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The aim of this study was to investigate the role of 17β‐estradiol (E2)‐mediated oestrogen receptor (ER) in modulating the depressive‐like behaviours of ovariectomy (OVX) mice and the associated mechanisms. E2 was administrated in OVX mice. The behaviour and physiological changes of OVX mice including immobility time in tail suspension test (TST) and forced swimming test (FST), levels of serum E2, inflammatory mediators, oxidative stress factors, indoleamine2,3‐dioxygenase 1 (IDO1) and the neurotransmitters mediated by IDO1 activation were then recorded. Cell injury models established by lipopolysaccharide (LPS) or H2O2 stimulation in HT22 and BV2 cells were employed to further explore the mechanisms of E2's function. E2 treatment improved OVX‐induced increase of immobility time in FST and TST. Meanwhile, E2 ameliorated the changes of inflammatory factors (NF‐κB, TNF‐α and IL‐6), IDO1, IDO1‐mediated TRP/KYN pathway and oxidative stress factors (iNOS, MDA, GSH and SOD) in the hippocampus of OVX mice. Interestingly, ERβ inhibitor abolished E2's inhibitory effects on the inflammation and IDO1‐mediated TRP/KYN pathway; ERβ inhibitor also abolished E2's anti‐oxidative stress effect. In cell experiments, ERβ small interfering RNA (siRNA) pretreatment reversed E2's anti‐inflammatory effect on LPS‐treated HT22 and BV2 cells and E2's inhibitory effect on IDO1 expression in LPS‐treated BV2 cells. ERβ siRNA pretreatment also reversed E2's anti‐oxidation effect on H2O2‐treated HT22 cells. E2 exert the antidepressant function in OVX mice via ERβ‐modulated suppression of NF‐κB‐mediated inflammatory pathway, oxidative stress factors and IDO1‐mediated TRP/KYN pathway in the hippocampus.

Abstract Introduction/Objective Significant technical issues are associated with methods used for the measurement of estradiol.The objective of this study was to qualify an electrochemiluminescent (ECL) assay for the quantification of 17β-estradiol (E2) in rat serum. Hemolysis has been identified as a factor that interferes with accurate measurement.The impact of hemolysis was also assessed. Methods Approximately 1.0 mL of whole blood was collected from male and female rats into separate red top tubes and processed to serum. The LoQ for E2 was evaluated by analyzing the low calibrator or at least 6 serum samples diluted to produce a value at the low end of the reportable range 8 times in the same run.The mean, standard deviation, and %CV were calculated for each sample.The data set was analyzed by plotting the data and determining the concentration at the intersection of the precision profile curve. Linearity of dilution was performed using commercially available calibration verification material and E2 stripped rat serum.The correlation coefficient, the slope, and the % Nominal were calculated. Intra assay precision was evaluated by analyzing 8 consecutive times in a single run one rat serum sample that was not diluted or spiked. This analysis was performed during the evaluation of the LoQ.The mean, SD and %CV were calculated. The interference of hemolysis with the E2 assay was tested by analyzing at least 5 rat serum samples/pools spiked with hemolyzed rat serum at different hemoglobin concentrations.The %RE was calculated. Results The LoQ assays were acceptable. For all samples tested, the % CV was less than or equal to 25%.The LoQ was verified to be 8.50 pg/mL. The %CV was 15.6%. For samples with estradiol concentrations below the LoQ, a value of 4.25 pg/ml was reported. Linearity of dilution for E2 was acceptable.The correlation coefficients were greater than or equal to 0.9000, the slopes were between 0.7500 and 1.2500, and the % nominals for each level were between 75-125%. The intra-assay precision was considered acceptable with a %CV of 8.6%. There was no hemolysis interference in the assay when samples were spiked with hemoglobin concentrations of up to 70 mg/dL, based on the %RE of less than or equal to 25% of non-hemolyzed samples. Conclusion Qualification of the ECL method, demonstrates the assay is suitable for the determination of E2 in serum samples from rats and absence of hemolysis interference up to 70 mg/dL of hemoglobin concentration.

Epidemiological studies have suggested a lower incidence of arrhythmia‐induced sudden cardiac death in women than in men. 17β‐oestradiol (E2) has been reported to have a post‐myocardial infarction antiarrhythmic effect, although the mechanisms have yet to be elucidated. We investigated whether E2‐mediated antioxidation regulates macrophage polarization and affects cardiac sympathetic reinnervation in rats after MI. Ovariectomized Wistar rats were randomly assigned to placebo pellets, E2 treatment, or E2 treatment +3‐morpholinosydnonimine (a peroxynitrite generator) and followed for 4 weeks. The infarct sizes were similar among the infarcted groups. At Day 3 after infarction, post‐infarction was associated with increased superoxide levels, which were inhibited by administering E2. E2 significantly increased myocardial IL‐10 levels and the percentage of regulatory M2 macrophages compared with the ovariectomized infarcted alone group as assessed by immunohistochemical staining, Western blot and RT‐PCR. Nerve growth factor colocalized with both M1 and M2 macrophages at the magnitude significantly higher in M1 compared with M2. At Day 28 after infarction, E2 was associated with attenuated myocardial norepinephrine levels and sympathetic hyperinnervation. These effects of E2 were functionally translated in inhibiting fatal arrhythmias. The beneficial effect of E2 on macrophage polarization and sympathetic hyperinnervation was abolished by 3‐morpholinosydnonimine. Our results indicated that E2 polarized macrophages into the M2 phenotype by inhibiting the superoxide pathway, leading to attenuated nerve growth factor‐induced sympathetic hyperinnervation after myocardial infarction.

Even at low concentrations, steroid hormones pose a significant threat to ecosystem health and are classified as micropollutants. Among these, 17β-estradiol (molecular formula: C 18 H 24 O 2 ; pK a  = 10.46; Log K ow  = 4.01; solubility in water = 3.90 mg L −1 at 27 °C; molecular weight: 272.4 g mol −1 ) is extensively studied as an endocrine disruptor due to its release through natural pathways and widespread use in conventional medicine. 17β-estradiol (E2) is emitted by various sources, such as animal and human excretions, hospital and veterinary clinic effluents, and treatment plants. In aquatic biota, it can cause issues ranging from the feminization of males to inhibiting plant growth. This review aims to identify technologies for remediating E2 in water, revealing that materials like graphene oxides, nanocomposites, and carbonaceous materials are commonly used for adsorption. The pH of the medium, especially in acidic to neutral conditions, affects efficiency, and ambient temperature (298 K) supports the process. The Langmuir and Freundlich models aptly describe isothermal studies, with interactions being of a low-energy, physical nature. Adsorption faces limitations when other ions coexist in the solution. Hybrid treatments exhibit high removal efficiency. To mitigate global E2 pollution, establishing national and international standards with detailed guidelines for advanced treatment systems is crucial. Despite significant advancements in optimizing technologies by the scientific community, there remains a considerable gap in their societal application, primarily due to economic and sustainable factors. Therefore, further studies are necessary, including conducting batch experiments with these adsorbents for large-scale treatment along with economic analyses of the production process. Graphical Abstract

Traumatic brain injury (TBI), which leads to high mortality and morbidity, is a prominent public health problem worldwide. Neuroinflammation involving microglia and astrocyte activation has been demonstrated to play critical role in the secondary injury induced by TBI. A1 astrocytes, which are induced by activated microglia, can directly kill neurons by secreting neurotoxic complement C3. Estrogen has been proved to possess neuroprotective effects, but the effect and underlying mechanism of estrogen on TBI-induced neuroinflammatory injury remain largely unclear. In this study, we constructed an adult male mouse model of TBI and immediately after injury treated the mice with 17β-estradiol (E2) (100 μg/kg, once every day via intraperitoneal injection) for 3 days. We found that E2 treatment significantly alleviated TBI-induced neurological deficits, neuronal injuries, and brain edema and significantly inhibited Iba1 and GFAP expression, which are markers of microglia and astrocyte activation, respectively. E2 treatment also significantly inhibited TLR4 and NF-κB protein expression, and significantly reduced the expression of the proinflammatory factors IL-1β, IL-6, and TNF-α. Moreover, E2 treatment significantly decreased the number of complement C3d/GFAP-positive cells and complement C3d protein expression. Taking these results together, we concluded that E2 treatment dramatically alleviates TBI neuroinflammatory injury by inhibiting TLR4/NF-κB pathway-mediated microglia and astrocyte activation and neuroinflammation and reducing A1-phenotype neurotoxic astrocyte activation. Our findings indicate that E2 treatment may be a potential therapy strategy for TBI-induced neuroinflammation injury.

The hypothalamic–pituitary–adrenal (HPA) axis, a neuroendocrine network that controls hormonal responses to internal and external challenges in an organism’s environment, exhibits strikingly sex-biased activity. In adult female rodents, acute HPA function following a stressor is markedly greater than it is in males, and this difference has largely been attributed to modulation by the gonadal hormones testosterone and estradiol. These gonadal hormones are produced by the hypothalamic–pituitary–gonadal (HPG) axis and have been shown to determine sex differences in adult HPA function after acute stress via their activational and organizational effects. Although these actions of gonadal hormones are well supported, the possibility that sex chromosomes similarly influence HPA activity is unexplored. Moreover, questions remain regarding sex differences in the activity of the HPA axis following chronic stress and the underlying contributions of gonadal hormones and sex chromosomes. The present review examines what is currently known about sex differences in the neuroendocrine response to stress, as well as outstanding questions regarding this sex bias. Although it primarily focuses on the rodent literature, a brief discussion of sex differences in the human HPA axis is also included.

Premature ovarian insufficiency (POI) is one form of female infertility, defined by loss of ovarian activity before the age of 40 and characterized by amenorrhea (primary or secondary) with raised gonadotropins and low estradiol. POI affects up to one in 100 females, including one in 1000 before the age of 30. Substantial evidence suggests a genetic basis for POI; however, the majority of cases remain unexplained, indicating that genes likely to be associated with this condition are yet to be discovered. This review discusses the current knowledge of the genetic basis of POI. We highlight genes typically known to cause syndromic POI that can be responsible for isolated POI. The role of mouse models in understanding POI pathogenesis is discussed, and a thorough list of candidate POI genes is provided. Identifying a genetic basis for POI has multiple advantages, such as enabling the identification of presymptomatic family members who can be offered counseling and cryopreservation of eggs before depletion, enabling personalized treatment based on the cause of an individual's condition, and providing better understanding of disease mechanisms that ultimately aid the development of improved treatments.

This study assessed psychosocial functioning for 2 years after the initiation of gender-affirming hormones in transgender and nonbinary youth. Hormone therapy improved appearance congruence and psychosocial functioning.

Endometriosis is a common cause of pelvic pain in women, for which current treatment options are suboptimal. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, combined with estradiol and a progestin, was evaluated for treatment of endometriosis-associated pain. In these two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled trials at 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America, we randomly assigned women aged 18–50 years with surgically or directly visualised endometriosis with or without histological confirmation, or with histological diagnosis alone. Participants were eligible if they had moderate to severe endometriosis-associated pain and, during the 35-day run-in period, a dysmenorrhoea Numerical Rating Scale (NRS) score of 4·0 or higher on two or more days and a mean non-menstrual pelvic pain NRS score of 2·5 or higher, or a mean score of 1·25 or higher that included a score of 5 or more on 4 or more days. Women received (1:1:1) once-daily oral placebo, relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0·5 mg), or delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks) for 24 weeks. During the double-blind randomised treatment and follow-up period, all patients, investigators, and sponsor staff or representatives involved in the conduct of the study were masked to treatment assignment. The co-primary endpoints were responder rates at week 24 for dysmenorrhoea and non-menstrual pelvic pain, both based on NRS scores and analgesic use. Efficacy and safety were analysed in the modified intent-to-treat population (randomised patients who received ≥1 study drug dose). The studies are registered at ClinicalTrials.gov (SPIRIT 1 [NCT03204318] and SPIRIT 2 [NCT03204331]) and EudraCT (SPIRIT 1 [2017–001588–19] and SPIRIT 2 [2017–001632–19]). Eligible patients who completed the SPIRIT studies could enrol in a currently ongoing 80-week open-label extension study (SPIRIT EXTENSION [NCT03654274, EudraCT 2017-004066-10]). Database lock for the on-treatment duration has occurred, and post-treatment follow-up for safety, specificially for bone mineral density and menses recovery, is ongoing at the time of publication. 638 patients were enrolled into SPIRIT 1 and randomly assigned between Dec 7, 2017, and Dec 4, 2019, to receive relugolix combination therapy (212 [33%]), placebo (213 [33%]), or relugolix delayed combination therapy (213 [33%]). 623 patients were enrolled into SPIRIT 2 and were randomly assigned between Nov 1, 2017 and Oct 4, 2019, to receive relugolix combination therapy (208 [33%]), placebo (208 [33%]), or relugolix delayed combination therapy (207 [33%]). 98 (15%) patients terminated study participation early in SPIRIT 1 and 115 (18%) in SPIRIT 2. In SPIRIT 1, 158 (75%) of 212 patients in the relugolix combination therapy group met the dysmenorrhoea responder criteria compared with 57 (27%) of 212 patients in the placebo group (treatment difference 47·6% [95% CI 39·3–56·0]; p<0·0001). In SPIRIT 2, 155 (75%) of 206 patients in the relugolix combination therapy group were dysmenorrhoea responders compared with 62 (30%) of 204 patients in the placebo group (treatment difference 44·9% [95% CI 36·2–53·5]; p<0·0001). In SPIRIT 1, 124 (58%) of 212 patients in the relugolix combination therapy group met the non-menstrual pelvic pain responder criteria versus 84 (40%) patients in the placebo group (treatment difference 18·9% [9·5–28·2]; p<0·0001). In SPIRIT 2, 136 (66%) of 206 patients were non-menstrual pelvic pain responders in the relugolix combination therapy group compared with 87 (43%) of 204 patients in the placebo group (treatment difference 23·4% [95% CI 13·9–32·8]; p<0·0001). The most common adverse events were headache, nasopharyngitis, and hot flushes. There were nine reports of suicidal ideation across both studies (two in the placebo run-in, two in the placebo group, two in the relugolix combination therapy group, and three in the delayed relugolix combination therapy group). No deaths were reported. Least squares mean percentage change in lumbar spine bone mineral density in the relugolix combination therapy versus placebo groups was –0·70% versus 0·21% in SPIRIT 1 and –0·78% versus 0·02% in SPIRIT 2, and in the delayed relugolix combination group was –2·0% in SPIRIT 1 and –1·9% in SPIRIT 2. Decreases in opioid use were seen in treated patients as compared with placebo. Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment. Myovant Sciences.

Observations of the disproportionate incidence of depression in women compared with men have long preceded the recent explosion of interest in sex differences. Nonetheless, the source and implications of this epidemiologic sex difference remain unclear, as does the practical significance of the multitude of sex differences that have been reported in brain structure and function. In this article, we attempt to provide a framework for thinking about how sex and reproductive hormones (particularly estradiol as an example) might contribute to affective illness. After briefly reviewing some observed sex differences in depression, we discuss how sex might alter brain function through hormonal effects (both organizational (programmed) and activational (acute)), sex chromosome effects, and the interaction of sex with the environment. We next review sex differences in the brain at the structural, cellular, and network levels. We then focus on how sex and reproductive hormones regulate systems implicated in the pathophysiology of depression, including neuroplasticity, genetic and neural networks, the stress axis, and immune function. Finally, we suggest several models that might explain a sex-dependent differential regulation of affect and susceptibility to affective illness. As a disclaimer, the studies cited in this review are not intended to be comprehensive but rather serve as examples of the multitude of levels at which sex and reproductive hormones regulate brain structure and function. As such and despite our current ignorance regarding both the ontogeny of affective illness and the impact of sex on that ontogeny, sex differences may provide a lens through which we may better view the mechanisms underlying affective regulation and dysfunction.