Healthy Postmenopausal Women Research Articles

The Influence of Hyperlipidemia on the Results of Mammography in Postmenopausal Women

Aim: To determine whether hyperlipidemia causes specific or nonspecific changes that can be detected by mammography in postmenopausal women. Materials and Method: This study was conducted retrospectively and designed as a case-control study in the gynecology clinics of Etlik Zubeyde Hanim Women’s Health Education and Training Hospital between January 2017 and January 2020. Healthy postmenopausal women with a total cholesterol (TC) level of 200 mg/dL and above 200 mg/dL, who were examined in our outpatient clinics and whose mammographic controls were performed in our hospital, were included in the study group (Group I). Healthy postmenopausal women with a TC level below 200 mg/dL who were followed up at the same clinic and whose mammographic controls were performed at our clinic were included in the control group (Group II). We analyzed TC, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides with mammography findings. Results: There were no significant differences between the groups in terms of age and body mass index. There were no significant differences between smoking status and family history of breast cancer. The BAC and BI-RADS scoring category scores differed significantly (p=0.006 and p=0.042, respectively). Conclusion: Postmenopausal women with hyperlipidemia have mammographic findings that can lead to breast cancer. Considering that hyperlipidemia may also have other causes of morbidity and mortality, such as hypertension, diabetes mellitus and cardiovascular disease, it is necessary to treat it with lifestyle changes and / or medications. As this was a retrospective study with a limited number of patients, it is clear that future randomized controlled trials could provide more reliable data on this topic.

Estimation of Some Antioxidant Factors in Postmenopausal Iraqi Women with Hypertension

Postmenopausal women with hypertension may be linked with cardiovascular risk factors like visceral obesity. Changes in antioxidant levels and lipid profile are considered risk factors concerning heart disease that arises during postmenopausal. Ninety Iraqi women aged between 53-70 years, sixty women with postmenopausal hypertension, and thirty healthy postmenopausal women were selected as control for this study. Blood samples were taken to measure some antioxidants through enzyme-linked immune sorbent assay (ELISA) and lipid profile by enzymatic technique. Results showed that the mean of catalase levels was significantly lower in patients (257.62±6.99) compared towith the control group (499.30±13.08). Glutathione results were significantly lower in patients (10.99±0.26) compared with the healthy control (39.32±2.03). Cholesterol levels were significantly higher in patients (236.09±1.91), while lower levels were observed in the control group (172.67±4.92). Triglyceride levels were significantly higher both in patients (182.10±2.68) and the healthy group (145.92±5.85). HDL levels were significantly lower in patients (29.91±0.37) compared with the control group (43.02±1.38). VLDL levels were significantly higher in patients (36.49±0.54) compared with the control (29.16±1.17). LDL levels were significantly higher in patients (169.74±2.20) than in the control group (1 00.48±5.41). It can be concluded from the results that antioxidant levels decreased in postmenopausal women than in the control group. Elevation in lipid profile of postmenopausal women was observed compared with the control group.

Shortened sleep duration impairs adipose tissue adrenergic stimulation of lipolysis in postmenopausal women.

The objective of this study was to examine the changes in adipose tissue lipolytic capacity and insulin signaling in response to shortened sleep duration (SSD) in postmenopausal women. Adipose tissue from a randomized crossover study of nine healthy postmenopausal women (mean [SD], age: 59 [4] years; BMI: 28.0 [2.6] kg/m2) exposed to four nights of habitual and SSD (60% of habitual sleep) while following a eucaloric diet was examined ex vivo. Tissue lipolytic capacity was determined by measurement of secreted glycerol. Cellular insulin signaling was determined by measuring insulin-mediated changes in Akt phosphorylation. RNA sequencing examined global transcriptional changes. With SSD, basal glycerol secretion was reduced, and isoproterenol-stimulated lipolysis was attenuated. Insulin concentration-dependent increases in phosphorylated Akt observed in samples after habitual sleep were abrogated after SSD. However, insulin-mediated suppression of lipolysis remained unaltered with changes in sleep duration. Increased transcription of genes involved in adipogenesis and fatty acid metabolism was observed after SSD. SSD blunts adrenergic stimulation of lipolysis without altering insulin-mediated suppression of lipolysis in postmenopausal women. These changes in adipose tissue may potentiate fat gain independent of caloric intake. Therefore, interventions promoting sleep may be considered to mitigate abdominal adiposity in postmenopausal women.

Elritercept, a modified activin receptor IIA ligand trap, increased erythropoiesis and thrombopoiesis in a phase 1 trial

AbstractThe transforming growth factor β (TGF-β) superfamily plays a crucial role in regulating biological processes of virtually every tissue and system in the body, including hemostasis and hematopoiesis. Elritercept (KER-050) is an investigational, modified activin receptor type IIA ligand trap designed to bind and inhibit activin A and other select TGF-β superfamily ligands, including activin B, growth differentiation factor 8 (GDF-8), and GDF-11. The objectives of this phase 1 randomized, placebo-controlled study of elritercept were to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic markers of activin inhibition and hematopoiesis in healthy postmenopausal women (N = 48). This study comprised 2 parts: single ascending doses ranging from 0.05 to 4.5 mg/kg; and multiple (up to 2 doses) ascending doses of 0.75 mg/kg administered subcutaneously (SC) every 4 weeks. Elritercept was generally well tolerated at all dose levels, with no dose-limiting toxicities observed. There were no severe or serious adverse events nor clinically significant changes in safety laboratory measures. Serum concentrations increased in dose-proportional manner after single SC doses, with peak concentrations achieved in 4.5 to 6 days and a mean elimination half-life of 12 days. These parameters were comparable after multiple doses. Elritercept elicited rapid, sustained, and dose-dependent increases in reticulocytes, red blood cells, hemoglobin, and platelets without eliciting detrimental changes in white blood cells such as neutrophils and lymphocytes. The time course and duration of changes in these cell populations supported a differentiated pharmacologic profile that is consistent with the stimulation of both early- and late-stage hematologic pathways. The trial was registered at www.anzctr.org.au/ as #ACTRN12619000318189.

Effects of Progesterone on Vasomotor Symptoms in Postmenopausal Women (PROGEST) - a Prospective Multi-Center Randomized Double-Blind Placebo-Controlled Trial (RDPCT).

Introduction Monotherapy with progesterone for treatment of vasomotor symptoms (VMS) was more effective than placebo treatment of postmenopausal healthy women in a Canadian trial. The PROGEST-trial was initiated to fulfill FDA-approval criteria for the indication of treatment of postmenopausal VMS. Methods This prospective randomized, double-blind placebo-controlled clinical trial studied three doses of oral micronized progesterone (200 mg, 300 mg, 400 mg) and placebo for 12 weeks. Postmenopausal women with moderate to severe VMS (> 50 per week) were screened for one week for VMS frequency, then randomized to 200, 300 or 400 mg progesterone daily or placebo for a double-blinded trial of 12 weeks duration. Results 74 women were recruited in 12 study centers. 44 terminated the study as per protocol (PP). Moderate to severe hot flushes decreased by 7.4/d in the placebo arm, 7.7 VMS/d with 200 mg/d progesterone (P4), 8.3 VMS/d on 300 mg/d and 9.0 VMS/d on 400 mg/d P4, respectively by week 12. 32treatment emergent adverse events were documented in 18 participants, mostly minor AEs. The only SAE was a syncope requiring hospitalization on the day after treatment initiation, leading to discontinuation of the drug. Discussion Baseline VMS frequency was much higher in the German than in the Canadian study and the course of the placebo group had a markedly stronger decrease in VMS-frequency during the PROGEST study (-7.4/d) than in the Canadian trial (-1.4/d). Trial populations differed by age, BMI, the number of women with natural menopause, and comorbidities, mainly hypertension. Conclusion Premature discontinuation of the trial due to insufficient subject accrual rate led to only 55 randomized participants for analysis, therefore the study results lack statistical power. Still, a slight dose-dependent improvement in VMS was seen for all doses, while AE frequency did not increase with progesterone dose.

Dietary eggs, egg nutrients, polygenic score for body mass index, “Western pattern” diet, and weight change, a prospective analysis in the Women's health initiative

Background & AimsEggs contain nutrients which could help enrich the diets of postmenopausal women. Egg consumption and elevated body weight have been associated with elevated risk of serious chronic disease. It is possible that elevated body weight mediates between egg consumption and serious chronic disease. However, few studies exist on the link between egg consumption and body weight in post-menopausal women, and none of them accounted for genetic weight gain predispositions. Our objective was to examine associations between egg consumption, body weight, and genetic predisposition for an elevated Body Mass Index (BMI), in postmenopausal women. MethodsWe analyzed data from 4,439 healthy Women’s Health Initiative participants of European descent during a 6-year follow up using multivariable generalized linear mixed models to prospectively evaluate egg and egg-nutrient intake (measured by a food frequency questionnaire) against body weight and a BMI polygenic score (PGS-BMI) derived from GWAS meta-analysis effect-allele frequencies. ResultsWe found a positive prospective association between change in egg intake and body weight during the 6-year follow up. For instance, at year 3, women whose intake had increased by 2.0 eggs/week had gained 0.70 kg (95%CI: 0.34, 1.07, p=.0002) more than women whose intake had decreased by 2.4 eggs/week, p-linear <.0001. Cholesterol-intake and choline-intake, but not betaine-intake, showed similar significant associations. Exploratory analysis revealed that: 1) women only demonstrated these significant associations if they exhibited higher intakes of “Western-pattern” foods including processed and red meats, French fries, sweets and deserts, sugar-sweetened beverages, fried foods, and dietary fat, and energy; and 2) there was a significant positive prospective association between PGS-BMI and body-weight change, but only in the top quintile of egg-intake change. ConclusionsWe found significant positive prospective associations between weight change and changes in egg intake, cholesterol intake, and choline intake among healthy postmenopausal women of European ancestry in the Women’s Health Initiative. Exploratory analyses revealed that: 1) these significant associations only obtained among women who ate large amounts of “Western-pattern” foods; and 2) women with a higher genetic susceptibility for an elevated BMI gained more weight only if they increased their egg intake considerably. Our results require confirmation.

Analysis of combinatory effects of free weight resistance training and a high-protein diet on body composition and strength capacity in postmenopausal women - A 12-week randomized controlled trial

BackgroundMenopause has a significant impact on the endocrine system of middle-aged women, resulting in a loss of skeletal muscle mass (SMM), changes in fat mass (FM) and a reduction in strength capacity. Resistance training (RT) and a high-protein diet (HPD) are effective methods for maintaining or increasing SMM. This study aims to determine the effects of HPD and RT on body composition, muscle thickness and strength capacity in postmenopausal women. MethodsIn total 55 healthy postmenopausal women (age: 58.2 ± 5.6 years, weight 69.1 ± 9.6 kg, height 166.5 ± 6.5 cm) successfully participated in the study. The women were randomly assigned to either group: training + protein (2.5 g/kg fat-free mass (FFM)) (n = 15; TP); only training (n = 12; T); only protein (2.5 g/kg FFM) (n = 14; CP) or control (n = 14; C). TP and T performed RT for 12 weeks with three training sessions and five exercises each. CP and C were prohibited from training during the period. The main parameters analysed for body composition were FFM, SMM, FM, muscle thickness of the M. rectus femoris, M. biceps femoris, M. triceps brachii and M. biceps brachii muscles. Strength was tested using a dynamometer for grip strength and 1-RM in the squat (BBS) and deadlift (DL). ResultsThe SMM significantly increased by RT (TP: (Δ+1.4 ± 0.9 kg; p < 0.05; d = 0.4; T: Δ+1.2 ± 1.3kg; p < 0.05; d = 0.3) and FM could be reduced only in T: (Δ−2.4 ± 2.9 kg; p < 0.05; d = 0.3). In muscle thickness a significant increase in the M. biceps brachii in both training groups (TP: (Δ+0.4 ± 0.3 cm; p < 0.05; d = 1.6; T: (Δ+0.3 ± 0.3 cm; p < 0.05; d = 0.9) and in M. biceps femoris only in TP (Δ+0.3 ± 0.4 cm; p < 0.05; d = 0.9) were observed. HPD without training does not affect body composition, A significant increase in grip strength (TP: Δ+4.7 ± 2.4 kg; (p < 0.05; d = 1.5; T: (Δ+3.6 ± 3.0 kg; p < 0.05; d = 0.8), in BBS (TP: (Δ+30.0 ± 14.2 kg; p < 0.05; d = 1.5; T: (Δ+34.0 ± 12.0 kg; p < 0.05; d = 2.4) and in DL (TP: (Δ+20.8 ± 10.3 kg; p < 0.05; d = 1.6; T: (Δ+22.1 ± 7.6 kg; p < 0.05; d = 2.0) was observed in both training groups. The CP also recorded a significant increase in the BBS (Δ+7.5 ± 5.4 kg; p < 0.05; d = 0.4) and in DL (Δ+5.5 ± 7.7 kg; p < 0.05; d = 0.5). No significant differences were detected for TP and T for any of the parameters. ConclusionThe results indicate that RT enhances body composition and strength capacity in postmenopausal women and is a preventive strategy against muscle atrophy. Besides HPD without training has a trivial significant effect on BBS and DL. HPD with RT has no clear additive effect on body composition and strength capacity. Further studies are needed to confirm these observations.

Effects of rhamnose consumption on bone mineral density in healthy postmenopausal women: a randomised, placebo-controlled, double-blind, parallel-group pilot study

Preventing the decrease in bone mineral density (BMD) is significant for postmenopausal women. We previously discovered that rhamnose, a deoxy monosaccharide used as a food additive, could suppress bone resorption; however, studies confirming this effect in postmenopausal women are lacking. Therefore, this pilot study aimed to explore whether rhamnose could help maintain BMD via bone resorption suppression in postmenopausal women. The participants consumed either 1.0 or 0.5 g/day of rhamnose or placebo for 24 weeks, and BMD (lumbar spine and femur) and bone turnover markers were measured. After 24 weeks, the group consuming rhamnose 1.0 g/day exhibited a significantly higher BMD of the lumbar spine than the placebo group. Furthermore, the levels of tartrate-resistant acid phosphatase 5b, a bone resorption marker, were significantly lower in both rhamnose groups. These results indicated that rhamnose might contribute to the maintenance of BMD by suppressing bone resorption in healthy postmenopausal women (UMIN000046570).

Establishing Reference Values for Vaginal Vestibule Elastography in Healthy Postmenopausal Women.

Objective This study aims to establish normative elastography values for the vaginal vestibule in healthy postmenopausal women and assess the variability of these values with age and measurement time during the day. Methods The study included 111 women aged 40-90, excluding those with medical histories or treatments affecting vaginal health. Elastography measurements were taken twice daily, between 9-10 AM and 3-4 PM, using real-time tissue elastography technology. Statistical analysis evaluated the effects of age, body mass index (BMI), and diurnal variation on vaginal vestibule elasticity. Results A significant positive correlation between age and elastography values was found (p=8.36×10⁻⁷), with elastography values increasing by approximately 0.0040 units per year. The mean elastography value was 28.32% (SD=5.87%) in the morning and 28.10% (SD=5.90%) in the afternoon, with a statistically significant difference (p=0.016). BMI showed a weak negative correlation with elastography values (r=-0.2021, p=0.0334). Conclusion Establishing reference values for vaginal vestibule elastography provides a foundation for improved diagnostic accuracy and early detection of gynecological conditions. The findings support the use of elastography as a non-invasive, reliable diagnostic tool in clinical practice. Future research should validate these results across different age groups and in women with specific gynecological conditions to further solidify the clinical applicability of vaginal vestibule elastography.

Predictors of subclinical atherosclerosis in asymptomatic healthy non-diabetic postmenopausal women

Predictors of subclinical atherosclerosis in asymptomatic healthy non-diabetic postmenopausal women

Polymorphic variants of the hOGG1, APEX1, XPD, SOD2, and CAT genes involved in DNA repair processes and antioxidant defense and their association with breast cancer risk.

Breast cancer is one of the leading causes of mortality among women. The most frequently encountered tumors are luminal tumors. Associations of polymorphisms in the hOGG1 (rs1052133), APEX1 (rs1130409), XPD (rs13181), SOD2 (rs4880), and CAT (rs1001179) genes were studied in 313 nonsmoking postmenopausal patients with luminal B subtype breast cancer. The control group consisted of 233 healthy nonsmoking postmenopausal women. Statistically significant associations of the XPD and APEX1 gene polymorphisms with the risk of developing luminal B Her2-negative subtype of breast cancer were observed in a log-additive inheritance model, while the CAT gene polymorphism showed an association in a dominant inheritance model (OR = 1.41; CI 95 %: 1.08-1.85; Padj.= 0.011; OR = 1.39; CI 95 %: 1.07-1.81; Padj = 0.013 и OR = 1.70; CI 95 %: 1.19-2.43; Padj = 0.004, respectively). In the group of elderly women (aged 60-74 years), an association of the CAT gene polymorphism with the risk of developing luminal B subtype of breast cancer was found in a log-additive inheritance model (OR = 1.87; 95 % CI: 1.22-2.85; Padj = 0.0024). Using MDR analysis, the most optimal statistically significant 3-locus model of gene-gene interactions in the development of luminal B Her2-negative subtype breast cancer was found. MDR analysis also showed a close interaction and mutual enhancement of effects between the APEX1 and SOD2 loci and the independence of the effects of these loci from the CAT locus in the formation of luminal B subtype breast cancer.

Vascular endothelial growth factor I/D variant and postmenopausal osteoporosis risk in the Turkish population

Introduction Postmenopausal osteoporosis (PMOP) is a common metabolic bone disorder manifested by low bone mineral density and increased fracture risks in postmenopausal women. Vascular endothelial growth factor (VEGF) has been shown to play an important role in bone formation. In this study, we investigated the potential association between the VEGF insertion/deletion (I/D) variant (rs35569394) and PMOP in a cohort of postmenopausal Turkish women. Methods This study included 300 women, including 150 PMOP patients and 150 healthy postmenopausal women. A T score was used in the diagnosis of OP. DNA was extracted from all subjects. The VEGF I/D polymorphism was analyzed by the PCR method. The Hardy-Weinberg equilibrium (HWE) test and odds ratio (OR) were analyzed, considering CI 95% and p ≤ 0.05. Results The mean age of patients aged between 40 and 74 was 60.32 ± 8.65. The frequency of the I/I, I/D, and D/D genotypes was 7.34% versus 6.66%; 67.33% versus 65.34%; and 25.33% versus 28%, in patients and the control group, respectively. The allele frequencies were I: 41% (patients) and 39.4% (controls); D: 59% (patients) and 60.66% (controls). There was no statistically significant difference in the VEGF − 2549 I/D allele and genotype distribution between patients with PMOP and control subjects (p = 0.349, p = 0.864, respectively). Conclusion Our results showed that the VEGF I/D variant was not a significant factor in the development of PMOP in a Turkish population sample. These findings need confirmation in other ethnic populations.

Abstract PO3-18-05: Pharmacokinetics (PK) of lasofoxifene (LAS) monotherapy and combined with abemaciclib (Abema)

Abstract Introduction: LAS is a selective estrogen receptor modulator (SERM)/tissue-selective estrogen agonist/antagonist studied in women with osteoporosis and vulvar-vaginal atrophy, and most recently, metastatic breast cancer (mBC) with ESR1 mutations. LAS data in healthy postmenopausal women and young men show linear PK and no differences by age or race (Gardner. J Clin Pharmacol 2006;46:52-58; Prakash. Drug Metab Dispos 2008;26:1218-26; Data on file). Also, no PK differences were found between Caucasian and Japanese patients (Jhee. AACR-JCA 2022, abstract A83; Fountaine. J Clin Pharmacol 2006;46:693-99). Here we report select PK data of LAS (5 mg/day) from women with mBC in the ELAINE 1 and ELAINE 2 oncology trials to indirectly investigate possible drug-drug interactions between LAS and Abema. Methods: Patients with mBC and ESR1 mutations who progressed on endocrine therapy and CDK4/6 inhibitors received LAS 5 mg/day as monotherapy (ELAINE 1) or combined with Abema (provided by Eli Lilly and Co) 150 mg BID (ELAINE 2). Blood was collected prior to daily dosing at weeks 2, 4, 8, and every 4 weeks up to the final visit in ELAINE 1, and visits during the first 8 weeks in ELAINE 2, to determine the plasma trough steady-state concentrations (Css) of LAS, Abema, and two active Abema metabolites (M2 and M20). LAS was assayed using validated high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS; detection 0.025 to 25.0 ng/mL); levels below the lower limit of quantification (LLOQ) were reported as 0 ng/mL. Abema and its M2 and M20 metabolites were measured by validated Turbo Ion Spray LC/MS/MS (detection 1.00 to 500 ng/mL); values below the LLOQ were reported as &amp;lt; LLOQ ng/mL. Mean trough Css at each visit were calculated for LAS (ELAINE 1 and 2), and Abema and its M2 and M20 metabolites (ELAINE 2). LAS levels from ELAINE 1 and 2 were compared, while Abema, M2 and M20 plasma levels in ELAINE 2 were compared with previously reported levels. Such indirect comparisons may help determine if Abema altered the metabolism of LAS, or if LAS altered that of Abema, M2, or M20. The relationships of LAS and Abema levels with progression-free survival (PFS) were also explored. Results: Across all time points for subjects who had PK samples assessed, the LAS mean trough Css was 33.6 ng/mL (CV%, 39.8) in ELAINE 1 (n=40) and 30.9 ng/mL (CV 50.5%) in ELAINE 2 (n=29); in both studies, LAS concentrations were consistent across visits. LAS levels in ELAINE 2 were similar to those in ELAINE 1 with no evidence of accumulation. Mean (CV%) Abema plasma concentrations at weeks 2, 4, 6 and 8 were 199 (102%), 107 (130%), 82 (271%), and 94.3 (223%) ng/mL, respectively. Minimum and maximums of the mean trough Css for LAS, Abema, M2, and M20 are shown in Table 1. No relationships between LAS or Abema levels and antitumor activity measured by PFS were seen (data to be presented). Conclusion: The steady-state PK of 5 mg LAS in the ELAINE 1 and 2 studies suggest that the addition of abemaciclib to LAS did not result in an obvious or significant LAS-Abema, drug-drug interaction. Abema PK data from ELAINE 2 were consistent with published data (European Medicines Agency, Verzenio). These results support the continued development of LAS alone and combined with Abema for treating ER+/HER2-, ESR1-mutated mBC that progressed on endocrine therapy and CDK4/6 inhibitors. Table. Mean trough, steady-state concentrations of lasofoxifene and abemaciclib. XX- XX aData from patients who received oral LAS (5 mg/day) plus Abema (150 mg BID). Abema, abemaciclib; LAS, lasofoxifene; M2 and M20 are Abema metabolites. Citation Format: Senthil Damodaran, Paul V. Plourde, Simon Jenkins, Phil Mayer, David J Portman, Matthew Goetz. Pharmacokinetics (PK) of lasofoxifene (LAS) monotherapy and combined with abemaciclib (Abema) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-05.

Abstract PO2-05-05: ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis (mets) from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC)

Abstract Background: Currently, there are no approved systemic treatment options specifically for patients with ER+/HER2- BC who have brain metastasis. The prevalence of brain metastases from ER+/HER2- BC is approximately 14% of women (Aversa, 2014). Elacestrant is a next-generation oral SERD that was evaluated in a pivotal phase 3 trial, EMERALD, as monotherapy vs. standard of care (SOC) endocrine therapy. The EMERALD trial reported significantly prolonged progression-free survival (PFS) with elacestrant vs SOC endocrine therapy in patients with ER+/HER2− ESR1 mutated (ESR1-mut) mBC following progression on prior endocrine therapy (Bidard, 2022). Elacestrant was well tolerated with a manageable safety profile. Most adverse events, including nausea, were low-grade and consistent with other endocrine therapies. A clinical study in healthy postmenopausal women demonstrated the ability of elacestrant to cross the blood-brain barrier (Conlan, 2020). Abemaciclib, a CDK4/6i, has been shown to achieve therapeutic concentrations in brain metastases tissue (Tolaney, 2020). Given the lack of current systemic treatments, elacestrant is now being evaluated with abemaciclib in patients with ER+/HER2- BC and brain metastasis (NCT05386108). Methods: ELECTRA (NCT05386108) is an open-label phase 1b/2, multicenter study evaluating elacestrant in combination with abemaciclib in patients with brain metastasis from ER+, HER2- BC. Eligibility are patients with ER+/HER2− locally advanced or mBC and measurable brain metastasis. For phase 1b, the presence of brain metastases is allowed but not required for eligibility. For phase 2, patients must have ≥ 1 active and measurable brain metastasis per RECIST v1.1. Patients must have received prior therapy in the metastatic setting, including ≥ 1 ET, ≤2 chemotherapy regimens, and 0-2 prior CDK4/6i (excluding abemaciclib). The primary objectives of Phase 1b are to determine the recommended Phase 2 dose (RP2D). Phase 1b secondary objectives include safety, PK, objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), PFS, and overall survival (OS). Phase 2 primary objective is ORR per RECIST version 1.1. Phase 2 secondary objectives include intracranial response rate (RR), DoR, CBR, PFS, OS, PK, and quality of life (QoL). The phase 1b portion evaluated dose-limiting toxicities (DLTs) of the combination during the first cycle (28 days) of treatment in up to three 6-patient cohorts, starting at elacestrant 300 mg daily plus abemaciclib 100 mg twice daily. Here we report initial safety results from the phase 1b portion. Results: As of June 2023, 15 patients have been enrolled in the phase 1b portion of the trial. At dose level 1, elacestrant 300 mg QD + abemaciclib 100 mg BID, no patient experienced DLTs, and the combination was feasible. Dose level 2, elacestrant 400 mg QD + abemaciclib 100 mg BID has been completed, and no patients experienced DLTs. In dose level 1, 4/7 patients remain on treatment at cycle 5. Additional safety and PK data for the cohorts will be provided. Conclusion: In the phase 1b portion of ELECTRA, dose level 1 and dose level 2 have been completed. No patients experienced DLTs in either dose level 1 or dose level 2, and the combination was considered feasible in the respective dose levels. Dose level 3 (elacestrant 400 mg QD + abemaciclib 150 mg BID) is proceeding. Recruitment is actively ongoing, enabling oral-oral combinations to determine a RP2D. Citation Format: Nuhad Ibrahim, Sung-Bae Kim, Nancy Lin, Ahmad Awada, Eva Ciruelos Gil, Giulia Tonini, Bartomeu Piza Vallespir, Kathy Puvana Theall, Erika Hamilton. ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis (mets) from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-05.

Age Comparisons of Cardiac Work During Exercise in Women: Insight from Acute β1 Adrenergic Blockade

Postmenopausal women exhibit exaggerated increases in blood pressure during activities of daily living and exercise. The decreased size and increased stiffening of postmenopausal women's hearts elevate myocardial oxygen demand when compared to age-matched men and younger cohorts. Together, this poses a risk to the safety of, and capacity for, exercise in postmenopausal women. We recently studied the effects of esmolol, a fast-acting, cardio-selective β1 antagonist, on oxygen transport variables during dynamic exercise in healthy young (Y) and older (O) women to better understand differences in cardiovascular responses to exercise. Objective: Determine the effects of acute cardiac specific blockade on myocardial oxygen demand (rate pressure product, RPP) and cardiac work (CW) in healthy young premenopausal and older postmenopausal women. Methods: Thirteen healthy young (20-32 yr) and older postmenopausal (58-70 yr) women performed moderate (85% of lactate threshold) and heavy (50% between lactate threshold and the respiratory compensation point) recumbent leg cycling exercise during IV infusion of saline or esmolol in randomized order. Whole body oxygen consumption (VO2, indirect calorimetry), brachial systolic blood pressure (SBP, automated cuff), heart rate (HR, ECG), and cardiac output (CO, bioimpedance) were measured continuously. RPP (HR×SBP), CW (CO×SBP), and cardiac effciency (CE, CW/VO2) were calculated. Mixed model repeated measures ANOVAs were used to determine the effect of treatment and age group. Results: Power outputs were lower in O vs. Y at both moderate (45±9W and 72±15W, p&lt;0.001) and heavy (81±21W vs. 117±32W, p&lt;0.001) intensities. During the saline trial CO was lower (p&lt;0.001), and RPP was higher (p&lt;0.001) in the O vs. Y group during both intensities. There was a main effect of treatment on RPP, CW, and CE. Esmolol reduced RPP (4638±775 SD, p&lt;0.001), CW (547±89, p&lt;0.001) and CE (1682±62, p&lt;0.001) in both O and Y. There was a main effect of age group on CE, pairwise comparisons showed CE was lower in O than Y (441±112, p&lt;0.001). Conclusions: Older postmenopausal women experience higher myocardial oxygen demand and perform more cardiac work for a given whole body liter oxygen consumed during dynamic leg exercise compared to younger premenopausal women. Acute β1 adrenergic blockade narrows the gap between central cardiovascular function in young and old women and provides a powerful tool to investigate age-related cardiovascular differences. NIH R21 AG054940. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pre-Existing Metabolic Conditions Impair the Beneficial Effects of Estrogen on Memory and Cognition in Ovariectomized Mice

Loss of estrogen, as a result of menopause, has been associated with cognitive decline and memory loss. Intriguingly, studies conducted with postmenopausal healthy women suggest that hormone replacement therapy improves cognitive functions. In contrast, clinical data involving subjects with a wide range of health conditions indicate that the effect of estrogen treatment varies. In addition to the cognitive decline, postmenopausal women have an increased risk of developing metabolic disorders including obesity, insulin resistance, and diabetes. In this study, we tested the hypothesis that pre-existing metabolic conditions reduce the beneficial effects of estradiol treatment and are responsible for the conflicting findings in cognitive functions after menopause. Female, seven-month-old C57BL/6J mice were fed with either a high-fat diet (HFD, BioServ #F3282) or a control diet (LFD, BioServ #F4031) for 10 to 14 weeks, then ovariectomized (OVX). In a randomized manner, mice received a silastic tube implant containing either 17β-estradiol (E2) or vehicle (VEH, cholesterol) and stayed on their respective diets. Body composition and metabolic parameters were measured in the four groups (HFD+VEH, HFD+E2, LFD+VEH, LFD+E2) to assess metabolic status, and novel object recognition test was performed to assess memory and cognition. Before OVX, HFD fed mice had significantly increased body weight, fat mass, basal blood glucose and insulin levels compared to mice fed with LFD. After OVX, LFD-VEH mice developed obesity and had elevated blood glucose and insulin levels, whereas E2 treatment prevented the metabolic changes. Interestingly, HFD-VEH mice had a reduction in fat mass after OVX, which was further decreased with E2 treatment. Overall, mice treated with E2 had lower body weight, fat mass, blood glucose and insulin levels compared to VEH treated mice regardless of their diet, and HFD fed mice had a higher body weight than mice fed the LFD, irrespective of their treatment. The novel object recognition test revealed that LFD-E2 mice spent significantly more time exploring the novel object than LFD-VEH mice. In contrast, there was no difference in exploration time between HFD-VEH and HFD-E2 treated mice. These preliminary results suggest that 1) E2 treatment may be beneficial to prevent the development of metabolic changes and improve cognitive function in LFD fed mice; 2) OVX alone did not worsen the metabolic status of diet-induced obese mice; 3) E2 treatment partially improved the metabolic status of HFD fed mice by decreasing fat mass, blood glucose and insulin levels; and 4) E2 treatment did not improve memory and cognition of HFD fed mice. Source of funding: P01AG071746 8456. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Central and peripheral cardiovascular responses after acute dietary nitrate supplementation in post-menopausal women

The transition to menopause is accompanied by augmented cardiovascular disease risk, partially attributed to reduced nitric oxide (NO) bioavailability. Despite a lower arterial stiffness than men, postmenopausal women are susceptible to increased aortic pulsatile hemodynamic load because of greater pressure wave reflection and vascular dysfunction. Increasing bioavailable NO with dietary nitrate has shown promise to reduce aortic (aSBP) and brachial (bSBP) systolic pressure healthy postmenopausal women. However, there are limited reports comparing hypertensive (HTN) and normotensive (NTN) postmenopausal women regarding wave separation analysis and vascular function following dietary nitrate supplementation. This study investigated if acute dietary nitrate supplementation would improve aortic hemodynamics, wave reflection characteristics, vascular stiffness, and vasodilatory function. We hypothesized that dietary nitrate would lower pulse wave velocity in hypertensives, lower aortic and brachial blood pressures and forward and backward wave magnitude and increase microvascular, but not macrovascular function in both groups. Fourteen postmenopausal women (n=7 HTN; n=7 NTN) participated in a two-day randomized crossover study design with dietary nitrate (nitrate rich, NR) or a placebo control (NP). Central and peripheral hemodynamics and carotid-femoral pulse wave velocity (cfPWV) were performed with a SphygmoCOR Excel, simultaneous resting macro- and- microvascular function was assessed using flow-mediated vasodilation (FMD) and post occlusive reactive hyperemia (PORH) using near-infrared spectroscopy. aSBP was reduced significantly following NR supplement within groups (HTN: NP 126±2 NR 120±1mmHg) and NTN group (NP 110± 1 NR 104±3mmHg p&lt;0.05). Forward pulse height HTN (NP 29±1.4 NR 26.3±1.4mmHg) NTN (NP 25.6±0.9 NR 24±2.7mmHg) and reflected pulse height HTN (NP 18.2±0.08 NR 17.2±0.4mmHg) NTN (NP 17.7±0.2 NR 15.7±1.07mmHg) were not different. cfPWV was faster in the HTN group and slowed with a NR supplement (HTN: NP 8.2±0.29 NR 7.4±0.31m/s; NTN NP 7.1±0.23 NR 6.6±0.62m/s p&lt;0.05). A significant interaction for %FMD was found (HTN: NP 7.3±0.8 NR 6.2±0.8%; NTN NP 6.6±0.7 NR 9.4±0.7%). Further, we found no difference in the NIRS derived microvascular function measurements (HTN: NP 1.9±0.2 NR 1.7±0.3%/s; NTN NP 1.6±0.1 NR 1.4±0.2%/s p&gt;0.05). These data indicate that dietary nitrate consumption led to a substantial reduction in aortic hemodynamics and reduced pulse wave velocity regardless of hypertension status. Interestingly, macrovascular, but not microvascular vasodilatory function was improved in the NTN women only. Dietary nitrate supplementation appears to have differential effects when considering HTN and NTN postmenopausal women. Supported with funds from The University of Wisconsin-La Crosse RSEL graduate grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dampened circadian amplitude of EEG power in women after menopause.

Postmenopausal women are at high risk of developing sleep-wake disturbances. We previously reported dampened circadian rhythms of melatonin, alertness and sleep in postmenopausal compared with young women. The present study aims to further explore electroencephalography power spectral changes in the sleep of postmenopausal women. Eight healthy postmenopausal women were compared with 12 healthy, naturally ovulating, young women in their mid-follicular phase. Participants followed a regular 8-hr sleep schedule for ≥ 2 weeks prior to laboratory entry. The laboratory visit included an 8-hr baseline sleep period followed by an ultradian sleep-wake cycle procedure, consisting of alternating 1-hr wake periods and nap opportunities. Electroencephalography power spectral analysis was performed on non-rapid eye movement sleep obtained over a 48-hr period. The baseline nocturnal sleep of postmenopausal women comprised lower power within delta and sigma, and higher power within alpha bands compared with that of younger women. During nighttime naps of the ultradian sleep-wake cycle procedure, lower power within delta and sigma, and higher power within beta bands were observed in postmenopausal women. During the ultradian sleep-wake cycle procedure, postmenopausal women presented lower power of delta, theta and sigma (14-15 Hz), undetectable rhythms of delta and theta, and a dampened or undetectable rhythm of sigma (12-15 Hz) power compared with younger women. Our results support the hypothesis of a dampened circadian variation of sleep microstructure in healthy-sleeping postmenopausal women. Circadian changes with aging are potential mechanisms for increased susceptibility to develop sleep disturbances; however, further research is needed to clarify their clinical implications and contribution to insomnia.

The Effectiveness of a Lactobacilli-Based Probiotic Food Supplement on Bone Mineral Density and Bone Metabolism in Australian Early Postmenopausal Women: Protocol for a Double-Blind Randomized Placebo-Controlled Trial.

Osteoporosis affects one in three women over the age of 50 and results in fragility fractures. Oestrogen deficiency during and after menopause exacerbates bone loss, accounting for higher prevalence of fragility fractures in women. The gut microbiota (GM) has been proposed as a key regulator of bone health, as it performs vital functions such as immune regulation and biosynthesis of vitamins. Therefore, GM modulation via probiotic supplementation has been proposed as a target for potential therapeutic intervention to reduce bone loss. While promising results have been observed in mouse model studies, translation into human trials is limited. Here, we present the study protocol for a double-blind randomized controlled trial that aims to examine the effectiveness of three lactobacilli strains on volumetric bone mineral density (vBMD), trabecular, and cortical microstructure, as measured using High Resolution peripheral Quantitative Computed Tomography (HR-pQCT). The trial will randomize 124 healthy early postmenopausal women (up to 8 years from menopause) to receive either probiotic or placebo administered once daily for 12 months. Secondary outcomes will investigate the probiotics' effects on areal BMD and specific mechanistic biomarkers, including bone metabolism and inflammatory markers. The trial is registered with Australian New Zealand Clinical Trials Registry (ACTRN12621000810819).

Differences in dietary intake in early postmenopausal women with different levels of areal and volumetric bone mineral density: a cross-sectional analysis of baseline data from an intervention study

Osteoporosis is a degenerative disease of the bone. The rate of bone loss is accelerated during the first postmenopausal years in women which results in their disproportionate prevalence of osteoporosis(2). Some of the factors contributing to the development and maintenance of bone mineral density (BMD) relate to diet, particularly the intake of protein, calcium and other micronutrients that play a crucial role in bone composition(3). The most common method of measuring BMD is dual-energy X-ray absorptiometry (DXA) which generates a two-dimensional image of the scan site (typically spine, hip and/or forearm) to determine areal BMD (aBMD). However, new methods have recently emerged, including High Resolution peripheral Quantitative Computed Tomography (HRpQCT), that offer more accurate three-dimensional measurements of volumetric BMD (vBMD) and microstructure of distal tibia and radius(4). The aim of this study was to examine the differences in the dietary intake of nutrients that represent organic or inorganic components of the bone, in early postmenopausal women with different spine aBMD and tibia and radius vBMD levels. One hundred and fourteen healthy early postmenopausal women with a lumbar spine or total hip BMD T score &gt; −2.5 (measured by DXA) were recruited as part of a larger interventional study. Dietary intake was recorded using a 297-point self-reported validated food frequency questionnaire(5) for assessing the intake of energy, macro and micronutrients. Physical activity was self-reported using the validated Active Australia Questionnaire. Years since menopause were self-reported. DXA and HRpQCT scans measured L1-L4 spine, proximal femur aBMD, and distal tibia and radius vBMD respectively. Non-parametric statistical tests examined differences in dietary intake and physical activity levels between women at different levels of aBMD and vBMD. Data reported as median and interquartile ranges. There were no significant differences observed in the total sample between tertiles of aBMD and vBMD, regarding nutrient intake. However, for women with less than 3 years since menopause (i.e., the time-period of accelerated bone loss), lower dietary intakes of energy [8,658(3,324) vs 10,068(3,688) kJ/day; p = 0.047], protein [94(29) vs 103(32) g/day; (p = 0.044)], sodium [1,927(992) vs 2,625(2,185) mg/d; (p = 0.044)], potassium [4,064(1,373) vs 5,121(2,377) mg/d; (p = 0.041)], calcium [969(325) vs 1,214(652) mg/d; (p = 0.028)] and zinc [10(3) vs 12(4) mg/d; (p = 0.005)] were observed for women with osteopenia (−1&lt; L1-L4 aBMD T-score &lt;2.5) compared to those with normal L1-L4 aBMD (i.e., T-score &gt; −1). No significant differences were observed for women with more than 3 years since menopause, with the only exception of alcohol intake (p = 0.033), which was found to be lower in women with osteopenia compared to those with normal aBMD. These findings highlight the importance of targeting osteopenic women within the first 3 years following menopause as candidates for tailored dietary intervention programs for preventing osteoporosis.