Search

Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER+ human epidermal growth factor receptor-negative (HER2-) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3-4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144-fulvestrant combination (n = 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2-46.1%) and the median PFS was 10.7 (5.3-not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER+HER2- mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration: NCT04606446 .

The prevalence and progression of cancer differ in males and females, and thus, sexual dimorphism in tumor development directly impacts clinical research and medicine. Long non-coding RNAs (lncRNAs) are increasingly recognized as important players in gene expression and various cellular processes, including cancer development and progression. In recent years, lncRNAs have been implicated in the differences observed in cancer incidence, progression, and treatment responses between men and women. Here, we present a brief overview of the current knowledge regarding the role of lncRNAs in cancer sex dimorphism, focusing on how they affect epigenetic processes in male and female mammalian cells. We discuss the potential mechanisms by which lncRNAs may contribute to sex differences in cancer, including transcriptional control of sex chromosomes, hormonal signaling pathways, and immune responses. We also propose strategies for studying lncRNA functions in cancer sex dimorphism. Furthermore, we emphasize the importance of considering sex as a biological variable in cancer research and the need to investigate the role lncRNAs play in mediating these sex differences. In summary, we highlight the emerging link between lncRNAs and cancer sex dimorphism and their potential as therapeutic targets.

BACKGROUND: A bioactive myelin basic protein (MBP) fragment, comprising MBP84-104, is released in sciatic nerve after chronic constriction injury (CCI). Intraneural injection (IN) of MBP84-104 in an intact sciatic nerve is sufficient to induce persistent neuropathic pain-like behavior via robust transcriptional remodeling at the injection site and ipsilateral dorsal root ganglia (DRG) and spinal cord. The sex (female)-specific pronociceptive activity of MBP84-104 associates with sex-specific changes in cholesterol metabolism and activation of estrogen receptor (ESR)1 signaling. METHODS: In male and female normal and post-CCI rat sciatic nerves, we assessed: (i) cholesterol precursor and metabolite levels by lipidomics; (ii) MBP84-104 interactors by mass spectrometry of MBP84-104 pull-down; and (iii) liver X receptor (LXR)α protein expression by immunoblotting. To test the effect of LXRα stimulation on IN MBP84-104-induced mechanical hypersensitivity, the LXRα expression was confirmed along the segmental neuraxis, in DRG and spinal cord, followed by von Frey testing of the effect of intrathecally administered synthetic LXR agonist, GW3965. In cultured male and female rat DRGs exposed to MBP84-104 and/or estrogen treatments, transcriptional effect of LXR stimulation by GW3965 was assessed on downstream cholesterol transporter Abc, interleukin (IL)-6, and pronociceptive Cacna2d1 gene expression. RESULTS: CCI regulated LXRα ligand and receptor levels in nerves of both sexes, with cholesterol precursors, desmosterol and 7-DHC, and oxysterol elevated in females relative to males. MBP84-104 interacted with nuclear receptor coactivator (Ncoa)1, known to activate LXRα, injury-specific in nerves of both sexes. LXR stimulation suppressed ESR1-induced IL-6 and Cacna2d1 expression in cultured DRGs of both sexes and attenuated MBP84-104-induced pain in females. CONCLUSION: The injury-released bioactive MBP fragments induce pronociceptive changes by selective inactivation of nuclear transcription factors, including LXRα. By Ncoa1 sequestration, bioactive MBP fragments render LXRα function to counteract pronociceptive activity of estrogen/ESR1 in sensory neurons. This effect of MBP fragments is prevalent in females due to high circulating estrogen levels in females relative to males. Restoring LXR activity presents a promising therapeutic strategy in management of neuropathic pain induced by bioactive MBP.

PURPOSE: Treatment guidelines for gender-affirming hormone therapy with estrogen (GAHT-E) recommend specific dosing regimens based on limited data. Well-controlled efficacy trials are essential to tailoring treatment to patient goals as the guidelines recommend. The goal of this study was to take a foundational step toward designing community-centered effectiveness trials for gender-diverse individuals seeking GAHT-E. METHODS: Our team developed a cross-sectional survey based on broad clinical experience and consultation with our community advisory board. The survey included 60 items covering demographics, transition history, goals and priorities for treatment, indicators of treatment success, sexual function goals, and future research priorities. The survey was distributed during the summer of 2021, primarily through social networks designed for gender-expansive individuals seeking treatment with estrogen. RESULTS: A total of 1270 individuals completed the survey. Overall treatment goals most frequently rated extremely important or very important were the following: (1) improved satisfaction with life (81%), (2) appearing more feminine (80%), (3) appearing less masculine (77%), (4) improved mental health (76%), and (5) being seen as your true gender by others (75%). The three body characteristics most frequently rated highest priority or high priority among changes were the following: (1) facial hair (85%), (2) breast shape or size (84%), and (3) body shape (80%). The highest-rated research priority was comparing feminization with different routes of estrogen administration. CONCLUSION: The goals and experiences of individuals seeking GAHT-E are diverse. Future clinical trials of GAHT-E should be grounded in the needs and priorities of community stakeholders.

IntroductionReproductive health history may contribute to cognitive aging and risk for Alzheimer's disease, but this is understudied among Hispanic/Latina women.MethodsParticipants included 2126 Hispanic/Latina postmenopausal women (44 to 75 years) from the Study of Latinos-Investigation of Neurocognitive Aging. Survey linear regressions separately modeled the associations between reproductive health measures (age at menarche, history of oral contraceptive use, number of pregnancies, number of live births, age at menopause, female hormone use at Visit 1, and reproductive span) with cognitive outcomes at Visit 2 (performance, 7-year change, and mild cognitive impairment [MCI] prevalence).ResultsYounger age at menarche, oral contraceptive use, lower pregnancies, lower live births, and older age at menopause were associated with better cognitive performance. Older age at menarche was protective against cognitive change. Hormone use was linked to lower MCI prevalence.DiscussionSeveral aspects of reproductive health appear to impact cognitive aging among Hispanic/Latina women.

Aster proteins mediate the nonvesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER). However, the importance of nonvesicular sterol movement for physiology and pathophysiology in various tissues is incompletely understood. Here we show that loss of Aster-B leads to diet-induced obesity in female but not in male mice, and that this sex difference is abolished by ovariectomy. We further demonstrate that Aster-B deficiency impairs nonvesicular cholesterol transport from the PM to the ER in ovaries in vivo, leading to hypogonadism and reduced estradiol synthesis. Female Aster-B-deficient mice exhibit reduced locomotor activity and energy expenditure, consistent with established effects of estrogens on systemic metabolism. Administration of exogenous estradiol ameliorates the diet-induced obesity phenotype of Aster-B-deficient female mice. These findings highlight the key role of Aster-B-dependent nonvesicular cholesterol transport in regulating estradiol production and protecting females from obesity.

BACKGROUND: The most aggressive form of breast cancer is triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR), and does not have overexpression of the human epidermal growth factor receptor 2 (HER2). Treatment options for women with TNBC tumors are limited, unlike those with ER-positive tumors that can be treated with hormone therapy, or those with HER2-positive tumors that can be treated with anti-HER2 therapy. Therefore, we have sought to identify novel targeted therapies for TNBC. In this study, we investigated the potential of a novel phosphatase, NUDT5, as a potential therapeutic target for TNBC. METHODS: The mRNA expression levels of NUDT5 in breast cancers were investigated using TCGA and METABRIC (Curtis) datasets. NUDT5 ablation was achieved through siRNA targeting and NUDT5 inhibition with the small molecule inhibitor TH5427. Xenograft TNBC animal models were employed to assess the effect of NUDT5 inhibition on in vivo tumor growth. Proliferation, death, and DNA replication assays were conducted to investigate the cellular biological effects of NUDT5 loss or inhibition. The accumulation of 8-oxo-guanine (8-oxoG) and the induction of γH2AX after NUDT5 loss was determined by immunofluorescence staining. The impact of NUDT5 loss on replication fork was assessed by measuring DNA fiber length. RESULTS: In this study, we demonstrated the significant role of an overexpressed phosphatase, NUDT5, in regulating oxidative DNA damage in TNBCs. Our findings indicate that loss of NUDT5 results in suppressed growth of TNBC both in vitro and in vivo. This growth inhibition is not attributed to cell death, but rather to the suppression of proliferation. The loss or inhibition of NUDT5 led to an increase in the oxidative DNA lesion 8-oxoG, and triggered the DNA damage response in the nucleus. The interference with DNA replication ultimately inhibited proliferation. CONCLUSIONS: NUDT5 plays a crucial role in preventing oxidative DNA damage in TNBC cells. The loss or inhibition of NUDT5 significantly suppresses the growth of TNBCs. These biological and mechanistic studies provide the groundwork for future research and the potential development of NUDT5 inhibitors as a promising therapeutic approach for TNBC patients.

Cardiometabolic disorders (CMD) are a growing public health problem across the world. Among the known cardiometabolic risk factors are compounds that induce endocrine and metabolic dysfunctions, such as endocrine disrupting chemicals (EDCs). To date, how EDCs influence molecular programs and cardiometabolic risks has yet to be fully elucidated, especially considering the complexity contributed by species-, chemical-, and dose-specific effects. Moreover, different experimental and analytical methodologies employed by different studies pose challenges when comparing findings across studies. To explore the molecular mechanisms of EDCs in a systematic manner, we established a data-driven computational approach to meta-analyze 30 human, mouse, and rat liver transcriptomic datasets for 4 EDCs, namely bisphenol A (BPA), bis(2-ethylhexyl) phthalate (DEHP), tributyltin (TBT), and perfluorooctanoic acid (PFOA). Our computational pipeline uniformly re-analyzed pre-processed quality-controlled microarray data and raw RNAseq data, derived differentially expressed genes (DEGs) and biological pathways, modeled gene regulatory networks and regulators, and determined CMD associations based on gene overlap analysis. Our approach revealed that DEHP and PFOA shared stable transcriptomic signatures that are enriched for genes associated with CMDs, suggesting similar mechanisms of action such as perturbations of peroxisome proliferator-activated receptor gamma (PPARγ) signaling and liver gene network regulators VNN1 and ACOT2. In contrast, TBT exhibited highly divergent gene signatures, pathways, network regulators, and disease associations from the other EDCs. In addition, we found that the rat, mouse, and human BPA studies showed highly variable transcriptomic patterns, providing molecular support for the variability in BPA responses. Our work offers insights into the commonality and differences in the molecular mechanisms of various EDCs and establishes a streamlined data-driven workflow to compare molecular mechanisms of environmental substances to elucidate the underlying connections between chemical exposure and disease risks.

Background: Fat grafting is widely used in breast reconstruction and aesthetic plastic surgery. However, the success rate and effects of fat grafting, especially in elderly female donors, are observed. This study aimed to explore the difference in the survival rate of donor fat from elderly women and young women in fat grafting. Methods: We collected adipose tissue samples from two healthy Chinese women: a young woman and an elderly woman. In addition, adipose tissue samples were collected from female nude mice in four experimental groups—CON-Y, CON-O, OVX-Y, and OVX-O—after fat transplantation. Grafts were harvested, weighed, and subjected to assessment of histology and angiogenesis. Results: An ovariectomy model was successfully established to validate the effect of low estrogen levels on fat grafting results. Due to the influence of low estrogen levels, the graft survival rate of donor site fat was significantly higher in elderly women than in young women, accompanied by a lesser degree of angiogenesis. Low estrogen levels led to adipocyte hypertrophy, which may be related to decreased AQP-7 expression. Conclusions: AQP-7 downregulation due to low estrogen levels induces adipocyte hypertrophy, and donor fat from elderly women exhibits a higher survival rate after fat transplantation. Level of Evidence V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. [ABSTRACT FROM AUTHOR]

Previous studies indicate a positive correlation between the duration of estrus prior to ovulation and likelihood of pregnancy in embryo recipient mares. However, the mechanisms by which the duration of estrus before may affect fertility remains unclear. This study aimed to determine the effect of different durations of estradiol exposure, prior to progesterone administration, on embryo viability in anestrous recipient mares, and endometrial expression of genes thought to influence embryo survival. Three groups of anestrous recipient mares treated with different duration of estradiol were used: long (LE), short (SE) and no treatment (NE). Day 8 embryos were transferred into recipient mares four days after long-acting progesterone administration and recovered 48h later to examine embryo growth and viability. The endometrial gene expression profile of selected genes was also investigated. The likelihood of recovering an embryo 48h after transfer was 46.1% (6/13), 62.5% (5/8) and 85.7% (6/7) for recipient mares from the NE, SE and LE groups, respectively (P =.09). Embryos recovered from the different groups of recipients did not, however, differ in size, morphology or the proportion of nuclei undergoing mitosis (P >.05). Abundance of mRNA for uterocalin (P19) and insulin-like growth factor 1 (IGF1) were increased in the LE compared to the NE group, while fibroblast growth factor 2 (FGF2), progesterone receptor (PGR) and insulin-like growth factor 1 receptor (IGF1R) transcript abundances were increased (P < 0.05) in the NE group compared to both SE and LE groups. In conclusion, a longer exposure of the endometrium to estradiol before progesterone tended to improve embryo survival within 48h of transfer. However, the grade, growth rate, and proportion of mitotic cells in surviving embryos did not differ among groups. If embryos are destined to fail in a suboptimal endometrial environment, they die and disappear quickly. Moreover, a more adequately estradiol-primed uterus, before the progesterone rise, seems to create a uterine environment, in terms of P19 , IGF1 , FGF2 and PGR gene expression, more conducive to embryo survival and further development. • Embryo survival after transfer tended to be influenced by the duration of estradiol treatment. • Viability of surviving embryos within 48h of transfer was not affected by estradiol-primed uterus. • Endometrial expression of selected genes was influenced by estradiol-primed uterus. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the relationship between phthalates exposure and estrogen and progesterone levels, as well as their role in late-onset preeclampsia. Methods: A total of 60 pregnant women who met the inclusion and exclusion criteria were recruited. Based on the diagnosis of preeclampsia, participants were divided into two groups: normotensive pregnant women (n = 30) and pregnant women with late-onset preeclampsia (n = 30). The major metabolites of phthalates (MMP, MEP, MiBP, MBP, MEHP, MEOHP, MEHHP) and sex steroid hormones (estrogen and progesterone) were quantified in urine samples of the participants. Results: No significant differences were observed in the levels of MMP, MEP, MiBP, MBP, MEHP, MEOHP, and MEHHP between women with preeclampsia and normotensive pregnant women (P > 0.05). The urinary estrogen showed a negative correlation with systolic blood pressure (rs= -0.46, P < 0.001) and diastolic blood pressure (rs= -0.47, P < 0.001). Additionally, the urinary estrogen and progesterone levels were lower in women with preeclampsia compared to those in normotensive pregnant women (P < 0.05). After adjusting for confounding factors, we observed a significant association between reduced urinary estrogen levels and an increased risk of preeclampsia (aOR = 0.09, 95%CI = 0.02–0.46). Notably, in our decision tree model, urinary estrogen emerged as the most crucial variable for identifying pregnant women at a high risk of developing preeclampsia. A positive correlation was observed between urinary progesterone and MEHP (rs = 0.36, P < 0.05) in normotensive pregnant women. A negative correlation was observed between urinary estrogen and MEP in pregnant women with preeclampsia (rs= -0.42, P < 0.05). Conclusions: Phthalates exposure was similar in normotensive pregnant women and those with late-onset preeclampsia within the same region. Pregnant women with preeclampsia had lower levels of estrogen and progesterone in their urine, while maternal urinary estrogen was negatively correlated with the risk of preeclampsia and phthalate metabolites (MEP). Trial registration: Registration ID in Clinical Trials: NCT04369313; registration date: 30/04/2020. [ABSTRACT FROM AUTHOR]

Background: The causal relationships between testosterone, estradiol, estrogen sulfotransferase, and idiopathic pulmonary fibrosis (IPF) are not well understood. This study employs a bidirectional two-sample Mendelian Randomization (MR) approach to explore these associations. Methods: All genetic data utilized in our study were obtained from the IEU Open GWAS project. For the MR analysis, we employed the inverse variance weighted (IVW), MR-Egger, and weighted median methods to assess the causal relationships. We also conducted a multivariate MR (MVMR) analysis, with adjustments made for smoking. To ensure the robustness of our findings, sensitivity analyses were conducted using Cochran's Q test, MR-Egger regression, the MR-PRESSO global test, and the leave-one-out method. Results: Genetically predicted increases in serum testosterone levels by one standard deviation were associated with a 58.7% decrease in the risk of developing IPF (OR = 0.413, PIVW=0.029, 95% CI = 0.187 ∼ 0.912), while an increase in serum estrogen sulfotransferase by one standard deviation was associated with a 32.4% increase in risk (OR = 1.324, PIVW=0.006, 95% CI = 1.083 ∼ 1.618). No causal relationship was found between estradiol (OR = 1.094, PIVW=0.735, 95% CI = 0.650 ∼ 1.841) and the risk of IPF. Reverse MR analysis did not reveal any causal relationship between IPF and testosterone (OR = 1.001, PIVW=0.51, 95% CI = 0.998 ∼ 1.004), estradiol (OR = 1.001, PIVW=0.958, 95% CI = 0.982 ∼ 1.019), or estrogen sulfotransferase (OR = 0.975, PIVW=0.251, 95% CI = 0.933 ∼ 1.018). The MVMR analysis demonstrated that the association between testosterone (OR = 0.442, P = 0.037, 95% CI = 0.205 ∼ 0.953) and estrogen sulfotransferase (OR = 1.314, P = 0.001, 95% CI = 1.118 ∼ 1.545) and the risk of IPF persisted even after adjusting for smoking. Conclusions: Increased serum levels of testosterone are associated with a reduced risk of IPF, while increased levels of serum estrogen sulfotransferase are associated with an increased risk. No causal relationship was found between estradiol and the development of IPF. No causal relationship was identified between IPF and testosterone, estradiol, or estrogen sulfotransferase. [ABSTRACT FROM AUTHOR]

Background: Women are three times more likely to be diagnosed with thyroid cancer than men, with incidence rates per 100,000 in the United States of 20.2 for women and 7.4 for men. Several reproductive and hormonal factors have been proposed as possible contributors to thyroid cancer risk, including age at menarche, parity, age at menopause, oral contraceptive use, surgical menopause, and menopausal hormone therapy. Our study aimed to investigate potential reproductive/hormonal factors in a multiethnic population. Methods: Risk factors for thyroid cancer were evaluated among female participants (n = 118,344) of the Multiethnic Cohort Study. The cohort was linked to Surveillance, Epidemiology, and End Results cancer incidence and statewide death certificate files in Hawaii and California, with 373 incident papillary thyroid cancer cases identified. Exposures investigated include age at menarche, parity, first pregnancy outcome, birth control use, and menopausal status and type. Multivariable Cox proportional hazards models were used to obtain relative risk (RR) of papillary thyroid cancer and their 95% confidence intervals (CI). Covariates included age, race and ethnicity, reproductive history, body size, smoking, and alcohol consumption. Results: We observed a statistically significant increased risk of papillary thyroid cancer for oophorectomy (adjusted RR 1.58, 95% CI: 1.26, 1.99), hysterectomy (adjusted RR 1.65, 95% CI: 1.33, 2.04), and surgical menopause (adjusted RR 1.55, 95% CI: 1.22, 1.97), and decreased risk for first live birth at ≤20 years of age versus nulliparity (adjusted RR 0.66, 95% CI: 0.46, 0.93). These associations did not vary by race and ethnicity (p het > 0.44). Conclusion: The reproductive risk factors for papillary thyroid cancer reported in the literature were largely confirmed in all racial and ethnic groups in our multiethnic population, which validates uniform obstetric and gynecological practice. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the effect of the MC and endogenous sex hormone concentrations on performance-determining variables in three distinctMC phases in endurance-trained females. Methods: Twenty-one eumenorrheic trained/highly trained endurance athletes completed a standardized test battery during the early follicular phase (EFP), ovulatory phase (OP), and midluteal phase (MLP) for either one (n = 7) or two test cycles (n = 14). MC phases were determined using calendar-based counting, urinary ovulation testing, and verified with serum hormone analysis. MCs were retrospectively classified as eumenorrheic or disturbed. Disturbed MCs were excluded from analysis. The test battery consisted of 4-6 x 5-min submaximal stages with stepwise speed increases, a 30-s all-out double-poling ski ergometer test, and a maximal incremental treadmill running test. Results: At a group level, there was no effect of MC phase or the serum concentrations of estrogen and progesterone on peak oxygen uptake (...), oxygen uptake at 4 mmol⋅L-1 blood lactate concentration, time to exhaustion, running economy, or mean 30-s power output (MPO30s). Serum testosterone concentration was positively associated with MPO30s (P = 0.016). Changes in ... from EFP to MLP were inconsistent between individuals and across cycles. Conclusions: None of the measured performance-determining variables were influenced by MC phase or serumestrogen or progesterone concentrations. Although some individual patterns could be observed, there was no indication that any single MC phase is consistently associated with improved or impaired ... on a group level. [ABSTRACT FROM AUTHOR]

Anxiety disorders are more prevalent in females than males, in part due to the change in ovarian hormones during the late luteal phase of the menstrual cycle. Estradiol and progesterone (EþP) peak in the luteal phase before dropping rapidly in the late luteal phase. This drop is associated with increased anxiety, and EþP may decrease anxiety. It is important to find a way to counteract the negative symptoms associated with ovarian hormone changes. Omega-3 fatty acid supplementation has been found to decrease anxiety-like behavior in male rats, but the effects on anxiety-like behavior in females are unknown. To determine the effect of omegas and EþP on anxiety-like behavior in female rats, we observed two trials of the elevated plus maze (EPM) and light-dark box after omega-3 fatty acid and EþP treatments. There was a decrease in time spent and crosses in the open arm of the EPM and the light side of the light-dark box across trials and no effect of omega-3 fatty acids or EþP. Further research into the potential interaction of omega-3 fatty acids and EþP is needed. [ABSTRACT FROM AUTHOR]

Objective Conventional imaging of cancer with modalities such as computed tomography or magnetic resonance imaging provides little information about the underlying biology of the cancer and consequently little guidance for systemic treatment choices. Accurate identification of aggressive cancers or those that are likely to respond to specific treatment regimens would allow more precisely tailored treatments to be used. The expression of the estrogen receptor α subunit is associated with a more aggressive phenotype, with a greater propensity to metastasize. We aimed to characterize the binding properties of an 18 F-estradiol positron emission tomography (PET) tracer in its ability to bind to the α and β forms of estrogen receptors in vitro and confirmed its binding to estrogen receptor α in vivo. Methods The 18 F-estradiol PET tracer was synthesized and its quality confirmed by high-performance liquid chromatography. Binding of the tracer was assessed in vitro by saturation and competitive binding studies to HEK293T cells transfected with estrogen receptor α (ESR1) and/or estrogen receptor β (ESR2). Binding of the tracer to estrogen receptor α in vivo was assessed by imaging of uptake of the tracer into MCF7 xenografts in BALB/c nu/nu mice. Results The 18 F-estradiol PET tracer bound with high affinity (94 nM) to estrogen receptor α, with negligible binding to estrogen receptor β. Uptake of the tracer was observed in MCF7 xenografts, which almost exclusively express estrogen receptor α. Conclusion 18 F-estradiol PET tracer binds in vitro with high specificity to the estrogen receptor α isoform, with minimal binding to estrogen receptor β. This may help distinguish human cancers with biological dependence on estrogen receptor subtypes. [ABSTRACT FROM AUTHOR]

Sufficient evidence within the past two decades have shown that osteoarthritis (OA) has a sex-specific component. However, efforts to reveal the biological causes of this disparity have emerged more gradually. In this narrative review, we discuss anatomical differences within the knee, incidence of injuries in youth sports, and metabolic factors that present early in life (childhood and early adulthood) that can contribute to a higher risk of OA in females. We compiled clinical data from multiple tissues within the knee joint—since OA is a whole joint disorder—aiming to reveal relevant factors behind the sex differences from different perspectives. The data gathered in this review indicate that sex differences in articular cartilage, meniscus, and anterior cruciate ligament are detected as early as childhood and are not only explained by sex hormones. Aiming to unveil the biological causes of the uneven sex-specific risks for knee OA, we review the current knowledge of sex differences mostly in young, but also including old populations, from the perspective of (i) human anatomy in both healthy and pathological conditions, (ii) physical activity and response to injury, and (iii) metabolic signatures. We propose that to close the gap in health disparities, and specifically regarding OA, we should address sex-specific anatomic, biologic, and metabolic factors at early stages in life, as a way to prevent the higher severity and incidence of OA in women later in life. [ABSTRACT FROM AUTHOR]

Background & Objective: A competent embryo, receptive endometrium and a series of highly coordinated molecular events between them are all essential for successful implantation. Evaluation of certain molecules which may be used as biomarkers may help to predict pregnancy outcome and detect subtle implantation defect. The present study was conducted with aim to assess the relationship between serum concentrations of adrenomedullin (ADM) and pentraxin3 (PTX3) measured at the day of embryo transfer and successful implantation in assisted reproductive technique cycles. Materials & Methods: This prospective cohort study included 88 frozen embryo transfer (FET) cycles. All patients received sequential oestrogen & progesterone medications. Embryo transfer (with a minimum of one top quality embryo) was scheduled after 4 days (D3 embryo), 6 days (D5 embryo) of progesterone administration. The serum ADM and PTX3 levels were analyzed 1 hour before the embryo transfer (ET) using ELISA kits. A possible association between these two markers levels and embryo implantation was evaluated. Results: Overall, biochemical pregnancy rate was 25% (22/88). Data were then categorized into pregnant (22/88) & non-pregnant (66/88). No significant difference were found between the two groups regarding female age, endometrial thickness, number of oocyte collected, oestradiol level (E2), FSH level, grade and number of embryo transferred (P>0.05). The ADM levels were higher on the day of ET, although was not significant in pregnant group (254.60 pg/ml vs 248.18pg/ml). PXT3 levels (pg/ml) were lower in pregnant compared to non-pregnant group (25.396±11.78 vs 28.431±16.51, P=0.428). Conclusion: Higher ADM and lower PTX3 levels at the day of embro transfer may be associated with successful implantation. [ABSTRACT FROM AUTHOR]

Purpose of Review: The present review critically assesses contemporary evidence characterizing the association between hormonal contraception (HC) and/or menopausal hormone replacement therapy (MHT) and breast cancer risk in patients considered "high risk." Recent Findings: Prospective studies of hormonal contraception methods for BRCA 1 mutation carriers do not demonstrate an association between combined oral contraceptives (COC) and hormone receptor-positive breast cancer, findings consistent with those seen from systematic reviews evaluating this risk in patients with a family history of breast cancer. The Centers for Disease Control and Prevention (CDC) assigns progesterone-only and combined contraception a medical eligibility criteria (MEC) rating of 1, denoting no restrictions on use for those with benign breast disease and a family history of breast cancer. These guidelines include the etonogestrel implant, injected medroxyprogesterone acetate, levonorgestrel intrauterine device, combined oral contraceptive pill, patch, and intravaginal ring, and the recommendation highlights their overall safety in this population. However, the intravaginal ring, which contains the lowest systemic dose of ethinyl estradiol, as well as the locally-acting progestin intrauterine device systems can be considered for those concerned about hormonal exposure. The small potential breast cancer risk increase observed with progesterone-based birth control methods in few studies should be evaluated in the context of other risk factors such as lower parity in those using long-acting reversible contraception (LARC) methods. A large meta-analysis did not find an increased risk of breast cancer in BRCA ½ mutation carriers receiving estrogen-alone menopausal hormone replacement therapy, although progestin-containing regimens may warrant further study in high-risk populations. Summary: Most of the existing literature analyzing the risk of breast cancer associated with the use of HC and MHT is comprised of observational data and, therefore, vulnerable to selection and information bias. [ABSTRACT FROM AUTHOR]

Despite advances in treatment strategies, breast cancer (BC) remains one of the most prevalent cancers worldwide. Recent studies implicate the gut microbiome as a potential risk factor for BC development. Alterations in gut microbial diversity resulting in dysbiosis have been linked to breast carcinogenesis by modulating host immune responses and inflammatory pathways, favoring tumorigenesis and progression. Moreover, gut microbiota populations are different between women with BC vs those that are cancer free, further implicating the role of the gut microbiome in cancer development. This alteration in gut microbiota is also associated with changes in estrogen metabolism, which strongly correlates with BC development. Gut microbiota that express the enzyme β-glucuronidase (GUS) may increase estrogen bioavailability by deconjugating estrogen-glucuronide moieties enabling reabsorption into circulation. Increased circulating estrogens may, in turn, drive estrogen receptor–positive BC. GUS-expressing microbiota also affect cancer therapy efficacy and toxicity by modifying glucuronide-conjugated drug metabolites. Therefore, GUS inhibitors have emerged as a potential antitumor treatment. However, the effectiveness of GUS inhibitors is still exploratory. Further studies are needed to determine how oral endocrine-targeting therapies may influence or be influenced by the microbiota and how that may affect carcinogenesis initiation and tumor recurrence. [ABSTRACT FROM AUTHOR]

Objectives: To investigate whether hormone replacement therapy (HRT) impacts health care resource utilization in the management of chronic rhinosinusitis (CRS) in older women. Methods: Using the TriNetX US health record database, women 55 years or older with a diagnosis of CRS were included and followed for 3 years. The cohort was stratified into two groups: women who received HRT at the beginning of the study were compared to women who did not receive HRT. The groups were matched by age, race, ethnicity, history of asthma, and history of nasal polyps. Outcomes included whether the patient underwent endoscopic sinus surgery (ESS) and frequency of antibiotic use. Measures of association, Kaplan–Meier analysis, and cohort descriptive statistics were calculated. Results: Of the 65,400 women included, the mean age was 66.9 years. 27.0% and 3.6% of patients had a history of asthma or nasal polyps, respectively. Overall, 2.0% of CRS patients underwent ESS, with the HRT group less likely to undergo ESS [OR: 0.28; 95% CI: (0.25–0.32)] compared to patients who did not receive HRT. When stratified by polyp status, HRT patients with nasal polyps had a greater decrease in ESS rates compared to control than HRT patients without nasal polyps. The HRT group had a higher mean number of antibiotic prescriptions compared to the non‐HRT group. Conclusion: HRT is associated with decreased utilization of ESS to treat CRS, with a greater effect size for ESS among CRSwNP patients. However, HRT was associated with higher antibiotic utilization. Level of Evidence: 3 Laryngoscope, 134:3921–3926, 2024 [ABSTRACT FROM AUTHOR]

Objective: The effects of hormonal therapy, estrogen-based hormone replacement therapy (HRT), and anti-tumor hormone therapy, such as tamoxifen, on the physiological uptake of the endometrium on 2-deoxy-2[18F]fluoro-d-glucose ([18F]F-FDG) positron emission tomography (PET) in postmenopausal women have not been determined. We explored the effect of hormone therapy, particularly HRT, on physiological uptake in the endometrium of postmenopausal women. Materials and methods: Postmenopausal women receiving hormone therapy who underwent cancer screening using PET/computed tomography (CT) between June 2016 and April 2023 were included in the hormone therapy group (n = 21). Postmenopausal women with no history of hormone therapy were included in the control group (n = 49). First, the physiological endometrial uptake at menopausal age and at least 1 year thereafter was compared quantitatively (SUVmax) and qualitatively (4-point scale) in the control group, to assess when the endometrium ceased to show significant physiological [18F]F-FDG uptake after menopause. Endometrial uptake was compared between the hormone therapy and control groups. The association between HRT duration (months) and endometrial uptake (SUVmax) was evaluated. Endometrial thickness, measured using transvaginal ultrasonography, was also compared between the two groups. Results: Endometrial uptake was significantly reduced both qualitatively and quantitatively (P < 0.05) at least 1 year after menopause in control patients, by which time most women (89.8%) no longer had significant endometrial uptake. The hormone therapy group (n = 21) showed higher FDG uptake in the endometrium compared to the control group (median SUVmax: 2.3 vs 1.9, P = 0.0011), as well as a higher visual score (P < 0.0001). HRT duration did not correlate with endometrial uptake (P = 0.097). Endometrial thickness in the hormone therapy group was significantly thicker than in the control group (median: 3.9 mm vs 1.8 mm, P = 0.002). Conclusion: Hormone therapy may affect physiological uptake in the endometrium in postmenopausal women. [ABSTRACT FROM AUTHOR]

This study examined the effects of time restricted eating (TRE) on sex hormones in males and females, versus daily calorie restriction (CR). Adults with obesity (n = 90) were randomized to 1 of 3 groups for 12-months: 8-h TRE (eating only between 12:00 to 8:00 pm, with no calorie counting); CR (25% energy restriction daily); or control. Body weight decreased (P < 0.01) in the TRE and CR groups, relative to controls, in males, premenopausal females, and postmenopausal females, by month 12. Total testosterone, dehydroepiandrosterone (DHEA), and sex hormone binding globulin (SHBG) levels did not change over time, or between groups, in males, premenopausal females, and postmenopausal females. Estradiol, estrone, and progesterone were only measured in postmenopausal females, and remained unchanged. These findings suggest that TRE produces significant weight loss but does not impact circulating sex hormone levels in males and females with obesity over 12 months, relative to CR and controls. [ABSTRACT FROM AUTHOR]

Background: Venous thromboembolism (VTE) poses a significant global health challenge, notably exacerbated by the use of combined oral contraceptives (COCs). Evidence mainly focuses on the type of progestogen used in COCs to establish the increased risk of VTE with less data assessed on the type of estrogen used. This meta-analysis aims to assess the risk of VTE associated with COCs containing synthetic estrogens like ethinylestradiol (EE) versus natural estrogens like estradiol (E2). Methods: A systematic review and meta-analysis was conducted following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Literature searches were performed in December 2023 in MEDLINE and EMBASE to identify clinical studies comparing the VTE risk between COCs containing synthetic versus natural estrogens. Studies were selected through rigorous screening, and data extraction followed standardized protocols, with statistical analyses employing a random effects model. Results: The search yielded five relevant studies, involving over 560,000 women/time, demonstrating a significant 33% reduction in VTE risk among users of natural estrogen-based COCs compared to synthetic estrogen-based COCs (OR 0.67, 95% CI 0.51–0.87). Stratification analyses using adjusted hazard ratios (HR) of the main observationnal studies showed a 49% reduced VTE risk of E2-based pills compared to EE in association with levonorgestrel. Discussion and conclusion: Despite the longstanding use of EE-based COCs, emerging evidence supports a lower thrombotic risk associated with natural estrogens. This meta-analysis substantiates the lower VTE risk associated with natural estrogen-based COCs compared to synthetic alternatives, advocating for a re-evaluation of contraceptive guidelines to prioritize patient safety and reduce thrombotic risks. [ABSTRACT FROM AUTHOR]

Introduction: The occurrence of cervical cancer may be related to estrogen and estrogen receptors. This study investigated the expression of lnc-CCDC170-4:1, ESR1 (estrogen receptor 1), lncRNA SRA, and CYP19A1 (aromatase) in cervical squamous cell carcinoma tissues, as well as their relationship with the clinical characteristics of patients. Methods: Whole transcriptome sequencing analysis was performed on cervical squamous cell carcinoma tissues (n=4) and normal tissues (n=4). The expressions of lnc-CCDC170-4:1, ESR1, lncRNA SRA, and CYP19A1 were validated in 26 cases of cervical cancer tissue and 30 cases of normal cervical tissue using qRT-PCR. The relationship of gene expression with the clinical characteristics and 5-year overall survival rates of cervical cancer patients was analyzed. Results: The expression levels of CYP19A1 and lncRNA SRA were upregulated, while those of ESR1 and lnc-CCDC170-4:1 were downregulated in cervical squamous cell carcinoma tissue. However, their expression was not related to 5-year overall survival rates (p>0.05). Low expression of lnc-CCDC170-4:1 was associated with lymph node metastasis (p=0.030) and Tumor size (p=0.047), Low expression of ESR was associated with FIGO Staging (p=0.041)and Tumor size(p=0.002),High expression of LncSRA was associated with FIGO Staging(p=0.004). Conclusion: Estrogenandestrogen receptorsmay play a role intheoccurrence and development of cervical squamous cell carcinoma. Low expression of lnc- CCDC170-4:1 and ESR1 are associated with lymph node metastasis and FIGO stage, so it may be a potential biomarker to evaluate the prognosis of cervical cancer. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress (OS) is one of the major causes of ovarian aging and dysfunction. Indole-3-propionic acid (IPA) is an indole compound derived from tryptophan with free radical scavenging and antioxidant properties, and thus may have potential applications in protecting ovarian function, although the exact mechanisms are unknown. This study aims to preliminarily elucidate the potential mechanisms of IPA that benefit ovarian reserve function through network pharmacology, molecular docking, and experimental verification. Methods: The related protein targets of IPA were searched on SwissTargetPrediction, TargetNet, BATMAN-TCM, and PharmMapper databases. The potential targets of diminished ovarian reserve (DOR) were identified from OMIM, GeneCards, DrugBank, and DisGeNET databases. The common targets were uploaded directly to the STRING database to construct PPI networks. We then performed GO and KEGG enrichment analysis on the targets. Subsequently, molecular docking and molecular dynamics simulation were used to validate the binding conformation of IPA to candidate targets. Furthermore, we carried out in vitro experiments to validate the prediction results of network pharmacology. Results: We identified a total of 61 potential targets for the interaction of IPA with DOR. The PPI network topological parameter analysis yielded 13 hub genes for DOR treatment. The GO biological process enrichment analysis identified 293 entries, mainly enriched in aging, signal transduction, response to hypoxia, negative regulation of apoptotic process, and positive regulation of cell proliferation. The KEGG enrichment analysis mainly included lipid and atherosclerosis, progesterone-mediated oocyte maturation, AGE-RAGE, relaxin, estrogen, and other signaling pathways. The molecular docking further revealed the direct binding of IPA with six hub proteins including NOS3, AKT1, EGFR, PPARA, SRC, and TNF. In vitro experiments showed that IPA pretreatment attenuated H2O2-induced cellular oxidative stress damage, while IPA exerted cytoprotective and antioxidant damage effects by regulating the six hub genes and antioxidant proteins. Conclusion: We systematically illustrated the potential protective effects of IPA against DOR through multiple targets and pathways using network pharmacology, and further verified the cytoprotective effect and antioxidant properties of IPA through in vitro experiments. These findings provide new insights into the targets and molecular mechanisms whereby IPA improves DOR. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effects of the estrogen depression during orthodontic tooth movement on alveolar bone microarchitecture and periodontal ligament. Female Wistar rats were divided into two groups, one consisting of non‐ovariectomized animals subjected to orthodontic tooth movement, and one comprising ovariectomized animals subjected to orthodontic tooth movement. Micro‐CT assessment of bone volume to total volume (BV/TV), total porosity, trabecular thickness (Tb.Th), trabecular number (Tb.N), and trabecular separation (Tb.Sp) in the alveolar bone of the orthodontically moved tooth was performed. Histomorphometric analyses were made in the periodontal ligament, and immunoexpression of RANK, RANKL, OPG, and TUNEL were quantified. Orthodontic tooth movement in the group of ovariectomized rats was faster than in non‐ovariectomized animals. The alveolar bone area showed lower values of BV/TV and trabecular thickness, and higher bone porosity and trabeculae numbers in the ovariectomized rats. Histological analyses in the ovariectomized group revealed an increase in collagen fibers in the periodontal ligament. The apoptotic cell counts in the periodontal ligament were higher in the group of ovariectomized rats than in the sham‐operated rats. Ovariectomy resulted in an increase in tooth movement and alteration of the alveolar bone microstructure in the first 7 day of orthodontic tooth movement, and in the presence of apoptotic cells in the periodontal ligament. [ABSTRACT FROM AUTHOR]

Dysfunctional RNA‐binding proteins (RBPs) have been implicated in several geriatric diseases, including Alzheimer's disease (AD). However, little is known about the nuclear molecular actions and cooperative functions mediated by RBPs that affect gene regulation in sporadic AD or aging. In the present study, we investigated aging‐ and AD‐associated changes in the expression of PSF and G3BP2, which are representative RBPs associated with sex hormone activity. We determined that both PSF and G3BP2 levels were decreased in aged brains compared to young brains of mice. RNA sequencing (RNA‐seq) analysis of human neuronal cells has shown that PSF is responsible for neuron‐specific functions and sustains cell viability. In addition, we showed that PSF interacted with G3BP2 in the nucleus and stress granules (SGs) at the protein level. Moreover, PSF–mediated gene regulation at the RNA level correlated with G3BP2. Interestingly, PSF and G3BP2 target genes are associated with AD development. Mechanistically, quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR) analysis demonstrated that the interaction of RBPs with the pre‐mRNA of target genes enhanced post‐transcriptional mRNA stability, suggesting a possible role for these RBPs in preserving neuronal cell viability. Notably, in the brains of patients with sporadic AD, decreased expression of PSF and G3BP2 in neurons was observed compared to non‐AD patients. Overall, our findings suggest that the cooperative action of PSF and G3BP2 in the nucleus is important for preventing aging and AD development. [ABSTRACT FROM AUTHOR]

Estrogens produced in peripheral tissues and locally in the brain are potent neuromodulators. The function of the hippocampus, a brain region essential for episodic memory and spatial navigation, relies on the activity of ensembles of excitatory neurons whose activity is temporally and spatially coordinated by a wide diversity of inhibitory neurons (INs) types. Over the last years, we have accumulated evidence that indicates that estrogens regulate the function of hippocampal INs through different mechanisms, including transcriptional regulation and rapid nongenomic signaling. Here, we argue that the well‐documented influence of estrogens on episodic memory may be related to the actions of local and peripheral estrogens on the heterogenous populations of hippocampal INs. We discuss how physiological changes in peripheral sex hormone levels throughout lifespan may interact with local brain sources to regulate IN function at different stages of life, from early hippocampal development to the aging brain. We conclude that considering INs as mediators of sex hormone actions in the hippocampus across the healthy life span will benefit our understanding of sex‐biased neurodevelopmental disorders and physiological aging. [ABSTRACT FROM AUTHOR]

Premenopausal women generally exhibit lower blood pressure and a lower prevalence of hypertension than men of the same age, but these differences reverse postmenopause due to estrogen withdrawal. Sexual dimorphism has been described in different components of kidney physiology and pathophysiology, including the renin–angiotensin–aldosterone system, endothelin system, and tubular transporters. This review explores the sex-specific differences in kidney function and blood pressure regulation. Understanding these differences provides insights into potential therapeutic targets for managing hypertension and kidney diseases, considering the patient's sex and hormonal status. [ABSTRACT FROM AUTHOR]

Breast cancer is the most diagnosed cancer in the world, and it is the primary cause of cancer death for women. The risk of breast cancer is increased by endogenous factors like hormones and exogenous factors like radiation exposure that causes damage to the mammary epithelial cells leading to an inflammatory response. Chronic inflammation creates a microenvironment composed of, among other factors, chemokines, and interleukins, which promote cancer. The gene expression of the interleukin 1 receptor type 1, the interleukin 1 receptor antagonist, the Interleukin 1 Receptor Accessory Protein, the interleukin 6 cytokine family signal transducer, the C-X-C motif chemokine ligand 3, the C-X-C motif chemokine ligand 5, and the C-X-C motif chemokine ligand 6 were analyzed in an estrogen and radiation experimental breast cancer model. Furthermore, the expression of these genes was correlated with immune cell infiltration, estrogen receptor expression, and their clinical relevance in breast cancer patients based on data provided by The Cancer Genome Atlas database online. Results given by the experimental breast cancer model showed that all genes related to inflammation respond to ionizing radiation alone or in combination with estrogen. On the other hand, the immune response depended on the breast cancer type and on the expression of the gene that encoded the estrogen receptor. Finally, the importance of the expression of these genes in breast cancer is such that high IL1R1 or IL1RAP is strongly related to patient survival. These findings may help to improve the understanding of the role of immune molecules in carcinogenesis and enhance therapeutic approaches. [ABSTRACT FROM AUTHOR]

Female hormones, functioning as neuroactive steroids, are utilized beyond menopausal hormone therapy. The rapid onset of allopregnanolone analogs, such as brexanolone and zuranolone, in treating depression, and the effectiveness of megestrol acetate in addressing appetite and weight gain, prompted the Food and Drug Administration to authorize the use of progesterone for treating postpartum depression and cancer-related cachexia. Progesterone has also been found to alleviate neuropathic pain in animal studies. These off-label applications offer a promising option for patients with advanced cancer who often experience various mood disorders such as depression, persistent pain, social isolation, and physical complications like cachexia. These patients have shown low tolerance to opioids and mood-regulating medications. However, the potential risks and uncertainties associated with hormone therapy treatment modalities can be daunting for both patients and medical professionals. This review aims to offer a comprehensive understanding of the non-reproductive functions and mechanisms of female hormones in brain health. [ABSTRACT FROM AUTHOR]

Like the ovaries and prostate, the thyroid exhibits characteristic hormone secretion and regulation. Thyroid cancer (TC), especially differentiated thyroid carcinoma, has typical sex-specific and age-specific hormone-driven clinical features. Previous research has primarily focused on the effects of thyroid stimulating hormone, thyroid hormones, and estrogens on the onset and progression of TC, while the roles of growth hormone (GH), androgens, and glucocorticoids have largely been overlooked. Similarly, few studies have investigated the interactions between hormones and hormone systems. In fact, numerous studies of patients with acromegaly have shown that serum levels of GH and insulin-like growth factor-1 (IGF-1) may be associated with the onset and progression of TC, although the influences of age, sex, and other risk factors, such as obesity and stress, remain unclear. Sex hormones, the GH/IGF axis, and glucocorticoids are likely involved in the onset and progression of TC by regulating the tumor microenvironment and metabolism. The aim of this review was to clarify the roles of hormones and hormone systems in TC, especially papillary thyroid carcinoma, as references for further investigations. [ABSTRACT FROM AUTHOR]

Background: There is a growing need to offer guidance and instruction to those who use herbal medicines in order to enhance their understanding of the scientifically supported risks associated with these therapies. This study investigates the adverse effects of the Ziziphus spina-christi (ZSC) aqueous extract on the biochemical markers and histological alterations in the ovaries of female rats. Methods: A total of fifteen female rats, with five rats in each group, were given the extract of ZSC orally at doses of 10, 50 and 100 mg/kg bw/day for a duration of 14 days. Five more ladies were designated as a control group and provided just with water. During a span of fifteen days, clinical findings of toxicity were documented. The ovarian function was evaluated by assessing the biochemical indicators and measuring the quantities of serum estradiol and progesterone. Furthermore, an assessment was conducted to examine the histological changes in the organs. Result: The results did not show any clear toxicity on the animal's weight or body organs. Estrogen and progesterone levels in female rats who received ZSC extract for 14 days. In addition, no pathological changes were revealed in the ovary histological sections. Significant differences were detected in the numbers of ovarian follicles in females treated with the ZSC extract compared to the control. In conclusion, the results showed indications of side effects of ovarian follicles after treating female rats with ZSC extract for 14 days. [ABSTRACT FROM AUTHOR]

Declines in estrogen levels occur in women transitioning to menopause. Estrogen hormones play important roles in multiple systems of the body, and estrogen loss is associated with a variety of symptoms that can decrease quality of life. The gut microbiota is involved in regulating endogenous estrogen levels. A portion of estrogen glucuronides can be reactivated in the gut by the microbial enzyme β-glucuronidase, and the resulting free estrogens can return to the bloodstream. Here, we carried out in vitro screening of β-glucuronidase activities for 84 strains belonging to 16 different species of lactic acid bacteria and bifidobacteria and found that one and three strains of Levilactobacillus brevis and Lacticasebacillus rhamnosus, respectively, can deconjugate estrogens. Among these strains, L. brevis KABP052 had the highest β-glucuronidase activity. Moreover, in an exploratory, randomized, double-blind, placebo-controlled trial, we demonstrated that serum estrogen levels in healthy peri- and postmenopausal women given a probiotic formula containing KABP052 were maintained over time, whereas levels significantly decreased in the group given a placebo. Significantly higher levels of estradiol (31.62 ± 7.97 pg/mL vs. 25.12 ± 8.17 pg/mL) and estrone (21.38 ± 8.57 pg/mL vs. 13.18 ± 8.77 pg/mL) were observed in the probiotic versus placebo group after 12 weeks of intervention. This clinical study demonstrated for the first time the estrogen modulation capacity of a probiotic formula containing a bacterial strain having β-glucuronidase activity in women during the menopausal transition and formed the basis for future investigations using probiotics in the menopausal population. [ABSTRACT FROM AUTHOR]

The lifetime risk of heart failure (HF) is comparable in men and women; nevertheless, disparities exist in our understanding of how HF differs between sexes. Several differences in cardiac physiology exist between men and women including the propensity to develop specific HF phenotypes. Men are more likely to be diagnosed with HF failure with reduced ejection fraction, while women have a greater propensity to develop HF with preserved ejection fraction. The mechanisms responsible for these differences remain unclear. Post-translational modifications (PTMs) of myofilament proteins likely contribute to these sex-specific propensities. The role of PTMs in heart disease is an expanding field with immense potential therapeutic targets. However, numerous PTMs remain underexplored, particularly in the context of the female heart. Estrogen, a key gonadal hormone, cardioprotective in pre-menopausal women and its loss with menopause likely contributes to disease in aging women. However, how estrogen regulates PTMs to contribute to HF development is not fully clear. This review outlines key sex differences in HF along with characterizing the contributions of novel myocardial PTMs in cardiac physiology and their regulation by estrogen. Collectively, we highlight the necessity for further investigation into women's heart health and the distinctive mechanisms distinguishing women from men. [ABSTRACT FROM AUTHOR]

We examined performance across one menstrual cycle (MC) and 3 weeks of hormonal contraceptives (HC) use to identify whether known fluctuations in estrogen and progesterone/progestin are associated with functional performance changes. National Rugby League Indigenous Women's Academy athletes [n = 11 naturally menstruating (NM), n = 13 using HC] completed performance tests [countermovement jump (CMJ), squat jump (SJ), isometric mid‐thigh pull, 20 m sprint, power pass and Stroop test] during three phases of a MC or three weeks of HC usage, confirmed through ovulation tests alongside serum estrogen and progesterone concentrations. MC phase or HC use did not influence jump height, peak force, sprint time, distance thrown or Stroop effect. However, there were small variations in kinetic and kinematic CMJ/SJ outputs. NM athletes produced greater mean concentric power in MC phase four than one [+0.41 W·kg−1 (+16.8%), p = 0.021] during the CMJ, alongside greater impulse at 50 ms at phase one than four [+1.7 N·s (+4.7%), p = 0.031] during the SJ, without differences between tests for HC users. Among NM athletes, estradiol negatively correlated with mean velocity and power (r = −0.44 to −0.50, p < 0.047), progesterone positively correlated with contraction time (r = 0.45, p = 0.045), and both negatively correlated with the rate of force development and impulse (r = −0.45 to −0.64, p < 0.043) during the SJ. During the CMJ, estradiol positively correlated to 200 ms impulse (r = 0.45, p = 0.049) and progesterone to mean power (r = 0.51, p = 0.021). Evidence of changes in testing performance across a MC, or during active HC use, is insufficient to justify "phase‐based testing"; however, kinetic or kinematic outputs may be altered in NM athletes. Highlights: Evidence of changes in testing performance across a menstrual cycle, or during active hormonal contraceptives use, is insufficient to justify "phase‐based testing" at a group or team‐based level among female rugby league athletes.Kinetic or kinematic outputs in jumping movements may be altered in naturally menstruating athletes; however it could not be determined if the observed alterations exceeded between‐day variability. [ABSTRACT FROM AUTHOR]

Women are more prone to develop rheumatoid arthritis, with peak incidence occurring around menopause. Estrogen has major effects on the immune system and is protective against arthritis. We have previously shown that treatment with estrogen inhibits inflammation and joint destruction in murine models of arthritis, although the mechanisms involved remain unclear. Fibroblastic reticular cells (FRCs) are specialized stromal cells that generate the three‐dimensional structure of lymph nodes (LNs). FRCs are vital for coordinating immune responses from within LNs and are characterized by the expression of the chemokine CCL19, which attracts immune cells. The aim of this study was to determine whether the influence of estrogen on innate and adaptive immune cells in arthritis is mediated by estrogen signaling in FRCs. Conditional knockout mice lacking estrogen receptor α (ERα) in CCL19‐expressing cells (Ccl19‐CreERαfl/fl) were generated and tested. Ccl19‐CreERαfl/fl mice and littermate controls were ovariectomized, treated with vehicle or estradiol and subjected to the 28‐day‐long antigen‐induced arthritis model to enable analyses of differentiated T‐ and B‐cell populations and innate cells in LNs by flow cytometry. The results reveal that while the response to estradiol treatment in numbers of FRCs per LN is significantly reduced in mice lacking ERα in FRCs, estrogen does not inhibit joint inflammation or markedly affect immune responses in this arthritis model. Thus, this study validates the Ccl19‐CreERαfl/fl strain for studying estrogen signaling in FRCs within inflammatory diseases, although the chosen arthritis model is deemed unsuitable for addressing this question. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We explored the sex difference in lung ischemia–reperfusion injury (LIRI) and the role and mechanism of estrogen (E2) and angiotensin II (Ang II) in LIRI. We established a model of LIRI in mice. E2, Ang II, E2 inhibitor (fulvestrant), and angiotensin II receptor blocker (losartan) were grouped for treatment. The lung wet/dry weight ratio, natural killer (NK) cells (by flow cytometry), neutrophils (by flow cytometry), expression of key proteins (by Western blot, immunohistochemistry, ELISA, and immunofluorescence), and expression of related protein mRNA (by qPCR) were detected. The ultrastructure of the alveolar epithelial cells was observed by transmission electron microscopy. We found that E2 and Ang II played an important role in the progression of LIRI. The two signaling pathways showed obvious antagonism, and E2 regulates LIRI in the different sexes by downregulating Ang II, leading to a better prognosis. E2 and losartan reduced the inflammatory cell infiltration in lung tissue and key inflammatory factors in serum while fulvestrant and Ang II had the opposite effect. The protective effect of E2 was related with AKT, p38, COX2, and HIF-1α. [ABSTRACT FROM AUTHOR]

Certain antipsychotics elevate prolactin levels in patients with schizophrenia spectrum disorders (SSD), potentially affecting cognition, symptoms, and hormone levels. This study examines the association between prolactin, testosterone, and estrogen and cognition and symptoms in men with SSD, considering antipsychotic medication. This cross-sectional study included 128 men with SSD and 44 healthy men from two trials. Patients were divided into a prolactin-sparing (n = 53) and prolactin-raising group (n = 75) based on antipsychotic medication. We examined the association between hormones (testosterone, estrogen and prolactin), and cognition and symptoms using backward linear regression. Three domains of cognition were assessed including: processing speed, verbal fluency, and working memory, while symptoms were measured using the Positive and Negative Syndrome Scale (PANSS). Prolactin levels were highest in the prolactin-raising group, followed by the control group, and lowest in the prolactin-sparing group (H = 45.279, p <.001). Testosterone and estrogen levels did not differ significantly between groups. In the prolactin-raising group, prolactin negatively correlated with testosterone (r (73) = −0.32, p =.005). Higher testosterone predicted better cognitive functioning (working memory: β = 0.20, p =.007, verbal fluency: β = 0.30, p =.001) and lower symptom scores (total: β = −0.21, p =.001; negative: β = −0.24, p =.002) in men with SSD. Conversely, higher estrogen levels related to slower processing speed (β = −0.22, p <.001) and higher symptoms scores (β = 0.23, p =.010) in men with SSD. The results suggest positive associations between testosterone and cognition and symptoms in men with SSD, while suggesting that high prolactin levels could relate to lower testosterone levels, possibly worsening cognition and symptoms in men with SSD. [ABSTRACT FROM AUTHOR]

Gender-affirming estrogen therapy (GAET) is commonly used for feminization in transgender and nonbinary (TNB) individuals, yet the optimal rate of change (ROC) in estradiol levels for cardiovascular health is unclear. We examined the association between serum estradiol levels and cardiovascular-related mortality, adverse events, and risk factors in TNB adults using GAET. Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, and Web of Science were systematically searched (inception–April 2023) for original articles reporting serum estradiol levels and cardiovascular-related mortality, adverse events, and risk factors in TNB adults using GAET. Data extraction was completed in duplicate following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Stratified random effect meta-analyses using serum estradiol ROC (serum estradiolbaseline − serum estradiolfollow-up/study duration) was used to assess longitudinal studies (low, 0 < ROC ≤ 1 pg/mL/mo; moderate, 1 < ROC ≤ 3 pg/mL/mo; high, ROC ≥ 3 pg/mL/mo). Thirty-five studies (13 cross-sectional, 19 cohort, and 3 trials) were included. Two studies collectively reported 50 cardiovascular-related deaths, and four collectively reported 23 adverse cardiovascular events. Nineteen studies reporting cardiovascular risk factors were meta-analyzed by ROC stratum (low = 5; moderate = 6; high = 8), demonstrating an association between moderate [0.40, 95% confidence interval (CI): 0.22, 0.59 kg/m2, I2 = 28.2%] and high (0.46, 95% CI: 0.15, 0.78 kg/m2; I2 = 0.0%) serum estradiol ROC and increased body mass index. High (−6.67, 95% CI: −10.65, −2.68 mg/dL; I2 = 0.0%) serum estradiol ROC was associated with decreased low-density lipoproteins. Low (−7.05, 95% CI: −10.40, −3.70 mmHg; I2 = 0.0%) and moderate (−3.69, 95% CI: −4.93, −2.45 mmHg; I2 = 0.0%) serum estradiol ROCs were associated with decreases in systolic blood pressure. In TNB adults using GAET, serum estradiol ROC may influence cardiovascular risk factors, which may have implications for clinical cardiovascular outcomes. NEW & NOTEWORTHY: In this systematic review and meta-analysis of 35 studies involving 7,745 participants, high rates of serum estradiol change were associated with small increases in body mass index. Moderate to high rates of change were associated with decreases in low-density lipoprotein. Low rates of change were associated with small decreases in systolic blood pressure. Rate of serum estradiol change in adults using gender-affirming estrogen therapy may influence cardiovascular risk factors, though further research is warranted. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/serum-estradiol-and-cardiovascular-health-among-transgender-and-nonbinary-adults-using-gender-affirming-estrogen-therapy/. [ABSTRACT FROM AUTHOR]

Objectives The objectives of this project were to: (1) examine the relationship between the number of biological children and hippocampal-dependent cognitive performance among older African American women and (2) determine the influence of socioeconomic status (i.e. age, education, marital status, median household income), if any, on this relationship. Methods A total of 146 cognitively unimpaired African American women aged 60 and older were recruited from the greater Newark area and reported their number of biological children, marital status, educational level, and age. We retrieved median household income from census tract data based on the participants' addresses. Participants' cognitive performance was assessed using the Rey Auditory Verbal Learning Test (RAVLT) long delay recall and a Rutgers generalization task (Concurrent Discrimination and Transfer Task). Results As the number of biological children a woman has had increases, the number of generalization errors also increased, indicating poorer hippocampal-dependent cognitive performance when controlling for age, education, marital status, and median household income. There was no significant relationship between the number of children and performance on a standardized neuropsychological measure of episodic memory (RAVLT), although education was a significant covariate. Discussion Generalization tasks may better capture early changes in cognitive performance in older African American women who have had children than standardized neuropsychological assessments. This finding may be explained by the fluctuations in estrogen associated with having children. Future studies should explore how these findings can be applied to protecting cognitive function and preventing Alzheimer's disease in older African American women who have had children. [ABSTRACT FROM AUTHOR]

Background: Breast cancer, a leading cause of female mortality, is closely linked to mutations in estrogen receptor beta (ESR2), particularly in the ligand‐binding domain, which contributed to altered signaling pathways and uncontrolled cell growth. Objectives/Aims: This study investigates the molecular and structural aspects of ESR2 mutant proteins to identify shared pharmacophoric regions of ESR2 mutant proteins and potential therapeutic targets aligned within the pharmacophore model. Methods: This study was initiated by establishing a common pharmacophore model among three mutant ESR2 proteins (PDB ID: 2FSZ, 7XVZ, and 7XWR). The generated shared feature pharmacophore (SFP) includes four primary binding interactions: Hydrogen bond donors (HBD), hydrogen bond acceptors (HBA), hydrophobic interactions (HPho), and Aromatic interactions (Ar), along with halogen bond donors (XBD) and totalling 11 features (HBD: 2, HBA: 3, HPho: 3, Ar: 2, XBD: 1). By employing an in‐house Python script, these 11 features distributed into 336 combinations, which were used as query to isolate a drug library of 41,248 compounds and subjected to virtual screening through the generated SFP. Results: The virtual screening demonstrated 33 hits showing potential pharmacophoric fit scores and low RMSD value. The top four compounds: ZINC94272748, ZINC79046938, ZINC05925939, and ZINC59928516 showed a fit score of more than 86% and satisfied the Lipinski rule of five. These four compounds and a control underwent molecular (XP Glide mode) docking analysis against wild‐type ESR2 protein (PDB ID: 1QKM), resulting in binding affinity of −8.26, −5.73, −10.80, and −8.42 kcal/mol, respectively, along with the control −7.2 kcal/mol. Furthermore, the stability of the selected candidates was determined through molecular dynamics (MD) simulations of 200 ns and MM‐GBSA analysis. Conclusion: Based on MD simulations and MM‐GBSA analysis, our study identified ZINC05925939 as a promising ESR2 inhibitor among the top four hits. However, it is essential to conduct further wet lab evaluation to assess its efficacy. [ABSTRACT FROM AUTHOR]

Background Coronary spastic angina (CSA) in premenopausal women is not frequent but has also been suggested to be associated with oestrogen decline during the menstrual cycle and sometimes becomes refractory and difficult to control. We experienced two premenopausal women with CSA that showed the involvement of the menstrual cycle. Case summary Case 1: 41-year-old-woman had ST-segment elevation and chest pain during urosepsis, just 2 days after the onset of menstruation. The acetylcholine stress test was performed according to the menstrual cycle, and multiple coronary spasms were induced. Case 2: 40-year-old-woman had refractory chest pain as a symptom of premenstrual syndrome (PMS). Coronary angiography on drugs at the maximum dose revealed spontaneous multiple coronary spasms. Blood levels of oestrogen were normal, suggesting that hormonal change may be involved, and the introduction of low-dose pills made free from angina and the reduction of drug dose. Discussion In premenopausal female angina pectoris, oestrogen may play a role; it is important to ask about the menstrual cycle and history of PMS. Besides, the timing of catheterization in premenopausal women with suspected CSA should be considered. Low-dose pills may be effective in some cases, and active medical collaboration with other departments such as gynaecology is desirable. [ABSTRACT FROM AUTHOR]

The resurgence of interest in psychedelics as treatments for psychiatric disorders necessitates a better understanding of potential sex differences in response to these substances. Sex as a biological variable (SABV) has been historically neglected in medical research, posing limits to our understanding of treatment efficacy. Human studies have provided insights into the efficacy of psychedelics across various diagnoses and aspects of cognition, yet sex-specific effects remain unclear, making it difficult to draw strong conclusions about sex-dependent differences in response to psychedelic treatments. Compounding this further, animal studies used to understand biological mechanisms of psychedelics predominantly use one sex and present mixed neurobiological and behavioral outcomes. Studies that do include both sexes often do not investigate sex differences further, which may hinder the translation of findings to the clinic. In reviewing sex differences in responses to psychedelics, we will highlight the direct interaction between estrogen (the most extensively studied steroid hormone) and the serotonin system (central to the mechanism of action of psychedelics), and the potential that estrogen-serotonin interactions may influence the efficacy of psychedelics in female participants. Estrogen influences serotonin neurotransmission by affecting its synthesis and release, as well as modulating the sensitivity and responsiveness of serotonin receptor subtypes in the brain. This could potentially influence the efficacy of psychedelics in females by modifying their therapeutic efficacy across menstrual cycles and developmental stages. Investigating this interaction in the context of psychedelic research could aid in the advancement of therapeutic outcomes, especially for conditions with sex-specific prevalence. [ABSTRACT FROM AUTHOR]

Objectives: 17β‐estradiol (E2) is a steroidal hormone with immunomodulatory functions that play a role in infectious and inflammatory diseases. E2 was recently identified as the leading upstream regulator of differentially expressed genes in a comparative RNA sequencing study of pediatric patients with otitis media (OM) versus OM‐free counterparts and may therefore play a role in the inflammatory response to bacterial otopathogens during pediatric OM. This study examined the effect of E2 on bacterial‐induced inflammatory cytokine expression in an in vitro pediatric OM model. Methods: An immortalized middle ear (ME) epithelial cell line, ROM‐SV40, was developed from a pediatric recurrent OM patient. The culture was exposed to E2 at physiological levels for 1–48 h prior to 6 h‐stimulation with nontypeable Haemophilus influenzae (NTHi) whole cell lysate. TNFA, IL1B, IL6, and IL8 were assayed by qPCR and ELISA. Results: E2 pretreatment (24 h) abrogated NTHi induction of IL6; a longer pretreatment (1–10 nM, 48 h) abrogated IL1B induction (p < 0.05). E2 pretreatment (5 nM, 48 h) abrogated NTHi‐induced IL8 secretion (p = 0.017). Conclusion: E2 pretreatment partially rescued NTHi‐induced cytokine production by ME epithelia. These data support a role for E2 in moderating the excessive inflammatory response to middle ear infection that contributes to OM pathophysiology. Levels of Evidence: NA Laryngoscope, 134:3815–3819, 2024 [ABSTRACT FROM AUTHOR]

Unlike breast and prostate cancers, which are specifically affected by estrogens or androgens, hepatocellular carcinoma has been reported to be influenced by both sex hormones. Given the coincidental differences of hepatocellular carcinoma in men and women, we investigated the effects of β-estradiol and testosterone on the cell cycle, apoptosis, and Wnt signaling in a model of hepatocellular carcinoma to understand the sex hormone-related etiology. To determine the effective concentration of both hormones, an MTT assay was performed. The effects of β-estradiol and testosterone on cell proliferation and death were evaluated by specific staining and flow cytometry. In addition, gene expression levels of estimated factors involved in GPC3-Wnt survival signaling were analyzed using quantitative real-time polymerase chain reaction. Both hormones inhibited hepatic cell proliferation through arresting the cell cycle at S/G2 and increased the apoptosis rate in HepG2 cells. Both hormones dose-dependently decreased GPC3, Wnt, and DVL expression levels as activators of the Wnt-signaling pathway. In the case of Wnt-signaling inhibitors, the effects of both hormones on WIF were negligible, but they increased DKK1 levels in a dose-dependent manner. In each of the effects mentioned above, β-estradiol was notably more potent than testosterone. In contrast to the primary hypothesis of the project, in which testosterone was considered a stimulating carcinogenic factor in HCC pathogenesis, testosterone inhibited the occurrence of HCC similarly to β-estradiol. However, this inhibitory effect was weaker than that of β-estradiol and requires further study. [ABSTRACT FROM AUTHOR]