Protective Effect Of Estrogen Research Articles

Sex differences in pediatric sepsis—a systematic review protocol

BackgroundPediatric sepsis remains a leading cause of childhood morbidity and mortality worldwide. Despite advancements in modern medicine, it accounts for more than 3 million childhood deaths per year. Multiple studies have emphasized that sex and gender have an impact on the treatment and outcome of various diseases. Adult studies have revealed sex differences in pathophysiological responses to septic shock, as well as a possible protective effect of estrogens on critical illness. Sex-specific maturational and developmental differences in host immunology have been previously demonstrated for neonatal and pediatric age groups. At present, there are no studies assessing the impact of sex on outcomes of children with sepsis.MethodsThe goal of this study is to assess sex-specific differences in childhood sepsis survival outcomes. We will systematically assess associations of sex and gender with outcomes in pediatric sepsis in the literature by performing a systematic search of MEDLINE and Embase databases. We will include all English language randomized trials and cohort studies. The study population will include children > 37 weeks gestational age and < 18 years of age. Exposure will be sepsis, severe sepsis, and septic shock and the main comparison will be between male and female sex. The primary outcome will be hospital mortality. Secondary outcomes will be the pediatric intensive care unit and hospital length of stay.DiscussionResults from this review are expected to provide important information on the association of sex with the outcomes of pediatric sepsis. If an association is noted, this study may serve as a foundation for further research evaluating the pathophysiological aspects as well as potential socioeconomic factors responsible for the clinically detected sex differences.Systematic review registrationPROSPERO CRD42022315753.

Antipsychotic-induced prolactin elevation in premenopausal women with schizophrenia: associations with estrogen, disease severity and cognition.

Antipsychotic-induced prolactin elevation may impede protective effects of estrogens in women with schizophrenia-spectrum disorders (SSD). Our study sought to confirm whether the use of prolactin-raising antipsychotics is associated with lower estrogen levels, and to investigate how estrogen and prolactin levels relate to symptom severity and cognition in premenopausal women with SSD. This cross-sectional study included 79 premenopausal women, divided in three groups of women with SSD treated with prolactin-sparing antipsychotics (n = 21) or prolactin-raising antipsychotics (n = 27), and age-matched women without SSD (n = 31). Circulating 17β-estradiol was compared among groups. In patients, we assessed the relationship between prolactin and 17β-estradiol, and the relationships of these hormones to symptom severity and cognition, using correlation analyses and backward regression models. In women receiving prolactin-raising antipsychotics, 17β-estradiol levels were lower as compared to both other groups (H(2) = 8.34; p = 0.015), and prolactin was inversely correlated with 17β-estradiol (r=-0.42, p = 0.030). In the prolactin-raising group, 17β-estradiol correlated positively with verbal fluency (r = 0.52, p = 0.009), and 17β-estradiol and prolactin together explained 29% of the variation in processing speed (β17β-estradiol = 0.24, βprolactin=-0.45, F(2,25) = 5.98, p = 0.008). In the prolactin-sparing group, 17β-estradiol correlated negatively with depression/anxiety (r=-0.57, p = 0.014), and together with prolactin explained 26% of the variation in total symptoms (β17β-estradiol=-0.41, βprolactin = 0.32, F(2,18) = 4.44, p = 0.027). In women with SSD, antipsychotic-induced prolactin elevation was related to lower estrogen levels. Further, estrogens negatively correlated with symptom severity and positively with cognition, whereas prolactin levels correlated negatively with cognition. Our findings stress the clinical importance of maintaining healthy levels of prolactin and estrogens in women with SSD.

Female-specific risk factors for cardiovascular disease: an update.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. While it was previously believed that men have greater susceptibility to CVD, recent research suggests that women face an increased risk of CVD after the onset of menopause, primarily due to the loss of the protective effects of estrogens. Premature ovarian insufficiency (POI), polycystic ovarian syndrome (PCOS), and gestational factors, such as gestational diabetes mellitus (GDM), recurrent pregnancy loss, preterm delivery, and preeclampsia, are specific reproductive disorders that may contribute to an elevated risk of CVD at earlier ages, i.e., before the onset of menopause. This suggests that women with these conditions should be closely monitored for CVD risk factors even before reaching menopause. Such early intervention may help reduce the incidence of CVD and improve overall cardiovascular health in this population. The precise pathophysiological mechanism underlying the development of CVD in women with menopause, premature POI, PCOS, and gestational factors remains elusive. This review article seeks to elucidate the latest research on the relationship between these conditions and CVD in women, aiming to explore the underlying pathogenic mechanisms contributing to this association.

The impact of female sex hormones on cardiovascular disease: from mechanisms to hormone therapy.

Cardiovascular disease remains the leading cause of mortality in women, yet it has not raised the awareness from the public. The pathogenesis of cardiovascular disease differs significantly between females and males concerning the effect of sex hormones. Estrogen and progestogen impact cardiovascular system through genomic and non-genomic effects. Before menopause, cardiovascular protective effects of estrogens have been well described. Progestogens were often used in combination with estrogens in hormone therapy. Fluctuations in sex hormone levels, particularly estrogen deficiency, were considered the specific risk factor in women's cardiovascular disease. However, considerable heterogeneity in the impact of hormone therapy was observed in clinical trials. The heterogeneity is likely closely associated with factors such as the initial time, administration route, dosage, and formulation of hormone therapy. This review will delve into the pathogenesis and hormone therapy, summarizing the effect of female sex hormones on hypertension, pre-eclampsia, coronary heart disease, heart failure with preserved ejection fraction, and cardiovascular risk factors specific to women.

The Role of Estrogen and Estrogen Receptors in Head and Neck Tumors.

Head and neck squamous cell carcinoma (HNSCC) is the most common histological form of head and neck tumors (HNTs), which originate from the epithelium of the lips and oral cavity, pharynx, larynx, salivary glands, nasal cavity, and sinuses. The main risk factors include consumption of tobacco in all forms and alcohol, as well as infections with high-risk human papillomaviruses or the Epstein-Barr virus. Regardless of the etiological agent, the risk of developing different types of HNTs is from two to more than six times higher in males than in females. The reason for such disparities probably lies in a combination of both biological and psychosocial factors. Therefore, it is hypothesized that exposure to female sex hormones, primarily estrogen, provides women with protection against the formation and metastasis of HNTs. In this review, we synthesized available knowledge on the role of estrogen and estrogen receptors (ERs) in the development and progression of HNTs, with special emphasis on membrane ERs, which are much less studied. We can summarize that in addition to epidemiologic studies unequivocally pointing to the protective effect of estrogen in women, an increased expression of both nuclear ERs, ERα, and ERβ, and membrane ERs, ERα36, GPER1, and NaV1.2, was present in different types of HNSCC, for which anti-estrogens could be used as an effective therapeutic approach.

Loss of ADAM15 in female mice does not worsen pressure overload cardiomyopathy, independent of ovarian hormones.

Cardiac hypertrophy is a common feature in several cardiomyopathies. We previously reported that loss of ADAM15 (disintegrin and metalloproteinase 15) worsened cardiac hypertrophy and dilated cardiomyopathy following cardiac pressure overload. Here, we investigated the impact of ADAM15 loss in female mice following cardiac pressure overload induced by transverse aortic constriction (TAC). Female Adam15-/- mice developed the same degree of cardiac hypertrophy, dilation, and dysfunction as the parallel female wild-type (WT) mice at 6 wk post-TAC. To determine if this is due to the protective effects of estrogen, which could mask the negative impact of Adam15 loss, WT and Adam15-/- mice underwent ovariectomy (OVx) 2 wk before TAC. Cardiac structure and function analyses were performed at 6 wk post-TAC. OVx similarly impacted females of both genotypes post-TAC. Calcineurin (Cn) activity was increased post-OVx-TAC, and more in Adam15-/- mice; however, this increase was not reflected in the total-to-phospho-NFAT levels. Integrin-α7 expression, which was upstream of Cn activation in male Adam15-/- -TAC mice, remained unchanged in female mice. However, activation of the mitogen-activated protein kinases (ERK, JNK, P38) was greater in Adam15-/--OVx-TAC than in WT-OVx-TAC mice. In addition, ADAM15 protein levels were significantly increased post-TAC in male but not in female WT mice. Myocardial fibrosis was comparable in non-OVx WT-TAC and Adam15-/- -TAC mice. OVx increased the perivascular fibrosis more in Adam15-/- compared with WT mice post-TAC. Our data demonstrate that loss of ovarian hormones did not fully replicate the male phenotype in the female Adam15-/- mice post-TAC. As ADAM15 levels were increased in males but not in females post-TAC, it is plausible that ADAM15 does not play a prominent role in post-TAC events in female mice. Our findings highlight the significance of factors other than sex hormones in mediating cardiomyopathies in females, which require a more thorough understanding.NEW & NOTEWORTHY Loss of ADAM15 in female mice, unlike the male mice, does not worsen the cardiomyopathy following cardiac pressure overload. Ovariectomy does not worsen the post-TAC cardiomyopathy in female Adam15-/- mice compared with female WT mice. Lack of deleterious impact of Adam15 deficiency in female mice is not because of the protective effects of ovarian hormones but could be due to a less prominent role of ADAM15 in cardiac response to post-TAC remodeling in female mice.

Sex dimorphism controls dysbindin-related cognitive dysfunctions in mice and humans with the contribution of COMT.

Cognitive dysfunctions are core-enduring symptoms of schizophrenia, with important sex-related differences. Genetic variants of the DTBPN1 gene associated with reduced dysbindin-1 protein (Dys) expression negatively impact cognitive functions in schizophrenia through a functional epistatic interaction with Catechol-O-methyltransferase (COMT). Dys is involved in the trafficking of dopaminergic receptors, crucial for prefrontal cortex (PFC) signaling regulation. Moreover, dopamine signaling is modulated by estrogens via inhibition of COMT expression. We hypothesized a sex dimorphism in Dys-related cognitive functions dependent on COMT and estrogen levels. Our multidisciplinary approach combined behavioral-molecular findings on genetically modified mice, human postmortem Dys expression data, and in vivo fMRI during a working memory task performance. We found cognitive impairments in male mice related to genetic variants characterized by reduced Dys protein expression (pBonferroni = 0.0001), as well as in male humans through a COMT/Dys functional epistatic interaction involving PFC brain activity during working memory (t(23) = -3.21; pFDR = 0.004). Dorsolateral PFC activity was associated with lower working memory performance in males only (p = 0.04). Also, male humans showed decreased Dys expression in dorsolateral PFC during adulthood (pFDR = 0.05). Female Dys mice showed preserved cognitive performances with deficits only with a lack of estrogen tested in an ovariectomy model (pBonferroni = 0.0001), suggesting that genetic variants reducing Dys protein expression could probably become functional in females when the protective effect of estrogens is attenuated, i.e., during menopause. Overall, our results show the differential impact of functional variants of the DTBPN1 gene interacting with COMT on cognitive functions across sexes in mice and humans, underlying the importance of considering sex as a target for patient stratification and precision medicine in schizophrenia.

Abstract TP287: Estrous Cycle Stages and Cerebral Blood Flow: Implications for Ischemic Tolerance in Stroke

Introduction: Previous stroke studies in female rodents have demonstrated that the severity of ischemic damage is differentially impacted by the estrous cycle. Estrogen is considered to be neuroprotective, but it is unclear whether this protection is dependent on the vasodilator properties of estrogen. In this study, we investigated the impact of estrus cycle stage on stroke lesion volume and whether that impact was dependent on cerebral blood flow (CBF) changes during stroke. Methods: Ischemia was induced in adult ( 10 weeks) male and female Sprague-Dawley rats by 30 minutes middle cerebral artery occlusion (MCAO) using the suture model. Prior to the stroke procedure, the phases of the estrous cycle (proestrus(P), estrus(E), metestrus(M) and diestrus (D)) were determined by vaginal smear tests in female rats. Cerebral blood flow (CBF) was measured by laser doppler and infarct volume were measured by TTC staining at d2 post-stroke. Results: Females in proestrus and diestrus (P/D) stages of the estrous cycle, which have reportedly high levels of estrogen, had significantly (p&lt;0.05) smaller CBF decreases during ischemia and a trend for smaller infarcts than those in estrous and metestrus stages, which have lower estrogen levels. This suggests that the protective effects of estrogen may be related to effects on blood flow. However, when compared to male rats, females in P/D stages had significantly (p&lt;0.05) smaller brain infarcts despite having similar CBF decreases. This implies that additional mechanisms are responsible for the neuroprotection observed in females when compared to males. Conclusion: Estrous cycle stage affects CBF decrease during ischemia, but this does not account for the difference in infarct size observed between male and female rats. Our study indicates that multiple mechanisms are responsible for ischemic tolerance in specific stages of the estrous cycle. Keywords: stroke, estrous cycle, CBF, estrogen

Investigating the therapeutic potential of hesperidin targeting CRISP2 in intervertebral disc degeneration and cancer risk mitigation.

Intervertebral disc degeneration (IDD) can lead to disc herniation and spinal instability, sometimes requiring surgical intervention. Currently, estrogen has a potential protective effect on IDD, and estrogen is associated with an increased risk of some cancers, such as breast and endometrial cancer. Therefore, it is important to identify natural compounds that estrogen analogues treat IDD while reducing the risk of tumor development. This study aims to explore a natural metabolic treatment strategy by targeting CRISP2 with the natural compound Hesperidin to mimic the protective effects of estrogen on IDD and reduce the risk of tumor development. Microarray data from healthy volunteers and IDD patients were extracted from the Gene Expression Omnibus (GEO) database, and RNA sequencing and clinical data from various cancer types were analyzed. Differentially expressed genes (DEGs) were identified using the Bioconductor Limma package, followed by principal component analysis, volcano plot, and heatmap visualization. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, CIBERSORT and ssGSEA immune cell infiltration assessments, survival analysis, metabolite enrichment analysis, and molecular docking were performed. Hesperidin's interaction with CRISP2 was further validated through molecular docking and experimental studies. Hesperidin significantly reduced the expression of CRISP2, iNOS, and COX2 in IDD models, decreased reactive oxygen species (ROS) and apoptosis, and diminished inflammatory markers. CIBERSORT and ssGSEA analyses revealed a correlation between CRISP2 and immune cell infiltration. Survival analysis demonstrated that CRISP2 expression levels were associated with patient survival across various cancer types. Hesperidin was found to mimic estrogen's effects on IDD and reduce tumor progression. Cell culture and experimental validation confirmed Hesperidin's protective effects on nucleus pulposus cells (NPCs). Hesperidin, as a potential natural metabolic regulator, not only has therapeutic effects on IDD but may also synergize with estrogen therapy to promote spinal health without increasing cancer risk. This study presents a new clinical approach for IDD treatment and lays the foundation for further drug development and experimental research.

Estrogen as a guardian of auditory health: Tsp1–CD47 axis regulation and noise-induced hearing loss

Objectives This study aimed to analyze the role of estrogen in noise-induced hearing loss (NIHL) and uncover underlying mechanisms. Methods An ovariectomized Sprague-Dawley rat model (OVX) was constructed to investigate the hearing threshold and auditory latency before and after noise exposure using the auditory brainstem response (ABR) test. The morphological changes were assessed using immunofluorescence, scanning electron microscopy and transmission electron microscopy. Proteomics and bioinformatics were used to analyze the mechanism. The findings were further verified through western blot and Luminex liquid suspension chip technology. Results After noise exposure, OVX rats exhibited substantially elevated hearing thresholds. A conspicuous delay in ABR wave I latency was observed, alongside increased loss of outer hair cells, severe collapse of stereocilia and pronounced deformation of the epidermal plate. Accordingly, OVX rats with estrogen supplementation exhibited tolerance to NIHL. Additionally, a remarkable upregulation of the thrombospondin 1 (Tsp1)–CD47 axis in OVX rats was discovered and verified. Conclusions OVX rats were more susceptible to NIHL, and the protective effect of estrogen was achieved through regulation of the Tsp1–CD47 axis. This study presents a novel mechanism through which estrogen regulates NIHL and offers a potential intervention strategy for the clinical treatment of NIHL.

The Effects of Estrogen on the Risk of Developing Dementia using the UK Biobank Data

AbstractBackgroundThe incidence of dementia increases with postmenopausal women, which prompted the investigation of the role of estrogen in the development of dementia. We aimed to investigate the role of estrogen in the UK Biobank.MethodA total of 273,201 women were included in this study. Comprehensive interviews, medical history, body mass index (BMI), and the apolipoprotein E (APOE) genotype were obtained. Reproductive characteristics, including estrogen length and history of surgery, were used as exposure variables. The Cox Proportional Hazard model was used to estimate hazard ratios (HR) for the development of dementia, adjusting for age, education, the Townsend deprivation score, the APOE genotype, family history of dementia, BMI, smoking status, diabetes mellitus, hypertension, and hyperlipidemia.ResultThe mean estrogen length was 37.25 years (8.03 years). About 19% of women had a history of surgery. Compared to women with the lowest overall exposure to estrogen (Estrogen length ≤33), women with higher levels of cumulative estrogen had a decreased risk of dementia (34≤Estrogen length ≤37, HR = 0.79, 95% CI = 0.72‐0.89, p&lt;0.001; 38≤Estrogen length ≤42, HR = 0.72, 95% CI = 0.65‐0.79, p&lt;0.001; 43≤Estrogen length, HR = 0.77, 95% CI = 0.70‐0.85, p&lt;0.001). Compared to women without a history of surgery, women with a history of surgery had an increased risk of dementia (HR = 1.08, 95%CI = 1.00‐1.17, p = 0.038).ConclusionThis study found that longer estrogen length had a decreased risk for dementia and a history of surgery had an increased risk for dementia. The results of this study suggested that estrogen might have a protective role in women’s development of dementia. The exact biological mechanism of the protective effects of estrogen in the brain needs to be elucidated in the future.

Tamoxifen in breast cancer and risk of Parkinson's disease: A meta-analysis

BackgroundTamoxifen is widely used for hormone-sensitive breast cancer, achieved by modulating the estrogen receptor activity in a tissue-specific manner. There is evidence to support the protective effects of estrogen against Parkinson's disease (PD), a common neurodegenerative condition. Some epidemiologic studies suggest the use of tamoxifen may modulate the PD risk. We conducted a meta-analysis to examine the association between tamoxifen and risk of PD. MethodsA search of PubMed using search terms synonymous with “tamoxifen” and “Parkinson's disease” was conducted. Outcomes of interest were the odds ratio (OR) of PD comparing tamoxifen-exposed to -unexposed women, as well as the incidence rate of PD in tamoxifen-exposed women. ResultsA total of 37,932 subjects with breast cancer, comprising 17,233 tamoxifen-exposed subjects and 20,699 tamoxifen-unexposed subjects, satisfied the inclusion criteria. The exposure to tamoxifen ranged from 30-96 months. Using the common-effect model, the pooled OR of PD was 2.4, with (95% CI 1.91-3.01, P < 0.0001), with high heterogeneity (I2 = 81.5%, Cochran's Q test P = 0.001). Pooling 28,640 tamoxifen-exposed patients under the common-effect model found an incidence rate of 5.86 events per 10,000 person-years (95% CI 4.82–7.12) with minimal heterogeneity (I2 = 26%, Cochran's Q test P = 0.258). ConclusionsOur meta-analysis suggests that tamoxifen use may be associated with an increased PD risk in women. However, due to heterogeneity and potential limitations of some of the studies, further clinical and functional validation will be needed. Longitudinal studies supported by imaging and biomarkers evaluation will be useful to identify the mechanisms linking tamoxifen and PD risk.

The impact of menopausal status on auditory brainstem responses

ObjectiveTo determine the effect of decreased estrogen levels due to menopause on auditory brainstem response measurements (ABR). Study designRetrospective chart review. SettingAcademic. PatientsPre- and post-menopausal females (pre-M, post-M) and age-matched males. MethodsABR measurements of wave I, III, and V latencies, and interpeak latencies; amplitudes of waves I, III, V, and V/I ratio. Outcome measureDifferences in ABR measurements between pre-M and post-M. Results164 subjects (101 female and 64 male) were included. Post-M had significantly greater latencies (msec) than pre-M of wave V. Post-M had a significantly smaller wave I amplitude (uV) than pre-M. Post-M had a significantly higher wave V/I amplitude ratio than pre-M. Pre-M had significantly shorter latencies than young males for wave III, and wave V. Post-M had significantly shorter latencies than older males at wave III, and wave V. A two-way ANOVA revealed a significant interaction between the effects of age category and gender on V/I amplitude. ConclusionPost-M group showed a significant drop in wave I amplitude compared with pre-M group, even in the absence of hearing loss, suggesting that the gender differences in hearing are related to estrogen signaling along the auditory pathway. If wave I amplitude changes between older and younger groups resulted from decreased peripheral hearing sensitivity, we would expect larger drops in amplitude in males since rates of presbycusis are higher. We observed much larger drops in wave I amplitude in females, which cannot be attributed to peripheral hearing loss. These results may assist in understanding gender differences in presbycusis and a possible protective effect of estrogen on the auditory system. Knowledge of gender differences in wave I may be important when ABR is used to assess possible synaptopathy.

Effect of diabetes mellitus on young female patients with acute coronary syndrome

BackgroundDiabetes mellitus (DM) is one of the most important risk factors of acute coronary syndrome (ACS). There have been many studies on the relationship between DM and ACS. However, the effect of DM on young females with ACS is still unclear. ObjectiveTo explore the effect of DM on coronary arteries lesions in young females with ACS. Methods1278 young females (age ≤ 44 years) undergoing coronary angiography were divided into DM group (n = 197) and control group (n = 1081) according to whether they had diabetes. Based on whether the patient has ACS, each group was further divided into DM-ACS subgroup and Non-DM-ACS subgroup to compare the characteristics and severity of coronary artery lesions and follow-up outcomes. ResultsThe prevalence of diabetes was 15.41% (197/1278). Overweight (58.88%) and depression or anxiety (11.17%) in the DM group was significantly higher than those (32.22% and 6.20%) in the control group (P < 0.05). The prevalence of ACS (85.28%) in the DM group was significantly higher than that (25.35%) in the control group (P < 0.05). The proportion of type A lesions in the DM-ACS subgroup was lesser than that in the Non-DM-ACS subgroup (P < 0.05). The type C lesions in the DM-ACS subgroup were significantly higher than that in the Non-DM-ACS subgroup (P < 0.01). The number of stents implantation in the DM-ACS subgroup was no significant difference compared with the Non-DM-subgroup (P > 0.05). The length of stent implantation in the DM-ACS subgroup was significantly longer than that in the Non-DM-ACS subgroup (P < 0.05). The rate of MACE was not statistically significant between the two subgroups (P > 0.05), but the rate of all-cause death (2.98%) in the DM-ACS subgroup was significantly higher than that (0.36%) in the Non-DM-ACS subgroup (P < 0.05). ConclusionsDM is an important risk factor in young females with ACS. Young women with diabetes are prone to coronary heart disease. The coronary artery lesions in DM patients were more severe than those in Non-DM patients, despite the protective effect of estrogen on the cardiovascular system. Therefore, young women with DM should be treated to prevent ACS and future events activelyandpurposefully.

Emotion recognition and mood along the menstrual cycle

Previous studies have demonstrated menstrual cycle dependent changes in the recognition of facial emotional expressions, specifically the expression of fear, anger, sadness or disgust. While some studies demonstrate an improvement of emotion recognition performance during the peri-ovulatory phase, when estradiol levels peak, other studies demonstrate a deterioration of emotion recognition performance during the mid-luteal phase, when progesterone levels peak. It has been hypothesized, that these changes in emotion recognition performance mirror mood changes along the menstrual cycle. In the present study, we investigate, whether changes in emotion recognition performance along the menstrual cycle are mediated by mood changes along the menstrual cycle. In a combined cross-sectional and longitudinal study design, two large samples of women completed an emotion recognition task, as well as several mood questionnaires during their menses, peri-ovulatory or mid-luteal cycle phase. 65 women completed the task thrice, once during each cycle phase, order counterbalanced. In order to control for potential learning effects, a sample of 153 women completed the task only once in one of the three cycle phases. In both samples, results demonstrated no significant changes in emotion recognition performance along the menstrual cycle, irrespective of the performance measure investigated (accuracy, reaction time, frequency of emotion classifications) and irrespective of the emotion displayed. Bayesian statistics provided very strong evidence for the null hypothesis, that emotion recognition does not change along the menstrual cycle. There was also no moderation of emotion recognition changes along the menstrual cycle by mood changes along the menstrual cycle. Mood changes along the menstrual cycle followed the expected pattern with highest positive affect and least premenstrual symptoms around ovulation and lowest positive affect, but strongest premenstrual symptoms during menses. Interestingly, premenstrual symptoms were negatively related to estradiol, suggesting a protective effect of estrogen during the luteal cycle phase against mood worsening during the premenstrual phase.

0097 Sleep and Eating Rhythms are Associated with Metabolic Risk in Postmenopausal Women

Abstract Introduction Postmenopausal women are particularly vulnerable to metabolic dysfunction. Compelling evidence suggests that this is due to their lacking the protective effect of estrogens. We have shown that circulating estrogens regulate daily eating and sleep-activity rhythms in female mice and protect them from obesity and diabetes. However, few studies have investigated whether postmenopausal women have disrupted eating and sleep-activity rhythms that could contribute to their metabolic dysfunction. The purpose of this study was to investigate the relationship between eating rhythms, sleep, and metabolic risk in postmenopausal women. Methods During 7 days, we studied sedentary, postmenopausal women who were not taking hormones (estrogens ± progestin) and were metabolically unhealthy, defined as prediabetic or normal glucose tolerance with at least 1 feature of the metabolic syndrome. Women taking medications affecting sleep or eating were excluded. Sleep timing and quality were assessed by actigraphy and sleep logs. Times of first and last meals were collected from participants with a texting system. Body composition (DXA), body mass index (BMI), and waist circumference were collected as markers of obesity. Lipid metabolism and glycemic control were assessed by fasting lipid panel and HbA1c as well as oral glucose tolerance test. Results Eighteen postmenopausal women (mean ± SEM; 57.2 ± 1.1 years) participated in the study. Both sleep timing and quality were associated with metabolic risk in postmenopausal women. Specifically, later timing of sleep onset was associated with later meal timing and greater BMI and body fat percentage. Increased sleep fragmentation was associated with reduced HDL. In addition, both the timing and duration of eating were associated with worse metabolic measures. Longer eating duration was associated with larger waist circumference. Later eating time was associated with greater waist circumference and BMI. Conclusion We found that late timing and poor quality of sleep, as well as long eating duration, are associated with markers of metabolic risk in postmenopausal women. These data suggest that interventions that reduce eating duration and advance the timing of last meal and sleep onset may improve metabolic risk in postmenopausal women. Support (if any) This study is supported by NIH awards R01DK124774, T32 AG078110, and UL1TR001998.

β-Arrestin 2 knockout prevents bone loss in response to continuous parathyroid hormone stimulation in male and female mice

ABSTRACT Background β-Arrestin 2 (β-arr2) binds activated parathyroid hormone (PTH) receptors stimulating internalization. PTH stimulates both anabolic and catabolic effect on bone depending on the way it is administered. Intermittent PTH stimulation increases trabecular bone formation in mice, but this is decreased in mice lacking β-arr 2, suggesting a role for β-arr 2 in the anabolic effects of PTH. The role of β-arr 2 in the catabolic effects of continuous PTH (cPTH) treatment is not known. Objective To assess the effects of cPTH administration on bone in mice lacking β-arr 2 compared to wild-type (WT). Methods Groups of male and female WT or β-arr2 knockout (KO) mice were administered either PTH or phosphate-buffered saline by osmotic pumps for 2 weeks. Following treatment, serum calcium and phosphate levels were measured, bone structure and mineral density were measured by microcomputed tomography, and bone cells measured by static and dynamic histomorphometry. Results β-arr2 KO had no effects on skeletal development in mice of either sex. PTH treatment caused hypercalcemia and hypophosphatemia and decreased trabecular and cortical bone only in male WT mice. β-arr2 KO in male mice completely abrogated the effects of PTH on bone, while in female β-arr2 KO mice, PTH treatment increased trabecular bone with no effects on cortical bone. Conclusions These results demonstrate a profound sex effect on skeletal responses to cPTH treatment, suggesting a protective effect of estrogen on bone loss. β-arr2 plays a role in restraining the anabolic effects of PTH in both male and female mice.

Sex Differences in Gastroesophageal Reflux Disease (GERD)

Gastroesophageal reflux disease (GERD) is the most commonly diagnosed digestive disorder in the United States. Higher rates of non-erosive reflux disease (NERD) are found in females while higher rates of erosive reflux disease (ERD) are found in males. Pre-menopausal females appear to be protected from esophageal mucosal damage, as they demonstrate lower rates of ERD, Barrett’s esophagus, and esophageal adenocarcinoma. A protective effect of estrogen on the esophageal mucosa is thought to contribute to this decreased prevalence. A better understanding of sex-related differences in GERD may help alleviate the reported differences in outcomes between sexes regarding medical and surgical management.

Apolipoprotein C3 is negatively associated with estrogen and mediates the protective effect of estrogen on hypertriglyceridemia in obese adults

BackgroundBoth estrogen and apolipoprotein C3 (ApoC3) play crucial roles in lipid metabolism. But the link between them remains unclear, and it is unknown whether estrogen regulates triglyceride (TG) levels via ApoC3. Researchers hypothesized that estrogen exerts a regulatory effect on ApoC3 metabolism, and that this regulation could play a significant role in lipid metabolism. To explore this potential link, the present investigation aimed to examine the associations between estradiol (E2), ApoC3, and TG levels in both males and females.MethodsA total of 519 obese people (133 males and 386 premenopausal females) were recruited. Based on their TG levels, the participants were split into two groups [hypertriglyceridemia (HTG) group: TG ≥ 1.7 mmol/L; control group: TG < 1.7 mmol/L]. Serum ApoC3, E2, and TG levels were measured and compared in those two groups for both sexes separately. To ascertain the connection among E2, ApoC3, and TG, linear regression and mediation analysis were used.ResultsParticipants in the HTG group presented higher levels of ApoC3 (P < 0.001). In contrast, they tend to have lower E2 levels than the control. Linear regression analysis proposed that in both sexes, E2 was negatively associated with ApoC3 levels. The relationship remained significant after adjustment for confounding factors (male: standardized β = -0.144, t = -2.392, P < 0.05; female: standardized β = -0.077, t = -2.360, P < 0.001). Furthermore, mediation analysis revealed the relationship between reduced E2 levels and elevated TG levels is directly mediated by ApoC3.ConclusionsIn obese men and premenopausal women, ApoC3 was negatively and linearly correlated with serum E2 levels. The findings showed that estrogen may suppress ApoC3 expression and thus lower TG levels.

17β-Estradiol promotes sex-specific dysfunction in isolated human arterioles.

Despite data showing that estrogen is vasculoprotective in large conduit arteries, hormone therapy (HT) during menopause has not proven to mitigate cardiovascular disease (CVD) risk. Estrogen exposure through prolonged oral contraceptive use and gender-affirming therapy can also increase cis- and trans-females' risk for future CVD, respectively. The microvasculature is a unique vascular bed that when dysfunctional can independently predict future adverse cardiac events; however, studies on the influence of estrogen on human microvessels are limited. Here, we show that isolated human arterioles from females across the life span maintain nitric oxide (NO)-mediated dilation to flow, whereas chronic (16-20 h) exposure to exogenous (100 nM) 17β-estradiol promotes microvascular endothelial dysfunction in vessels from adult females of <40 and ≥40 yr of age. The damaging effect of estrogen was more dramatic in arterioles from biological males, as they exhibited both endothelial and smooth muscle dysfunction. Furthermore, females of <40 yr have greater endothelial expression of estrogen receptor-β (ER-β) and G protein-coupled estrogen receptor (GPER) compared with females of ≥40 yr and males. Estrogen receptor-α (ER-α), the prominent receptor associated with protective effects of estrogen, was identified within the adventitia as opposed to the endothelium across all groups. To our knowledge, this is the first study to report the detrimental effects of estrogen on the human microvasculature and highlights differences in estrogen receptor expression.NEW & NOTEWORTHY Microvascular dysfunction is an independent predictor of adverse cardiac events; however, the effect of estrogen on the human microcirculation represents a critical knowledge gap. To our knowledge, this is the first study to report sex-specific detrimental effects of chronic estrogen on human microvascular reactivity. These findings may offer insight into the increased CVD risk associated with estrogen use in both cis- and trans-females.