibers, GnRH neurons, and gonadal steroid hormone receptors in adult female transgenic kisspeptin reporter mice (Kiss1(Cre-GFP)Coll; ROSA26tdTomato) exposed prenatally to di-hydrotestosterone or an oil vehicle (VEH) on gestational days 16-18 (n=7-10/group). PNA mice were acyclic and all tissue was collected in diestrus. Fixed coronal brain sections were immunofluorescently labelled for GnRH and kisspeptin reporter tdTomato and imaged on a confocal microscope to assess close fiber contacts to the soma and proximal dendrite of GnRH neurons. Neither the proportion of GnRH neurons with kisspeptin fiber contacts (VEH: 86.3±3.4%, PNA: 87.3±4.3%), nor the mean number of kisspeptin fiber close appositions per GnRH neuron (VEH: 6.1±0.6, PNA: 5.7±0.8) was different between groups. Kisspeptin neuron number and kisspeptin neuron co-expression with estrogen and progesterone receptors was evaluated in immunolabelled sections throughout the rostral periventricular nucleus of the 3rd ventricle (RP3V) and the arcuate nucleus (ARN). PNA had no significant impact on kisspeptin neuron number or the proportion of neurons with gonadal hormone co-expression in either population. Expression of neuropeptides was quantified by RT-qPCR in micro-dissected RP3V and ARN tissue from a separate cohort of adult PNA and VEH mice (n=5-8/group). PNA did not affect Kiss1, Tac2 or Pdyn expression in the ARN or Kiss1 expression in the RP3V. These data indicate that PNA does not modify anatomical connections between RP3V kisspeptin neurons and GnRH neurons, nor does it have a robust impact on steroid hormone responsiveness or neuropeptide expression of kisspeptin neurons. While the neuroanatomical relationship between ARN kisspeptin neurons and the GnRH neuron distal dendron in PNA mice remains to be determined, these data suggest that PNA-mediated neuroendocrine dysfunction is not due to programmed changes in the neuroanatomical projections or gonadal hormone sensitivity of kisspeptin neurons. Presentation: Friday, June 16, 2023

Taurine and N-acetylcysteine reverse reproductive and neuroendocrine dysfunctions in levetiracetam-treated epileptic male rats

ABSTRACT Reproductive neuroendocrine dysfunction is becoming common among patients with epilepsy, Notably, possible indication of taurine and N-acetylcysteine (NAC) in the management of reproductive impairment has increased over the years. However, scientific evidence to supplement our understanding of the impact of taurine and NAC in protecting reproductive neuroendocrine cells is lacking. Hence, this study aimed to investigate the possible effects of taurine and NAC on levetiracetam-induced reproductive neuroendocrine dysfunction in epileptic rats. The study was done in two experimental protocols: drug alone and reversal. In the drug-alone protocol, rats in groups 1–6 received treatment orally for 21 days, respectively. In the reversal-protocol, the animals in group 1, received saline (2.5 mL/kg) and served as normal control, while epilepsy was induced in animals in groups 2–5, after which groups 3–5 received levetiracetam (150 mg/kg), levetiracetam (150 mg/kg) + NAC (100 mg/kg), levetiracetam (150 mg/kg) + taurine (150 mg/kg) respectively for 14 days. Pilocarpine alone or in combination with levetiracetam significantly decreased neuro-endocrine related factors, hormonal profile, and spermatogenesis, whereas treatment with NAC and taurine reversed the effects induced by pilocarpinethrough neuro-endocrine-related factors and hormonal modulation mechanism.

Perspectives of PCOS Pathophysiology: Exploring the Interplay between PCOS and the Gut Microbiota

PCOS is a gynecological and metabolic concern for numerous women of reproductive age. Its pathophysiology broadly entails hyperandrogenism, insulin resistance, and neuroendocrine dysfunction, and is heavily influenced by genetic and epigenetic factors. However, its precise aetiology remains unclear. The gut microbiome is a major endocrine organ and plays a key role in host metabolism through its metabolites which regulate diverse host physiology like metabolism, immunity, etc. Numerous studies have described associations of altered microbiota in the progress and development of major human diseases. The studies conducted on animals and humans have suggested that the gut microbiota and its metabolites are involved in the pathogenesis of PCOS and its associated attributes such as insulin resistance, obesity and inflammation. Moreover, supplementation of probiotics/prebiotics has been reported to relieve the adverse metabolic and hormonal parameters effectively. Knowledge of this link between gut dysbiosis and PCOS has also spurred research interest in exploring novel management of PCOS. In this review, we have discussed the role of gut microbiota dysbiosis and its metabolite in the progression and treatment of PCOS.

Sex-dependent effects of angiotensin II type 1 receptor blocker on molecular and behavioral changes induced by single prolonged stress

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that not only entails alterations in fear behavior and anxiety but also includes neuroendocrine dysfunctions involving the hypothalamic pituitary adrenal (HPA) axis and the renin-angiotensin system. Recent preclinical studies demonstrate that activation of the angiotensin type 1 receptor (AT1R) in the paraventricular region of the hypothalamus (PVR) promotes anxiety-like behaviors and enables microglia proliferation. An increase in microglia and anxiety-like behavior also occurs in the PTSD animal model single-prolonged stress (SPS). In the present study, we tested whether AT1Rs contribute to the effects of SPS on behavior and microglia in brain structures important for HPA axis regulation and fear behavior. To test this, male and female animals were exposed to SPS and then given the oral AT1R antagonist candesartan beginning one week later. Candesartan did not alter auditory fear conditioning or extinction in SPS-exposed male or female animals. However, we found that the male animals exposed to SPS showed increased anxiety-like behavior, which was reversed by candesartan. In contrast, neither SPS nor candesartan altered anxiety-like behavior in the female animals. At the molecular level, SPS increased the cellular expression of AT1Rs in the PVR of male animals and candesartan reversed this effect, whereas AT1Rs in the PVR of females were unaltered by either SPS or candesartan. Iba1-expressing microglia increased in the PVR after SPS exposure and was reversed by candesartan in both sexes suggesting that SPS stimulates AT1Rs to increase microglia in the PVR. Collectively, these results suggest that the contribution of AT1Rs to the molecular and behavioral effects of SPS is sex-dependent.

Linkage and association of variants in the dopamine receptor 2 gene (DRD2) with polycystic ovary syndrome

Polycystic ovarian syndrome (PCOS) is a disorder with a foundation of neuroendocrine dysfunction, characterized by increased gonadotropin-releasing hormone (GnRH) pulsatility, which is antagonized by dopamine. The dopamine receptor 2 (DRD2), encoded by the DRD2 gene, has been shown to mediate dopamine’s inhibition of GnRH neuron excitability through pre- and post-synaptic interactions in murine models. Further, DRD2 is known to mediate prolactin (PRL) inhibition by dopamine, and high blood level of PRL have been found in more than one third of women with PCOS. We recently identified PRL as a gene contributing to PCOS risk and reported DRD2 conferring risk for type 2 diabetes and depression, which can both coexist with PCOS. Given DRD2 mediating dopamine’s action on neuroendocrine profiles and association with metabolic-mental states related to PCOS, polymorphisms in DRD2 may predispose to development of PCOS. Therefore, we aimed to investigate whether DRD2 variants are in linkage to and/or linkage disequilibrium (i.e., linkage and association) with PCOS in Italian families. In 212 Italian families, we tested 22 variants within the DRD2 gene for linkage and linkage disequilibrium with PCOS. We identified five novel variants significantly linked to the risk of PCOS. This is the first study to identify DRD2 as a risk gene in PCOS, however, functional studies are needed to confirm these results.

Salivary testosterone and cortisol levels in borderline personality disorder before and after a 12-week group dialectical behavior therapy intervention.

Borderline Personality Disorder (BPD) is a chronic, debilitating, and difficult to treat condition. BPD has recently been linked to steroid hormone dysregulation and medical conditions characterized by disturbed androgen metabolism. This study aimed to investigate cortisol and testosterone levels in BPD, and changes in hormones following psychological treatment. Participants with BPD (n = 33) completed a 12-week Dialectical Behavior Therapy group program. Pre and post salivary testosterone and cortisol were analyzed. Baseline hormones in the BPD group were compared to age-and-sex matched controls (n = 33). Non-parametric tests were utilized to investigate group differences, pre-post treatment hormone and symptom changes, and associations between symptoms and hormone levels. Participants with BPD had significantly higher testosterone levels than controls. Mean testosterone levels in females with BPD were double that of female controls. Testosterone and cortisol levels were related, and some BPD symptoms were associated with with hormone levels. BPD symptoms reduced significantly with treatment, however pre to post hormone levels did not change. This study supports an association between BPD symptoms and neuroendocrine dysfunction at baseline, however we found no reduction in hormone dysfunction post treatment. Further research into relationships between stress signaling and neuroendocrine disturbances in BPD may inform aetiological and treatment models. Australian New Zealand Clinical Trials Registry ACTRN12618000477224. Registered on 3 April 2018.

BRAF–MEK Inhibition in Newly Diagnosed Papillary Craniopharyngiomas

BackgroundCraniopharyngiomas, primary brain tumors of the pituitary–hypothalamic axis, can cause clinically significant sequelae. Treatment with the use of surgery, radiation, or both is often associated with substantial morbidity related to vision loss, neuroendocrine dysfunction, and memory loss. Genotyping has shown that more than 90% of papillary craniopharyngiomas carry BRAF V600E mutations, but data are lacking with regard to the safety and efficacy of BRAF–MEK inhibition in patients with papillary craniopharyngiomas who have not undergone previous radiation therapy.MethodsEligible patients who had papillary craniopharyngiomas that tested positive for BRAF mutations, had not undergone radiation therapy previously, and had measurable disease received the BRAF–MEK inhibitor combination vemurafenib–cobimetinib in 28-day cycles. The primary end point of this single-group, phase 2 study was objective response at 4 months as determined with the use of centrally determined volumetric data.ResultsOf the 16 patients in the study, 15 (94%; 95% confidence interval [CI], 70 to 100) had a durable objective partial response or better to therapy. The median reduction in the volume of the tumor was 91% (range, 68 to 99). The median follow-up was 22 months (95% CI, 19 to 30) and the median number of treatment cycles was 8. Progression-free survival was 87% (95% CI, 57 to 98) at 12 months and 58% (95% CI, 10 to 89) at 24 months. Three patients had disease progression during follow-up after therapy had been discontinued; none have died. The sole patient who did not have a response stopped treatment after 8 days owing to toxic effects. Grade 3 adverse events that were at least possibly related to treatment occurred in 12 patients, including rash in 6 patients. In 2 patients, grade 4 adverse events (hyperglycemia in 1 patient and increased creatine kinase levels in 1 patient) were reported; 3 patients discontinued treatment owing to adverse events.ConclusionsIn this small, single-group study involving patients with papillary craniopharyngiomas, 15 of 16 patients had a partial response or better to the BRAF–MEK inhibitor combination vemurafenib–cobimetinib. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03224767.)

Microglia: Sculptors of the polycystic ovary syndrome (PCOS)-like brain?

Several lines of evidence support a role for the brain in both the development and maintenance of polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility worldwide. Persistently elevated luteinizing hormone secretion and impaired gonadal steroid hormone feedback in PCOS patients suggests impairments within the neuronal networks that regulate the reproductive axis. Evidence from preclinical models has linked androgen excess during prenatal life with altered structure and function of the developing female brain that might underpin disease development in adulthood. Studies investigating the mechanisms by which excess androgens program changes in the female brain have highlighted an important role for microglia. This review discusses how these non-neuronal cells shape the developing female brain in response to excess androgens and focuses on how microglia may be involved in the development of the neuroendocrine dysfunctions associated with PCOS.