Effects of the Menstrual Cycle and Hormonal Contraceptive Use on Metabolic Outcomes, Strength Performance, and Recovery: A Narrative Review.

The effects of female sex hormones on optimal performance have been increasingly recognized as an important consideration in exercise and sport science research. This narrative review explores the findings of studies evaluating the effects of menstrual cycle phase in eumenorrheic women and the use of hormonal contraception (oral contraceptives and hormonal intrauterine devices) on metabolism, muscular strength, and recovery in active females. Ovarian hormones are known to influence metabolism because estrogen is a master regulator of bioenergetics. Importantly, the menstrual cycle may impact protein synthesis, impacting skeletal muscle quality and strength. Studies investigating muscular strength in eumenorrheic women report equivocal findings between the follicular phase and luteal phase with no differences compared to oral contraceptive users. Studies examining recovery measures (using biomarkers, blood lactate, and blood flow) do not report clear or consistent effects of the impact of the menstrual cycle or hormonal contraception use on recovery. Overall, the current literature may be limited by the evaluation of only one menstrual cycle and the use of group means for statistical significance. Hence, to optimize training and performance in females, regardless of hormonal contraception use, there is a need for future research to quantify the intra-individual impact of the menstrual cycle phases and hormonal contraceptive use in active females.

Overall Survival and Exploratory Biomarker Analyses of Abemaciclib plus Trastuzumab with or without Fulvestrant versus Trastuzumab plus Chemotherapy in HR+, HER2+ Metastatic Breast Cancer Patients.

PURPOSE: The monarcHER trial has shown that abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, combined with fulvestrant and trastuzumab, improves progression-free survival (PFS) in hormone receptor-positive (HR+), HER2-positive (HER2+) advanced breast cancer (ABC) compared with standard-of-care (SOC) chemotherapy combined with trastuzumab. We report the final overall survival (OS) analysis, updated safety and efficacy data, and exploratory biomarker results from monarcHER. PATIENTS AND METHODS: monarcHER (NCT02675231), a randomized, multicenter, open-label, phase II trial, enrolled 237 patients across Arm A (abemaciclib, trastuzumab, fulvestrant), Arm B (abemaciclib, trastuzumab), and Arm C (SOC chemotherapy, trastuzumab). Following the statistical plan, OS and PFS were estimated in all arms. RNA sequencing (RNA-seq) was performed on archival tissue. RESULTS: Median OS was 31.1 months in Arm A, 29.2 months in Arm B, and 20.7 months in Arm C [A vs. C: HR, 0.71; 95% confidence interval (CI), 0.48-1.05; nominal two-sided P value 0.086; B vs. C: HR 0.83 (95% CI, 0.57-1.23); nominal two-sided P value 0.365]. Updated PFS and safety findings were consistent with previous results. The most frequently reported treatment-emergent adverse events included diarrhea, fatigue, nausea, neutrophil count decrease, and anemia. In exploratory RNA-seq analyses, Luminal subtypes were associated with longer PFS [8.6 vs. 5.4 months (HR, 0.54; 95% CI, 0.38-0.79)] and OS [31.7 vs. 19.7 months (HR, 0.68; 95% CI, 0.46-1.00)] compared with non-Luminal. CONCLUSIONS: In this phase II trial, abemaciclib + trastuzumab ± fulvestrant numerically improved median OS in women with HR+, HER2+ ABC compared with SOC chemotherapy + trastuzumab.

Landscape of baseline and acquired genomic alterations in circulating tumor DNA with abemaciclib alone or with endocrine therapy in advanced breast cancer.

PURPOSE: To identify potential predictors of response and resistance mechanisms in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) treated with the CDK4/6 inhibitor abemaciclib +/- endocrine therapy (ET), baseline and acquired genomic alterations in circulating tumor DNA (ctDNA) were analyzed and associated with clinical outcomes. PATIENTS AND METHODS: MONARCH 3: postmenopausal women with HR+, HER2- ABC and no prior systemic therapy in the advanced setting were randomized to abemaciclib or placebo plus nonsteroidal aromatase inhibitor (NSAI). nextMONARCH: women with HR+, HER2- metastatic breast cancer that progressed on/after prior ET and chemotherapy were randomized to abemaciclib alone (two doses) or plus tamoxifen. Baseline and end-of-treatment plasma samples from patients in MONARCH 3 and nextMONARCH (monotherapy arms) were analyzed to identify somatic genomic alterations. Association between genomic alterations and median progression-free survival (mPFS) was assessed. RESULTS: Most patients had ≥1 genomic alteration detected in baseline ctDNA. In MONARCH 3, abemaciclib+NSAI was associated with improved mPFS versus placebo+NSAI, regardless of baseline alterations. ESR1 alterations were less frequently acquired in the abemaciclib+NSAI arm than placebo+NSAI. Acquired alterations potentially associated with resistance to abemaciclib +/- NSAI included RB1 and MYC. CONCLUSIONS: In MONARCH 3, certain baseline ctDNA genomic alterations were prognostic for ET but not predictive of abemaciclib response. Further studies are warranted to assess whether ctDNA alterations acquired during abemaciclib treatment differ from other CDK4/6 inhibitors. Findings are hypothesis-generating, further exploration is warranted into mechanisms of resistance to abemaciclib and ET.

Public Insurance and Single-Guardian Households Are Associated with Diagnostic Delay in Slipped Capital Femoral Epiphysis.

BACKGROUND: Extensive literature documents the adverse sequelae of delayed diagnosis of slipped capital femoral epiphysis (SCFE), including worsening deformity and surgical complications. Less is known about predictors of delayed diagnosis of SCFE, particularly the effects of social determinants of health. The purpose of this study was to evaluate the impact of insurance type, family structure, and neighborhood-level socioeconomic vulnerability on the delay of SCFE diagnosis. METHODS: We reviewed medical records of patients who underwent surgical fixation for stable SCFE at a tertiary pediatric hospital from 2002 to 2021. We abstracted data on demographic characteristics, insurance status, family structure, home address, and symptom duration. We measured diagnostic delay in weeks from the date of symptom onset to diagnosis. We then geocoded patient addresses to determine their Census tract-level U.S. Centers for Disease Control and Prevention (CDC) and Agency for Toxic Substances and Disease Registry (ATSDR) Social Vulnerability Index (SVI), using U.S. Census and American Community Survey data. We performed 3 separate logistic regression models to examine the effects of (1) insurance status, (2) family structure, and (3) SVI on a delay of ≥12 weeks (reference, <12 weeks). We adjusted for age, sex, weight status, number of siblings, and calendar year. RESULTS: We identified 351 patients with SCFE; 37% (129) had a diagnostic delay of ≥12 weeks. In multivariable logistic regression models, patients with public insurance were more likely to have a delay of ≥12 weeks than patients with private insurance (adjusted odds ratio [OR], 1.83 [95% confidence interval (CI), 1.12 to 2.97]; p = 0.015) and patients from single-guardian households were more likely to have a delay of ≥12 weeks than patients from multiguardian households (adjusted OR, 1.95 [95% CI, 1.11 to 3.45]; p = 0.021). We did not observe a significant increase in the odds of delay among patients in the highest quartile of overall SVI compared with patients from the lower 3 quartiles, in both the U.S. comparison (adjusted OR, 1.43 [95% CI, 0.79 to 2.58]; p = 0.24) and the Massachusetts comparison (adjusted OR, 1.45 [95% CI, 0.79 to 2.66]; p = 0.23). CONCLUSIONS: The delay in diagnosis of SCFE remains a concern, with 37% of patients with SCFE presenting with delay of ≥12 weeks. Public insurance and single-guardian households emerged as independent risk factors for diagnostic delay. Interventions to reduce delay may consider focusing on publicly insured patients and those from single-guardian households. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Clinical and Genomic Characteristics of Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Following Progression on Cyclin-Dependent Kinase 4 and 6 Inhibitors.

PURPOSE: We explored the clinical and genomic characteristics of hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC) after progression on cyclin-dependent kinase 4 and 6 inhibitors (CDK4 and 6i) ± endocrine therapy (ET) to understand potential resistance mechanisms that may aid in identifying treatment options. EXPERIMENTAL DESIGN: Patients in the United States with HR+, HER2- MBC had tumor biopsies collected from a metastatic site during routine care following progression on a CDK4 and 6i ± ET (CohortPost) or prior to initiating CDK4 and 6i treatment (CohortPre) and analyzed using a targeted mutation panel and RNA-sequencing. Clinical and genomic characteristics were described. RESULTS: The mean age at MBC diagnosis was 59 years in CohortPre (n = 133) and 56 years in CohortPost (n = 223); 14% and 45% of patients had prior chemotherapy/ET, and 35% and 26% had de novo stage IV MBC, respectively. The most common biopsy site was liver (CohortPre, 23%; CohortPost, 56%). CohortPost had significantly higher tumor mutational burden (TMB; median 3.16 vs. 1.67 Mut/Mb, P < 0.0001), ESR1 alteration frequency (mutations: 37% vs. 10%, FDR < 0.0001; fusions: 9% vs. 2%, P = 0.0176), and higher copy-number amplification of genes on chr12q15, including MDM2, FRS2, and YEATS4 versus patients in the CohortPre group. In addition, CDK4 copy-number gain on chr12q13 was significantly higher in CohortPost versus CohortPre (27% vs. 11%, P = 0.0005). CONCLUSIONS: Distinct mechanisms potentially associated with resistance to CDK4 and 6i ± ET, including alterations in ESR1 and amplification of chr12q15 and CDK4 copy-number gain, were identified.

The effects of L-Citrulline and Glutathione on Endurance performance in young adult trained males.

BACKGROUND: Citrulline may amplify the effects of L-arginine and nitric oxide concentration, which may augment vasodilation and blood flow, thereby enhancing aerobic exercise performance. The purpose of this randomized, double-blind, placebo-controlled crossover study was to investigate effects of L-citrulline + Glutathione on aerobic exercise performance and blood flow in well-trained men. METHODS: Twenty-five males (Mean ± SD; Age: 22.2 ± 2.4 yrs; Height: 177.0 ± 4.8 cm; Weight: 75.3 ± 6.9 kg) were randomly assigned to the L-citrulline + Glutathione (Setria Performance Blend: SPB; L-citrulline [2 g] + glutathione [200 mg], 6 capsules) or placebo (PL; 3.1 g cellulose, 6 capsules) group. Participants performed a maximal oxygen consumption treadmill test to determine peak velocity (PV) and returned after eight days of ingesting either PL or SPB. Three timed treadmill runs to exhaustion (TTE) were performed at 90%, 100%, and 110% PV. Brachial artery blood flow and vessel diameter were assessed using ultrasound at 1-hr prior to exercise (1hrPrEX), after each exercise bout, immediately post-exercise (immediate PEX), and 30 minutes post exercise (30minPEX) at visits 2 and 4. Blood analytes were assessed via venous blood draws at visit 1, visit 3, and 1hrPEX, immediate PEX, and 30minPEX at visits 2 and 4. After a 14-day washout, participants repeated the same procedures, ingesting the opposite treatment. Separate repeated measures ANOVAs were performed for TTE, vessel diameter, blood flow, and blood analytes. RESULTS: Blood flow was significantly augmented 30minPEX (p = 0.04) with SPB in comparison with PL. L-citrulline and L-arginine plasma concentrations were significantly elevated immediately PEX (p = 0.001) and 30-minPEX (p = 0.001) following SPB in comparison to PL. CONCLUSION: Acute ingestion of SPB after eight days may enhance blood flow, L-citrulline, and L-arginine plasma concentrations after high-intensity exercise, which may enhance performance. CLINICAL TRIAL REGISTRATION: [https://clinicaltrials.gov/ct2/show/nct04090138], identifier [NCT04090138].

Menopause Transition: A Cross-Sectional Evaluation on Muscle Size and Quality.

INTRODUCTION: The menopause transition yields significant physiological alterations. The purpose was to characterize lean soft tissue (LST), muscle size (muscle cross-sectional area (mCSA)), muscle quality (echo intensity (EI)), and strength across the menopause transition. A secondary aim was to evaluate whole-body protein turnover in a subsample of women. METHODS: Seventy-two healthy women were enrolled in this cross-sectional study based on menopause stage (PRE: n = 24; PERI: n = 24; POST: n = 24). Whole-body LST was measured via dual-energy x-ray absorptiometry, and muscle characteristics (mCSA and EI) were measured via B-mode ultrasound of the vastus lateralis. Maximal voluntary contractions (N·m) of the knee extensors were evaluated. Physical activity (in minutes per day) was accounted for using the International Physical Activity Questionnaire. A subsample of women ( n = 27) ingested 2.0 g of 15 N-alanine to determine whole-body net protein balance (NB; in grams per kilogram of body mass per day). RESULTS: Significant differences were evident in LST ( P = 0.022), leg LST ( P = 0.05), and EI ( P = 0.018) between menopause stages. Bonferroni post-hoc comparisons revealed greater LST in PRE versus PERI (mean difference (MD) ± SE, 3.8 ± 1.5 kg; P = 0.048) and POST (3.9 ± 1.5 lb; P = 0.049). Similarly, EI was significantly higher in PERI PRE (MD, 18.3 ± 7.1 a.u.; P = 0.036). There was no significant difference in mCSA ( P = 0.082) or in maximal voluntary contraction ( P = 0.167). NB was significantly different across groups ( P = 0.026); NB was greater in PRE compared with PERI (MD, 0.39 ± 0.17 g·kg -1 ; P = 0.090), and from PRE to POST (MD, 0.46 ± 0.17 g·kg -1 ; P = 0.042). Physical activity was not significantly different across groups but demonstrated a linear increase from PRE to POST. CONCLUSIONS: The current findings suggest that LST, muscle quality, and protein balance may be negatively influenced by the menopause transition.

Antimicrobial and cytotoxic synergism of biocides and quorum-sensing inhibitors against uropathogenic Escherichiacoli.

BACKGROUND: Uropathogenic Escherichia coli (UPEC) are a primary cause of catheter-associated urinary tract infections (CAUTIs), often forming mature recalcitrant biofilms on the catheter surface. Anti-infective catheter coatings containing single biocides have been developed but display limited antimicrobial activity due to the selection of biocide-resistant bacterial populations. Furthermore, biocides often display cytotoxicity at concentrations required to eradicate biofilms, limiting their antiseptic potential. Quorum-sensing inhibitors (QSIs) provide a novel anti-infective approach to disrupt biofilm formation on the catheter surface and help prevent CAUTIs. AIM: To evaluate the combinatorial impact of biocides and QSIs at bacteriostatic, bactericidal and biofilm eradication concentrations in parallel to assessing cytotoxicity in a bladder smooth muscle (BSM) cell line. METHODS: Checkerboard assays were performed to determine fractional inhibitory, bactericidal, and biofilm eradication concentrations of test combinations in UPEC and combined cytotoxic effects in BSM cells. FINDINGS: Synergistic antimicrobial activity was observed between polyhexamethylene biguanide, benzalkonium chloride or silver nitrate in combination with either cinnamaldehyde or furanone-C30 against UPEC biofilms. However, furanone-C30 was cytotoxic at concentrations below those required even for bacteriostatic activity. A dose-dependent cytotoxicity profile was observed for cinnamaldehyde when in combination with BAC, PHMB or silver nitrate. Both PHMB and silver nitrate displayed combined bacteriostatic and bactericidal activity below the half-maximum inhibitory concentration (IC50). Triclosan in combination with both QSIs displayed antagonistic activity in both UPEC and BSM cells. CONCLUSION: PHMB and silver in combination with cinnamaldehyde display synergistic antimicrobial activity in UPEC at non-cytotoxic concentrations, suggesting potential as anti-infective catheter-coating agents.

Effects of Essential Amino Acids on High-Intensity Interval Training Performance, Fatigue Outcomes, and Workload Progression.

OBJECTIVE: To explore the effects of essential amino acid (EAA) supplementation on high-intensity interval training (HIIT) fatigue, perceived exertion, and training progression in overweight and obese adults. A secondary aim was to explore potential sex-differences on these outcomes. METHODS: Thirty-seven untrained adults (51% female; 36.2 ± 5.9 yrs; 35.5 ± 6.7% body fat) completed eight weeks of HIIT, 2d/wk on a cycle ergometer, either with EAA supplementation (HIIT + EAA; 3.6 g of EAA twice daily, 30 minutes pre and post HIIT) or without supplementation (HIIT). Heart rate (HR) and ratings of perceived exertion (RPE) were recorded throughout each session as indices of within training fatigue. Time to exhaustion (TTE) was recorded for the final interval of each session. Workload progression was determined by change in watts. Differences between groups (with and without EAA) were evaluated at 1wk, 4wks, and 8wks by repeated measure ANOVAs (α = 0.05). RESULTS: There were no differences in TTE (p = 0.983) or workload progression (p = 0.655) with EAA supplementation at any time point. HR and RPE within HIIT sessions were not significantly different with EAA supplementation at any time point (p > 0.05). Results were similar when evaluating males and females separately, but in females, RPE was significantly lower with EAA supplementation at 4wks (Δ: 1.1-2.2; p = 0.016). CONCLUSION: EAA supplementation did not extend TTE during exercise or enhance workload progression across eight weeks of HIIT in untrained, overweight and obese adults. However, EAA consumed 30 minutes before exercise may reduce perceived exertion during the first four weeks of training in women, which may have implications for overall exercise enjoyment and long-term adherence.

Effectiveness of a vaccination education module for college freshmen.

Objective: To evaluate the effectiveness of a vaccination education module to improve vaccine expectations and behaviors among college freshmen. Participants: The participants were 177 college freshmen at one private Utah university. Participants were eligible for this study if admitted as new freshmen during the 2019-2020 school year. Methods: The study was a cross-sectional pre- and post-education evaluation assessing vaccine expectations and behaviors using Likert-type and open-ended questions. Results: After completing the vaccination education module, participants' vaccine expectations and behavioral intentions improved. Participants reported they were more likely to be up-to-date on personal vaccines and more likely to expect other students to be up-to-date on their vaccinations. Participants were more likely to ask other students to vaccinate and were also more likely to ask their family members to be vaccinated. Conclusions: This online vaccination education module effectively improved participants' vaccine expectations and behavioral intentions.

Targeting CDK4 and 6 in Cancer Therapy: Emerging Preclinical Insights Related to Abemaciclib.

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4 and 6) are approved for the treatment of subsets of patients with hormone receptor positive (HR+) breast cancer (BC). In metastatic disease, strategies involving endocrine therapy combined with CDK4 and 6 inhibitors (CDK4 and 6i) improve clinical outcomes in HR+ BCs. CDK4 and 6i prevent retinoblastoma tumor suppressor protein phosphorylation, thereby blocking the transcription of E2F target genes, which in turn inhibits both mitogen and estrogen-mediated cell proliferation. In this review, we summarize preclinical data pertaining to the use of CDK4 and 6i in BC, with a particular focus on several of the unique chemical, pharmacologic, and mechanistic properties of abemaciclib. As research efforts elucidate the novel mechanisms underlying abemaciclib activity, potential new applications are being identified. For example, preclinical studies have demonstrated abemaciclib can exert antitumor activity against multiple tumor types and can cross the blood-brain barrier. Abemaciclib has also demonstrated distinct activity as a monotherapeutic in the treatment of BC. Accordingly, we also discuss how a greater understanding of mechanisms related to CDK4 and 6 blockade highlight abemaciclib's unique in-class properties, and could pave new avenues for enhancing its therapeutic efficacy.

Differences in strength, leg lean mass, and lifestyle factors between premenopausal and perimenopausal women.

BACKGROUND: Menopausal changes coupled with age-related reductions in muscle strength can impact functionality. AIM: To evaluate the differences in muscle strength, dominant leg lean mass (DLMleg ), relative protein intake (r_PRO) and physical activity (PA) between premenopausal (PRE) and perimenopausal (PERI) women. METHODS: Twenty-four PRE- (age = 39.8 ± 3.3 years; BMI: 25.3 ± 5.0 kg/m2 ) and 24 PERI-women (age = 50.0 ± 3.3 years; BMI: 26.5 ± 5.4 kg/m2 ) participated in leg extensor isometric peak force (PF), DLMleg , r_PRO and PA. Independent samples t-tests and one-way analyses of covariance covaried for age and DLMleg were used to compare groups. RESULTS: The PRE group had significantly higher PF (mean difference ± standard error: 57.8 ± 28.0 N; p = 0.045) and DLMleg (0.7 ± 0.3 kg; p = 0.031) when compared to the PERI group. There were no significant differences in r_PRO, or PA between groups (p = 0.173-0.423). When covaried for age and DLMleg , there was no significant difference in PF (p = 0.982 and 0.405, respectively). CONCLUSIONS: Age and DLMleg may be important contributors to menopause-phase related differences in strength.

Harnessing the value of reproductive hormones in cattle production with considerations to animal welfare and human health.

The human population is ever increasing while the quality and quantity of natural resources used for livestock production decline. This calls for improved product efficiency and the development of improved and sustainable cattle production methods to produce higher quality products to satisfy the demands of both the modern and transient world. The goal of this review was to summarize the interactions, challenges, and opportunities in cattle production relating to their endocrine system, and how reproductive hormones and others impact economically important traits, animal welfare, and human health. A comprehensive literature search was conducted with a focus on analysis of natural hormones and the use of exogenous hormone administration for reproduction, growth, and development of beef and dairy cattle. Hormones regulate homeostasis and enhance important traits in cattle, including fertility, growth and development, health, and the production of both meat and milk products. Reproductive hormones such as testosterone, estradiol, progesterone, and related synthetics like trenbolone acetate and zeranol can be strategically utilized in both beef and dairy cattle production systems to enhance their most valuable traits, but the impact of these substances must account for the welfare of the animal as well as the health of the consumer. This scientific review provides a comprehensive analysis of the bovine endocrine system's impact on food animals and product quality which is vital for students, researchers, livestock producers, and consumers. Although important advances have been made in animal science and related technological fields, major gaps still exist in the knowledge base regarding the influence of hormones on the production and welfare of food animals as well as in the public perception of hormone use in food-producing animals. Filling these gaps through transformative and translational research will enhance both fundamental and applied animal science to feed a growing population.

The animal production industry is responsible for providing products like meat, dairy, and egg products to the growing human population of the world. Within each sector, there are production practices that can improve the overall productivity of the animals and contribute to their welfare. One such avenue for enhanced production is the inclusion of hormones. Hormones are naturally produced within the body by the endocrine system which helps initiate many life processes and transition the body to different stages of production. Hormones influence many important traits such as growth and development, milk production, fertility, and health within the cattle industry. Exogenous hormone use in animals has proven to improve a number of traits and qualities of animal products, but it has also struck up controversy. There are wide deficiencies in the full understanding of roles, applications, and implications of hormones in livestock, making it of high importance for further exploration. In this review, the mechanisms of hormones and their broad uses are explored to provide more context to the conversation of hormone use in animals. Knowledge of endocrinology is powerful and can aid in the advancement of fundamental science and animal development and production.

Body composition of NCAA division I football players pre- and post-COVID-19 stay-at-home advisory.

BACKGROUND: The COVID-19 pandemic forced collegiate athletes to train at home, without access to facilities. The purpose of this study was to evaluate the effect of the COVID-19 stay-at-home order on body composition of Division I Football Players, with a secondary aim to evaluate these changes between players with "higher" (>25 kg/m2) and "lower" (<25 kg/m2) Fat-Free Mass Index (kg/m2). METHODS: Body composition of 29 NCAA Division I Football Players (age=21.0±10 yr, Ht=186.7±5.6 cm, body mass=110.5±22.8 kg) were measured spring season (February) and prior to preseason (June). Whole body dual-energy X-ray absorptiometry scans were used to determine regional (arms, legs, trunk) and total body fat mass (FM), lean mass (LM), and fat-free mass (FFM). Fat-Free Mass Index (FFMI) was calculated as (LM+bone mineral content [BMC])/height2); participants were stratified by FFMI higher (N.=16) and lower (N.=13). RESULTS: Total LM (mean difference±standard error: 0.80±1.65 kg, P=0.016) increased from pre- to post-COVID stay-at-home. No significant changes in total FM were seen. Players with lower FFMI showed a significant decrease in trunk FM (-0.55±0.19 kg, P=0.016). Players with higher FFMI showed a significant increase in total LM (0.96±0.42 kg, P=0.038). CONCLUSIONS: These results suggest no detrimental effect on body composition.

Metabolic effects of menopause: a cross-sectional characterization of body composition and exercise metabolism.

OBJECTIVES: To evaluate body composition, fat distribution, and metabolism at rest and during exercise in premenopausal, perimenopausal, and postmenopausal women. METHODS: This cross-sectional study in 72 women ages 35 to 60 years evaluated body composition via a fourcompartment model, fat distribution using dual-energy x-ray absorptiometry-derived android to gynoid ratio, metabolic measures via indirect calorimetry, and lifestyle factors using surveys. One-way analyses of variance and one-way analyses of covariance covaried for age and hormone levels (estrogen and progesterone) were used to compare groups. RESULTS: Body fat percent was significantly lower in premenopausal than perimenopausal women (mean difference ± standard error: - 10.29 ± 2.73%, P = 0.026) despite similarities in fat mass and fat-free mass between groups (P≥0.217). Android to gynoid ratio was significantly lower in premenopausal than perimenopausal women (MD ± SE: -0.16 ± 0.05 a.u., P = 0.031). Resting energy expenditure was similar between groups (P = 0.999). Fat oxidation during moderate intensity cycle ergometer exercise was significantly greater in premenopausal than postmenopausal women (MD ± SE: 0.09 ± 0.03 g/min, P = 0.045). The change in respiratory exchange ratio between rest and moderate intensity exercise was significantly lower in premenopausal women than peri- (MD ± SE: -0.05 ± 0.03 a.u., P = 0.035) and postmenopausal women (MD ± SE: -0.06 ± 0.03 a.u., P = 0.040). Premenopausal women reported significantly fewer menopause symptoms than peri- (MD ± SE: -6.58 ± 1.52 symptoms, P = 0.002) and postmenopausal participants (MD ± SE: -4.63 ± 1.52 symptoms, P = 0.044), while similarities between groups were observed for lifestyle factors including diet and physical activity (P>0.999). CONCLUSIONS: Perimenopause may be the most opportune window for lifestyle intervention, as this group experienced the onset of unfavorable body composition and metabolic characteristics. VIDEO SUMMARY: http://links.lww.com/MENO/A932.

Clinical Significance of PIK3CA and ESR1 Mutations in Circulating Tumor DNA: Analysis from the MONARCH 2 Study of Abemaciclib plus Fulvestrant.

PURPOSE: PIK3CA and ESR1 mutations have been implicated in resistance to endocrine therapy (ET) in HR+, HER2- advanced breast cancer (ABC). Inhibition of CDK4 and 6 has been hypothesized as a therapeutic strategy to overcome endocrine resistance in patients with PIK3CA- or ESR1-mutant breast cancers. The objective of this exploratory analysis was to assess efficacy of abemaciclib plus fulvestrant in patients with or without PIK3CA or ESR1 mutations in MONARCH 2. PATIENTS AND METHODS: MONARCH 2 was a global, randomized, double-blind phase III trial of abemaciclib plus fulvestrant in 669 women with HR+, HER2- ABC, which had progressed on ET. Patients were randomized 2:1 to receive abemaciclib plus fulvestrant or placebo plus fulvestrant. Exploratory analyses assessed progression-free survival (PFS) and overall survival (OS), and other endpoints, in patients with or without PIK3CA or ESR1 mutations detectable in baseline ctDNA. RESULTS: From the MONARCH 2 population, 219 and 248 patient samples were successfully analyzed for either PIK3CA or ESR1 mutations, respectively. Abemaciclib plus fulvestrant improved PFS compared with placebo plus fulvestrant in both PIK3CA-wild-type (median 16.9 months vs. 12.3 months; HR, 0.51; 95% CI, 0.33-0.78) and PIK3CA-mutant subgroups (median 17.1 months vs. 5.7 months; HR, 0.53; 95% CI, 0.33-0.84), as well as both ESR1-wild-type (median 15.3 months vs. 11.2 months; HR, 0.44; 95% CI, 0.27-0.71) and ESR1-mutant subgroups (median 20.7 months vs. 13.1 months; HR, 0.54; 95% CI, 0.37-0.79). Additional endpoints, including OS, were also improved following treatment with abemaciclib plus fulvestrant regardless of PIK3CA or ESR1 mutation status. CONCLUSIONS: Abemaciclib plus fulvestrant was effective regardless of PIK3CA or ESR1 mutation status, with benefit in both PFS and OS, with a numerically greater improvement in median PFS relative to placebo plus fulvestrant for PIK3CA- or ESR1-mutant tumors compared with the respective wild-type subgroups, in women with HR+, HER2- ABC that had progressed on ET.

The validation of contemporary body composition methods in various races and ethnicities.

Few investigations have evaluated the validity of current body composition technology among racially and ethnically diverse populations. This study assessed the validity of common body composition methods in a multi-ethnic sample stratified by race and ethnicity. One hundred and ten individuals (55 % female, age: 26·5 (sd 6·9) years) identifying as Asian, African American/Black, Caucasian/White, Hispanic, Multi-racial and Native American were enrolled. Seven body composition models (dual-energy X-ray absorptiometry (DXA), air displacement plethysmography (ADP), two bioelectrical impedance devices (BIS, IB) and three multi-compartment models) were evaluated against a four-compartment criterion model by assessing total error (TE) and standard error of the estimate. For the total sample, measures of % fat and fat-free mass (FFM) from multi-compartment models were all excellent to ideal (% fat: TE = 0·94-2·37 %; FFM: TE = 0·72-1·78 kg) compared with the criterion. % fat measures were very good to excellent for DXA, ADP and IB (TE = 2·52-2·89 %) and fairly good for BIS (TE = 4·12 %). For FFM, single device estimates were good (BIS; TE = 3·12 kg) to ideal (DXA, ADP, IB; TE = 1·21-2·15 kg). Results did not vary meaningfully between each race and ethnicity, except BIS was not valid for African American/Black, Caucasian/White and Multi-racial participants for % fat (TE = 4·3-4·9 %). The multi-compartment models evaluated can be utilised in a multi-ethnic sample and in each individual race and ethnicity to obtain highly valid results for % fat and FFM. Estimates from DXA, ADP and IB were also valid. The BIS may demonstrate greater TE for all racial and ethnic cohorts and results should be interpreted cautiously.

Effects of adiposity and body composition on adjusted resting energy expenditure in women.

OBJECTIVES: Fat-free mass (FFM) accounts for ~80% of the variance in resting energy expenditure (REE), and this relationship is complicated by adiposity. The objective was to compare adjusted REE and contributions of skeletal lean mass and fat mass (FM) to adjusted REE in women with varying adiposity levels using a novel approach. METHODS: Women were divided into tertiles by body fat percent (%fat): Tertile 1 (T1): %fat = 18.5%-28.4%; Tertile 2 (T2): %fat = 28.5%-33.8%; Tertile 3 (T3): %fat = 34.0%-61.0%. Outcome measures were measured and adjusted REE, body composition (skeletal lean mass, FM, %fat) from dual-energy X-ray absorptiometry, and percent contribution of skeletal lean mass and FM to adjusted REE. RESULTS: The main effect for tertiles (T1 vs. T2 vs. T3) was significant (p = .001); REE was significantly higher in T3 versus both T1 by 281 kcal/day (p = .001) and T2 by 215 kcal/day (p = .001). Expenditure from skeletal lean mass in T1 was significantly higher than T3 by 3.2% (p = .001). T3 had a significantly higher FM contribution than T1 by 5.1% (p = .001) and T2 by 3.9% (p = .001). CONCLUSIONS: Women with elevated %fat experienced lower skeletal lean mass contribution and higher FM contribution to adjusted REE. FM may explain more of the variance in REE between women of different levels of adiposity.