A naturalistic study of plasma lipid alterations in female patients with anorexia nervosa before and after weight restoration treatment.

BACKGROUND: Plasma lipid concentrations in patients with anorexia nervosa (AN) seem to be altered. METHODS: We conducted a naturalistic study with 75 adult female patients with AN and 26 healthy female controls (HC). We measured plasma lipid profile, sex hormones and used self-report questionnaires at admission and discharge. RESULTS: Total cholesterol (median (IQR): 4.9 (1.2)) and triglycerides (TG) (1.2 (0.8)) were elevated in AN at admission (BMI 15.3 (3.4)) compared with HC (4.3 (0.7), p = 0.003 and 0.9 (0.3), p = 0.006) and remained elevated at discharge (BMI 18.9 (2.9)) after weight restoration treatment. Estradiol (0.05 (0.1)) and testosterone (0.5 (0.7)) were lower in AN compared with HC (0.3 (0.3), p = < 0.001 and 0.8 (0.5), p = 0.03) and remained low at discharge. There was no change in eating disorder symptoms. Depression symptoms decreased (33 (17) to 30.5 (19), (p = 0.007)). Regression analyses showed that illness duration was a predictor of TG, age was a predictor of total cholesterol and LDL, while educational attainment predicted LDL and TG. CONCLUSION: Lipid concentrations remained elevated following weight restoration treatment, suggesting an underlying, premorbid dysregulation in the lipid metabolism in AN that persists following weight restoration. Elevated lipid concentrations may be present prior to illness onset in AN. LEVEL OF EVIDENCE: III: Evidence obtained from well-designed cohort or case-control analytic studies.

Fat is essential for the human body. Too much fat in the blood can be a sign of underlying illness including heart disease. This study investigated how plasma lipids (fats) are affected in individuals with anorexia nervosa (AN). We included 75 adult female individuals with AN and 26 healthy female controls, and measured lipids, sex hormones, and used questionnaires upon admission and discharge from treatment. We found that low-weight individuals with AN had higher lipids than the healthy controls, and these lipids remained elevated after weight restoration treatment. Additionally, individuals with AN had lower levels of sex hormones (estradiol and testosterone) at their low weight, and they stayed low even after weight restoration treatment. Eating disorder symptoms remained unchanged, but depression symptoms decreased during treatment. In conclusion, the study suggests that individuals with AN have changes in their lipid metabolism, which persists even after weight restoration treatment. We don't know the reason behind these elevated lipids, and therefore, this should be investigated further in future study.

Glecaprevir-Pibrentasvir and Ethinyl Estradiol-Induced Liver Injury in a Patient Without Cirrhosis.

Most drug liver injury cases are the result of an unexpected interaction with medications. We present a 33-year-old woman, four months postpartum, on ethinyl estradiol/norgestrel, who presented in the ED with nausea, vomiting, abdominal pain, and severe pruritus six weeks after starting glecaprevir-pibrentasvir (GP) treatment. The patient was suspected to have a drug-induced liver injury (DILI), and GP was discontinued. Other potential causes of liver injury were ruled out via labs, imaging, and liver biopsy. The patient's liver function significantly improved after discontinuing GP. Few cases of DILI secondary to GP have been reported. However, to the best of our knowledge, DILI from the interaction of ethinyl estradiol and GP does not exist in published literature. In our case, DILI was likely due to the effect of GP and ethinyl estradiol on the liver's cytochrome 450 (CYP 450) system. The aim of this report is to raise awareness and improve pharmacovigilance, especially in patients receiving medications that are metabolized by the liver's CYP 450 system. Early detection of DILI secondary to drug-interaction and discontinuation of the culprit medication is the mainstay of treatment. However, there is a lack of evidence-based management strategies for premature discontinuation of GP in the setting of DILI while treating chronic hepatitis C virus (HCV) infection. Further investigations are warranted.

G protein-coupled estrogen receptor expression in postnatal developing mouse retina.

Introduction: Estrogen has emerged as a multifaceted signaling molecule in the retina, playing an important role in neural development and providing neuroprotection in adults. It interacts with two receptor types: classical estrogen receptors (ERs) alpha and beta, and G protein-coupled estrogen receptor (Gper). Gper differs from classical ERs in structure, localization, and signaling. Here we provide the first report of the temporal and spatial properties of Gper transcript and protein expression in the developing and mature mouse retina. Methods: We applied qRT-PCR to determine Gper transcript expression in wild type mouse retina from P0-P21. Immunohistochemistry and Western blot were used to determine Gper protein expression and localization at the same time points. Results: Gper expression showed a 6-fold increase during postnatal development, peaking at P14. Relative total Gper expression exhibited a significant decrease during retinal development, although variations emerged in the timing of changes among different forms of the protein. Gper immunoreactivity was seen in retinal ganglion cells (RGCs) throughout development and also in somas in the position of horizontal cells at early time points. Immunoreactivity was observed in the cytoplasm and Golgi at all time points, in the nucleus at early time points, and in RGC axons as the retina matured. Discussion: In conclusion, our study illuminates the spatial and temporal expression patterns of Gper in the developing mouse retina and provides a vital foundation for further investigations into the role of Gper in retinal development and degeneration.

Estrogen deprivation and estrogen receptor α antagonism decrease DSS colitis in female mice.

The association of hormonal contraception with increased risk of inflammatory bowel disease (IBD) observed in females suggests involvement of ovarian hormones, such as estradiol, and the estrogen receptors in the progression of intestinal inflammation. Here, we investigated the effects of prophylactic SERM2 and estradiol supplementation in dextran sulfate sodium-induced colitis using mice with intact ovaries and ovariectomized (OVX) female mice. We found that graded colitis score was threefold reduced in the OVX mice, compared to mice with intact ovaries. Estradiol supplementation, however, aggravated the colitis in OVX mice, increasing the colitis score to a similar level than what was observed in the intact mice. Further, we observed that immune infiltration and gene expression of inflammatory interleukins Il1b, Il6, and Il17a were up to 200-fold increased in estradiol supplemented OVX colitis mice, while a mild but consistent decrease was observed by SERM2 treatment in intact animals. Additionally, cyclo-oxygenase 2 induction was increased in the colon of colitis mice, in correlation with increased serum estradiol levels. Measured antagonist properties of SERM2, together with the other results presented here, indicates an exaggerating role of ERα signaling in colitis. Our results contribute to the knowledge of ovarian hormone effects in colitis and encourage further research on the potential use of ER antagonists in the colon, in order to alleviate inflammation.

Inhibitory Effects of Parabens on Human and Rat 17ß-Hydroxysteroid Dehydrogenase 1: Mechanisms of Action and Impact on Hormone Synthesis.

Parabens are commonly used preservatives in cosmetics, food, and pharmaceutical products. The objective of this study was to examine the effect of nine parabens on human and rat 17ß-hydroxysteroid dehydrogenase 1 (17ß-HSD1) in human placental and rat ovarian cytosols, as well as on estradiol synthesis in BeWo cells. The results showed that the IC50 values for these compounds varied from methylparaben with the weakest inhibition (106.42µM) to hexylparaben with the strongest inhibition (2.05µM) on human 17ß-HSD1. Mode action analysis revealed that these compounds acted as mixed inhibitors. For rats, the IC50 values ranged from the weakest inhibition for methylparaben (no inhibition at 100 µM) to the most potent inhibition for hexylparaben (0.87µM), and they functioned as mixed inhibitors. Docking analysis indicated that parabens bind to the region bridging the NADPH and steroid binding sites of human 17ß-HSD1 and the NADPH binding site of rat 17ß-HSD1. Bivariate correlation analysis demonstrated negative correlations between LogP, molecular weight, heavy atoms, and apolar desolvation energy, and the IC50 values of these compounds. In conclusion, this study identified the inhibitory effects of parabens and their binding mechanisms on human and rat 17ß-HSD1, as well as their impact on hormone synthesis.

Non-genomic ERα-AMPK signaling regulates sex-dependent Bcrp transport activity at the blood-brain barrier.

The blood-brain barrier (BBB) is an extensive capillary network that protects the brain from environmental and metabolic toxins while limiting drug delivery to the central nervous system (CNS). The ATP-Binding Cassette (ABC) transporter Breast cancer resistance protein (Bcrp) reduces drug delivery across the BBB by actively transporting its clinical substrates back into peripheral circulation before their entry into the CNS compartment. 17ß-estradiol (E2)-elicited changes in Bcrp transport activity and expression have been documented previously. We report a novel signaling mechanism by which E2 decreases Bcrp transport activity in mouse brain capillaries (MBCs) via rapid non-genomic signaling through estrogen receptor α (ERα). We extended this finding to investigate the effects of different endocrine-disrupting compounds (EDCs) and selective estrogen receptor modulators (SERMs) on Bcrp transport function. We also demonstrate sex-dependent expression of Bcrp and E2-sensitive Bcrp transport activity at the BBB ex vivo. This work establishes an explanted tissue-based model by which to interrogate EDCs and SERMs as modulators of nongenomic estrogenic signaling with implications for sex and hormonal regulation of therapeutic delivery into the CNS.

Effectiveness and Safety of Different Estradiol Regimens in Transgender Females: A Randomized Controlled Trial.

Background: A goal of gender-affirming hormone therapy (GAHT) for transgender women is to use estradiol to suppress endogenous production of testosterone. However, the effects of different estradiol regimens and route of administration on testosterone suppression is unknown. This is the first open-label randomized trial comparing different GAHT regimens for optimal estradiol route and dosing. Objective: To evaluate 1 month and 6 months testosterone suppression <50 ng/dL with pulsed (once- or twice-daily sublingual 17-beta estradiol) and continuous (transdermal 17-beta estradiol) GAHT. Methods: This study was conducted at an outpatient adult transgender clinic. Thirty-nine transgender women undergoing initiation of GAHT were randomly assigned to receive either once-daily sublingual, twice-daily sublingual, or transdermal 17-beta estradiol. All participants received spironolactone as an antiandrogen. Doses were titrated at monthly intervals to achieve total testosterone suppression <50 ng/dL. Results: Transdermal 17-beta estradiol resulted in more rapid suppression of total testosterone, lower estrone levels, with no differences in estradiol levels when compared to once-daily and twice-daily sublingual estradiol. Moreover, there was no difference in the mean estradiol dose between the once-daily and twice-daily sublingual 17-beta estradiol group. Conclusion: Continuous exposure with transdermal 17-beta estradiol suppressed testosterone production more effectively and with lower overall estradiol doses relative to once or twice daily sublingual estradiol. Most transgender women achieved cisgender women testosterone levels within 2 months on 1 or 2 0.1 mg/24 hours estradiol patches. Given no difference between once- or twice-daily sublingual estradiol, pulsed 17-beta estradiol likely provides no benefit for testosterone suppression.

Reproductive hormones in relation to white matter hyperintensity volumes among midlife women.

INTRODUCTION: Although reproductive hormones are implicated in cerebral small vessel disease in women, few studies consider measured hormones in relation to white matter hyperintensity volume (WMHV), a key indicator of cerebral small vessel disease. Even fewer studies consider estrone (E1), the primary postmenopausal estrogen, or follicle-stimulating hormone (FSH), an indicator of ovarian age. We tested associations of estradiol (E2), E1, and FSH to WMHV among women. METHODS: Two hundred twenty-two women (mean age = 59) underwent hormone assays (E1, E2, FSH) and 3T brain magnetic resonance imaging. Associations of hormones to WMHV were tested with linear regression. RESULTS: Higher E2 (B[standard error (SE)] = -0.17[0.06], P = 0.008) and E1 (B[SE] = -0.26[0.10], P = 0.007) were associated with lower whole-brain WMHV, and higher FSH (B[SE] = 0.26[0.07], P = 0.0005) with greater WMHV (covariates age, race, education). When additionally controlling for cardiovascular disease risk factors, associations of E1 and FSH to WMHV remained. DISCUSSION: Reproductive hormones, particularly E1 and FSH, are important to women's cerebrovascular health. HIGHLIGHTS: Despite widespread belief that sex hormones are important to women's brain health, little work has considered how these hormones in women relate to white matter hyperintensities (WMH), a major indicator of cerebral small vessel disease. We considered relations of estradiol (E2), estrone (E1), and follicle-stimulating hormone (FSH) to WMH in midlife women. Higher E2 and E1 were associated with lower whole-brain WMH volume (WMHV), and higher FSH with higher whole-brain WMHV. Associations of E1 and FSH, but not E2, to WMHV persisted with adjustment for cardiovascular disease risk factors. Findings underscore the importance of E2 and FSH to women's cerebrovascular health.

Ultra-low-dose continuous combined estradiol and dydrogesterone in postmenopausal women: A pooled safety and tolerability analysis.

Objective: To assess the safety and tolerability of ultra-low dose estradiol and dydrogesterone (E0.5 mg/D2.5 mg) among postmenopausal women. Methods: This pooled analysis of data from three clinical studies assessed the effects of continuous combined ultra-low-dose estradiol and dydrogesterone among postmenopausal women. Participants received E0.5 mg/D2.5 mg or placebo for 13 weeks (double-blind, randomized, European study), E0.5 mg/D2.5 mg or placebo for 12 weeks (double-blind, randomized, Chinese study), or E0.5 mg/D2.5 mg for 52 weeks (open-label, European study). Safety outcomes included treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), treatment discontinuation due to a TEAE, and adverse events of special interest (AESIs). Results: Overall, 1027 women were included in the pooled analysis (E0.5 mg/D2.5 mg, n = 736; placebo, n = 291). Mean treatment exposure was 288.9 days in the E0.5 mg/D2.5 mg group and 86.6 days in the placebo group. The proportion of women experiencing ≥1 TEAE was similar in the E0.5 mg/D2.5 mg and placebo groups (50.1% vs 49.5%, respectively). TESAEs occurred in 12 (1.6%) women receiving E0.5 mg/D2.5 mg and 9 (3.1%) women receiving placebo. Discontinuation of study treatment was infrequent in both groups (E0.5 mg/D2.5 mg: 1.5%; placebo: 2.4%). The occurrence of breast pain was more common in the E0.5 mg/D2.5 mg group than in the placebo group (2.0% vs 0.3%) as was uterine hemorrhage (6.5% vs 2.4%). The incidence of acne, hypertrichoses and weight increased was similar between groups. Conclusions: Across three studies, ultra-low-dose estradiol plus dydrogesterone was well tolerated among postmenopausal women, with no increase in TEAEs or TESAEs compared with placebo.

The Prodrug DHED Delivers 17ß-Estradiol into the Retina for Protection of Retinal Ganglion Cells and Preservation of Visual Function in an Animal Model of Glaucoma.

We report a three-pronged phenotypic evaluation of the bioprecursor prodrug 10ß,17ß-dihydroxyestra-1,4-dien-3-one (DHED) that selectively produces 17ß-estradiol (E2) in the retina after topical administration and halts glaucomatous neurodegeneration in a male rat model of the disease. Ocular hypertension (OHT) was induced by hyperosmotic saline injection into an episcleral vein of the eye. Animals received daily DHED eye drops for 12 weeks. Deterioration of visual acuity and contrast sensitivity by OHT in these animals were markedly prevented by the DHED-derived E2 with concomitant preservation of retinal ganglion cells and their axons. In addition, we utilized targeted retina proteomics and a previously established panel of proteins as preclinical biomarkers in the context of OHT-induced neurodegeneration as a characteristic process of the disease. The prodrug treatment provided retina-targeted remediation against the glaucomatous dysregulations of these surrogate endpoints without increasing circulating E2 levels. Collectively, the demonstrated significant neuroprotective effect by the DHED-derived E2 in the selected animal model of glaucoma supports the translational potential of our presented ocular neuroprotective approach owing to its inherent therapeutic safety and efficacy.

Protective effects of 17-ß-estradiol on liver injury: The role of TLR4 signaling pathway and inflammatory response.

Liver injury, a major global health issue, stems from various causes such as alcohol consumption, nonalcoholic steatohepatitis, obesity, diabetes, metabolic syndrome, hepatitis, and certain medications. The liver's unique susceptibility to ischemia and hypoxia, coupled with the critical role of the gut-liver axis in inflammation, underscores the need for effective therapeutic interventions. The study highlights E2's interaction with estrogen receptors (ERs) and its modulation of the Toll-like receptor 4 (TLR4) signaling pathway as key mechanisms in mitigating liver injury. Activation of TLR4 leads to the release of pro-inflammatory cytokines and chemokines, exacerbating liver inflammation and injury. E2 down-regulates TLR4 expression, reduces oxidative stress, and inhibits pro-inflammatory cytokines, thereby protecting the liver. Both classic (ERα and ERß) and non-classic [G protein-coupled estrogen receptor (GPER)] receptors are influenced by E2. ERα is particularly crucial for liver regeneration, preventing liver failure by promoting hepatocyte proliferation. Furthermore, E2 exerts anti-inflammatory, antioxidant, and anti-apoptotic effects by inhibiting cytokines such as IL-6, IL-1ß, TNF-α, and IL-17, and by reducing lipid peroxidation and free radical damage. The article calls for further clinical research to validate these findings and to develop estrogen-based treatments for liver injuries. Overall, the research emphasizes the significant potential of E2 as a therapeutic agent for liver injuries. It advocates for extensive clinical studies to validate E2 hepatoprotective properties and develop effective estrogen-based treatments.

Synthesis and anticancer properties of a hybrid molecule with the testosterone and estradiol head-groups.

This is the first report on a unique hybrid molecule made of estradiol and testosterone (TS). This distinctive hybrid molecule (1) was designed to interact with both the estrogen receptor (ER) and the androgen receptor (AR) found in hormone-dependent female and male cancer cells, and was synthesized using ethynylestradiol (17EE) as the estrogenic component and 7α-(4-azido-but-2-enyl)-4-androsten-17ß-ol-3-one as the androgenic counterpart in a seven-step reaction with ∼ 26 % overall yield. We reasoned that the dual receptor binding ability could allow 1 to act as an antihormone. This was tested on hormone-dependent and hormone-independent breast cancer (BCa) and prostate cancer (PCa) cells. The antiproliferative activity was also assessed on colon and skin cancer cells. We found that 1 was active against MCF7 (ER + ) BCa cells (IC50 of 4.9 µM), had lower inhibitory potency on LNCaP (AR + ) PCa cells (IC50 > 5 µM) and no effect on PC3 and DU145 (AR-) PCa cells. This suggests that the estrogenic component of 1 can interact with the ER on MCF7 cells more effectively than the androgenic component with the AR on LNCaP PCa cells, possibly due to a suboptimal spacer or linkage site(s). Nonetheless, the hybrid 1 was active against colon (HT-29) and melanoma (M21) cancer cells (IC50 of 3.5 µM and 2.3 µM, respectively), and had low cross-reactivity with the drug- and androgen-metabolizing cytochrome P450 3A4 (CYP3A4, IC50 ≫ 5 µM). These findings demonstrate the anticancer potential of 1 and warrant further explorations on this new type of hybrids.

Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: 12 months of an ongoing randomized phase 3 trial.

BACKGROUND: Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects. OBJECTIVE: To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol /0.5 mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain. STUDY DESIGN: This ongoing, 48-month, phase 3 study consists of a 12-month, double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for 6 months followed by elagolix with add-back therapy, or placebo. The co-primary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy versus placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density. RESULTS: A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% versus 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% versus 36.8%; P≤.001) at 6 months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of -2.43% (lumbar spine), -1.54% (total hip), and -1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of -1.58% to -1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and 12. CONCLUSION: Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6 months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12 months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was < 1% and was attenuated compared with bone loss observed with elagolix monotherapy.

Sex Differences of Neutrophil Extracellular Traps on Lipopolysaccharide-Stimulated Human Neutrophils.

Objective: Sex differences exist in sepsis, but the commitment of neutrophils to these differences remains unclear. Neutrophil extracellular traps (NETs) function to remove pathogens, yet excessive NETs release can contribute to organ damage. This study explores effects of the gender hormones on endotoxin-induced NETs using neutrophils from both male and female sources. Methods: Blood samples were collected from healthy volunteers. Isolated neutrophils were seeded in collagen-coated cell culture plates, and NETs were induced by lipopolysaccharide (LPS) treatment. After 15 minutes of LPS treatment, 17ß-estradiol (0.03-272.4 ng/mL), testosterone enanthate (0.01-10 ng/mL), dimethyl sulfoxide, or ethanol (vehicle control) was added to the plates. These were incubated for three hours at 37°C with 5% CO2. Neutrophil extracellular traps formation was assessed using immunofluorescence staining. Results: Lipopolysaccharide-induced NETs formation was significantly greater in females than in males. In male-derived neutrophils, 17ß-estradiol at above the blood concentrations significantly suppressed LPS-induced NETs. No effect was seen while using testosterone enanthate to NETs at any concentration. In female-derived neutrophils, 17ß-estradiol, which was near to the highest concentration of non-pregnant women's blood, tended to increase NETs. Testosterone enanthate, which was near to female blood concentration, significantly promoted NETs. Conclusions: Sex differences existed in LPS-induced NETs of human neutrophil. In males, high concentrations of 17ß-estradiol administration may have a suppressive effect on excessive NETs during infection. In females, endogenous gender hormones may promote NETs during infection. Sex differences in neutrophils may need to be considered in organ damage owing to NETs excess such as sepsis.

Targeting estrogen metabolism in high-grade serous ovarian cancer shows promise to overcome platinum resistance.

The high mortality rate due to chemoresistance in patients with high-grade ovarian cancer (HGSOC) emphasizes the urgent need to determine optimal treatment strategies for advanced and recurrent cases. Our study investigates the interplay between estrogens and chemoresistance in HGSOC and shows clear differences between platinum-sensitive and -resistant tumors. Through comprehensive transcriptome analyzes, we uncover differences in the expression of genes of estrogen biosynthesis, metabolism, transport and action underlying platinum resistance in different tissues of HGSOC subtypes and in six HGSOC cell lines. Furthermore, we identify genes involved in estrogen biosynthesis and metabolism as prognostic biomarkers for HGSOC. Additionally, our study elucidates different patterns of estrogen formation/metabolism and their effects on cell proliferation between six HGSOC cell lines with different platinum sensitivity. These results emphasize the dynamic interplay between estrogens and HGSOC chemoresistance. In particular, targeting the activity of steroid sulfatase (STS) proves to be a promising therapeutic approach with potential efficacy in limiting estrogen-driven cell proliferation. Our study reveals potential prognostic markers as well as identifies novel therapeutic targets that show promise for overcoming resistance and improving treatment outcomes in HGSOC.

Impact of different hormones on the regulation of nitric oxide in diabetes.

Polymetabolic syndrome achieved pandemic proportions and dramatically influenced public health systems functioning worldwide. Chronic vascular complications are the major contributors to increased morbidity, disability, and mortality rates in diabetes patients. Nitric oxide (NO) is among the most important vascular bed function regulators. However, NO homeostasis is significantly deranged in pathological conditions. Additionally, different hormones directly or indirectly affect NO production and activity and subsequently act on vascular physiology. In this paper, we summarize the recent literature data related to the effects of insulin, estradiol, insulin-like growth factor-1, ghrelin, angiotensin II and irisin on the NO regulation in physiological and diabetes circumstances.

Engineering of dual recognition functional aptamer-molecularly imprinted polymeric solid-phase microextraction for detecting of 17ß-estradiol in meat samples.

In this study, an enhanced selective recognition strategy was employed to construct a novel solid-phase microextraction fiber coating for the detection of 17ß-estradiol, characterized by the combination of aptamer biorecognition and molecularly imprinted polymer recognition. Benefiting from the combination of molecularly imprinted and aptamer, aptamer-molecularly imprinted (Apt-MIP) fiber coating had synergistic recognition effect. The effects of pH, ion concentration, extraction time, desorption time and desorption solvent on the adsorption capacity of Apt-MIP were investigated. The adsorption of 17ß-estradiol on Apt-MIP followed pseudo-second order kinetic model, and the Freundlich isotherm. The process was exothermic and thermodynamically spontaneous. Compared with polymers that only rely on imprinted recognition, non-imprinted recognition or aptamer affinity, Apt-MIP had the best recognition performance, which was 1.30-2.20 times that of these three materials. Furthermore, the adsorption capacity of Apt-MIP for 17ß-estradiol was 885.36-1487.52 times than that of polyacrylate and polydimethylsiloxane/divinylbenzone commercial fiber coatings. Apt-MIP fiber coating had good stability and could be reused for more than 15 times. Apt-MIP solid-phase microextraction coupled with high-performance liquid chromatography was successfully applied to the determination of 17ß-estradiol in pork, chicken, fish and shrimp samples, with satisfactory recoveries of 79.61 %-105.70 % and low limits of detection (0.03 µg/kg). This work provides new perspectives and strategies for sample pretreatment techniques based on molecular imprinting technology and improves analytical performance.

Demographic and physiological signals of reproductive events in humpback whales on a southwest pacific breeding ground.

The field of marine mammal conservation has dramatically benefited from the rapid advancement of methods to assess the reproductive physiology of individuals and populations from steroid hormones isolated from minimally invasive skin-blubber biopsy samples. Historically, this vital information was only available from complete anatomical and physiological investigations of samples collected during commercial or indigenous whaling. Humpback whales (Megaptera novaeangliae) are a migratory, cosmopolitan species that reproduce in warm, low-latitude breeding grounds. New Caledonia is seasonally visited by a small breeding sub-stock of humpback whales, forming part of the endangered Oceania subpopulation. To better understand the demographic and seasonal patterns of reproductive physiology in humpback whales, we quantified baseline measurements of reproductive hormones (progesterone-P4, testosterone-T and 17ß-estradiol-E2) using an extensive archive of skin-blubber biopsy samples collected from female humpback whales in New Caledonia waters between 2016 and 2019 (n = 194). We observed significant differences in the P4, T and E2 concentrations across different demographic groups of female humpback whales, and we described some of the first evidence of the endocrine patterns of estrous in live free-ranging baleen whales. This study is fundamental in its methodological approach to a wild species that has a global distribution, with seasonally distinct life histories. This information will assist in monitoring, managing and conserving this population as global ecological changes continue to occur unhindered.

Modeling Sex-Bias in Anxiety: Pros and Cons of a Larval Zebrafish Model.

Anxiety disorders are the most prevalent psychiatric disorders, exhibiting strong female bias. Clinical studies implicate declining estradiol levels in the exacerbation of anxiety symptoms in the premenstrual phase of the menstrual cycle. This study aimed to simulate estradiol fluctuation-linked anxiety behavior in larval zebrafish, using an estradiol treatment withdrawal model. Contrary to model aims, estradiol treatment withdrawal decreased both basal activity and anxiety-like hyperlocomotion (ANOVA main effect of dose, P < 0.0001 and P < 0.01, respectively) in the light/dark transition test. The accuracy of the estradiol washout model was not improved by longer durations of treatment or withdrawal. Basal activity was slightly altered by supraphysiological concentrations of WAY-200070 in the absence of added estradiol. Estrogen receptor (ER) ß expression was not upregulated in larvae exposed to physiologically relevant, low concentrations of estradiol. Longer exposure to low concentrations of estradiol increased antioxidant capacity (P < 0.01). In addition, acute exposure to low concentrations of estradiol increased basal activity. Data suggest that in the current models, estradiol-associated altered activity levels were linked to more favorable redox status, rather than reflecting altered anxiety levels. As such, it is recommended that zebrafish larval behavioral analysis be conducted in parallel with mechanistic studies such as redox indicators, for investigations focused on ER signaling.

Exploring gut microbiota's role in rheumatic valve disease: insights from a Mendelian randomization study and mediation analysis.

Background: Investigating the relationship between gut microbiota and Rheumatic Valve Disease (RVD) is crucial for understanding the disease's etiology and developing effective interventions. Our study adopts a novel approach to examine the potential causal connections between these factors. Methods: Utilizing a two-sample Mendelian Randomization (MR) framework, we incorporated a multi-variable MR (MVMR) strategy to assess the mediatory mechanisms involved. This approach involved analyzing data from the MiBioGen consortium for gut microbiota and the FinnGen for RVD, among other sources. Instrumental variables (IVs) were carefully selected based on rigorous MR principles, and statistical analysis was conducted using bidirectional two-sample MR, such as inverse variance-weighted (IVW), weighted median, MR-Egger regression and MR Steiger Test methods. The MR-PRESSO strategy was employed for outlier detection, and MVMR was used to untangle the complex relationships between multiple microbiota and RVD. Results: Our analysis highlighted several gut microbiota classes and families with potential protective effects against RVD, including Lentisphaerae, Alphaproteobacteria, and Streptococcaceae. In contrast, certain genera, such as Eubacterium eligens and Odoribacter, were identified as potential risk factors. The MVMR analysis revealed significant mediation effects of various immune cell traits and biomarkers, such as CD4-CD8- T cells, CD3 on Terminally Differentiated CD8+ T cell and Pentraxin-related protein PTX, elucidating the complex pathways linking gut microbiota to RVD. Conclusion: This study underscores the intricate and potentially causal relationship between gut microbiota and RVD, mediated through a range of immune and hormonal factors. The use of MVMR in our methodological approach provides a more comprehensive understanding of these interactions, highlighting the gut microbiota's potential as therapeutic targets in RVD management. Our findings pave the way for further research to explore these complex relationships and develop targeted interventions for RVD.