Left ventricular global longitudinal strain is worse in BRCA mutation positive breast cancer patients prior to cancer treatment and premature menopause.

PURPOSE: Breast cancer patients with mutations in human tumor suppressor genes BRCA1 and BRCA2 are at higher risk of cardiovascular disease (CVD) than the general population, as they are frequently exposed to cardiotoxic chemotherapy, anti-estrogen therapy, radiation, and/or oophorectomy for cancer-related treatment and prophylaxis. Animal and cell culture models suggest that BRCA mutations may play an independent role in heart failure. We sought to evaluate cardiac structure and function in female BRCA1 and BRCA2 mutation carriers with breast cancer compared to BRCA wildtype women with breast cancer. METHODS: We performed a 1:2 age- and hypertension-matched retrospective cohort study comparing BRCA1 and BRCA2 mutation carriers (n = 38) versus BRCA wildtype controls (n = 76) with a new diagnosis of breast cancer. Echocardiographic data were obtained within 6 months of breast cancer diagnosis and prior to chemotherapy, anti-estrogen therapy, radiation, or oophorectomy. Left ventricular global longitudinal strain (LV-GLS), a highly sensitive marker of LV function, was measured using QLab 15 (Philips Healthcare). RESULTS: In the total cohort of 114 patients with a new diagnosis of breast cancer, the median age was 45 ± 11 years and the prevalence of hypertension was 8%. There were no differences in traditional cardiovascular disease risk factors between cases and controls. BRCA carriers had lower LV-GLS (- 18.1% ± 4.7% vs. - 20.1% ± 3.8%, p = 0.02) and greater right atrial area (12.9 cm2 ± 2.7 cm2 vs. 11.8 cm2 ± 2.0 cm2, p = 0.04) compared to controls; however, both LV-GLS and right atrial area were within the normal range. Compared to controls, BRCA carriers had a trend toward worse LV posterior wall thickness (0.89 cm ± 0.15 cm vs. 0.83 cm ± 0.16 cm, p = 0.06) although not statistically significant. CONCLUSION: In women with newly diagnosed breast cancer and prior to treatment, LV-GLS was worse in BRCA1 and BRCA2 mutation carriers compared to those with BRCA wildtype. These findings suggest that BRCA mutations may be associated with subtle changes in cardiac function. Whether differences in GLS translate to increased cardiovascular risk in women with BRCA mutations needs to be further characterized.

Menopause in the workplace: Challenges, impact, and next steps.

INTRODUCTION: Menopause is a natural part of a woman's life that coincides with a time when many women play significant roles in the workforce. Menopause symptoms, such as hot flashes, fatigue, and difficulty with concentration and memory, can have a negative effect on work productivity and efficiency. OBJECTIVES: This paper summarizes the impact of menopause in the workplace, with an emphasis on the impact of symptoms on employed women and how the workplace influences their experiences. It highlights economic implications, promotes awareness, and suggests potential next steps. METHODS: A search for papers was conducted between August and November 2023 in the PubMed and Medline databases. Papers were selected based on personal experience and interpretation of the findings. Recommendations for managing menopause symptoms in the workplace and guidance on an optimal workplace intervention strategy were provided. RESULTS: Women experiencing severe menopause symptoms are more likely to report adverse work outcomes, including absenteeism and job-related decisions such as quitting, retiring early, or declining promotions than women experiencing few symptoms. Factors such as a lack of awareness about menopause, inflexible work conditions, and high-stress jobs can exacerbate the severity of these symptoms. Additionally, unaddressed menopause symptoms contribute to both direct and indirect economic costs, including medical resource utilization and lost work productivity, resulting in a substantial economic burden. CONCLUSION: Menopause symptoms impair women's work experiences and productivity. In addition to dismantling the stigma associated with menopause, it is critical to create and implement menopause workplace policies and interventions aimed at supporting women in this universal life stage.

Menopause transition and cardiovascular disease risk.

The risk of cardiovascular disease (CVD) notably increases in the fifth decade of a woman's life, coinciding with the onset of menopause and occurring 10 years later than the similar age-related increase in men. Menopause marks a significant transition in a woman's life and is accompanied by cardiometabolic changes, including a shift in body composition, increased blood pressure, disruptions in lipoproteins, and insulin resistance. There is increasing evidence that the menopause transition is a risk factor for CVD, independent of age-related changes, especially considering that the earlier the onset of menopause, the greater is the CVD risk. Further, menopause-related symptoms such as vasomotor symptoms, sleep disturbances, and mood changes may all have a direct impact on CVD risk. In this review, we summarize the current literature regarding CVD in midlife women, focusing on the cardiometabolic changes related to ovarian aging versus chronological aging, as well as those related to specific menopause characteristics, including age, type of menopause and the use of menopause hormone therapy.

Weight loss response to semaglutide in postmenopausal women with and without hormone therapy use.

OBJECTIVE: To compare weight loss response and changes in cardiometabolic risk markers in postmenopausal women using semaglutide with and without menopause hormone therapy (HT) use. METHODS: Retrospective cohort study of postmenopausal women treated with semaglutide for overweight or obesity for ≥3 months. Endpoints: total body weight loss percentage (TBWL%) at 3, 6, 9, and 12 months after semaglutide initiation; and percentage of women achieving ≥5% and ≥10% TBWL and changes in cardiometabolic risk markers (glucose, blood pressure, and lipids) at 12 months. RESULTS: There were 16 women on HT and 90 on no-HT; mean age 56 ± 8 vs 59 ± 8 yr, P = 0.2 and mean BMI 36 ± 5 vs 39 ± 8 kg/m 2 , P = 0.1; respectively. Among women on no-HT, White race, dyslipidemia, and depression were more prevalent. Women on HT had a higher TBWL% at 3, 6, 9, and 12 months: 7 ± 3% vs 5 ± 4%, P = 0.01; 13 ± 6% vs 9 ± 5%, P = 0.01; 15 ± 6% vs 10 ± 6%, P = 0.02; and 16 ± 6% vs 12 ± 8%, P = 0.04; respectively. After adjusting for potential confounders, this association remained significant across time. At 12 months, a greater percentage of women on HT achieved ≥5% and ≥10% TBWL. Both groups experienced an improvement in cardiometabolic risk markers. CONCLUSION: In postmenopausal women with overweight or obesity treated with semaglutide, HT use was associated with an improved weight loss response. This association was maintained when adjusted for confounders. Larger studies should be conducted to confirm these results.

Weight Gain in Midlife Women.

PURPOSE OF REVIEW: To summarize the evidence and clinical implications of weight and body composition changes during midlife in women and provide an overview of weight gain prevention and management in this population. RECENT FINDINGS: Aging-related changes such as decreased energy expenditure and physical activity are important culprits for weight gain in midlife women. The hormonal changes of menopause also influence body adiposity distribution and increase central adiposity. These body changes can have health consequences including the development of cardiometabolic diseases, osteoarthritis, cancer, worsening in cognition, mental health, and menopause symptoms. Midlife women experience changes related to aging, menopause, and lifestyle which favor weight gain. Clinical practice should focus on early counseling and anticipatory guidance on the importance of dietary changes and physical activity to attenuate this phenomenon. Future research should focus on the longitudinal relationship between weight trends in midlife and health consequences and mortality.

Proprotein convertase subtisilin/kexin 9 levels decline with hepatitis C virus therapy in people with HIV/hepatitis C virus and correlate with inflammation.

BACKGROUND: Proprotein convertase subtisilin/kexin 9 (PCSK9) raises low-density lipoprotein cholesterol (LDL-C) levels and is associated with inflammation, which is elevated in HIV and hepatitis C virus (HCV) infection. We compared PCSK9 levels in people with co-occurring HIV and HCV (HIV/HCV) vs. HIV alone, and evaluated the impact of HCV direct-acting antiviral (DAA) therapy on PCSK9. DESIGN: A prospective, observational cohort study. METHODS: Thirty-five adults with HIV/HCV and 37 with HIV alone were evaluated, all with HIV virologic suppression and without documented cardiovascular disease. Circulating PCSK9 and inflammatory biomarkers were measured at baseline and following HCV treatment or at week 52 (for HIV alone) and compared using Wilcoxon tests and Spearman correlations. RESULTS: At baseline, PCSK9 trended higher in HIV/HCV vs. HIV alone (307 vs. 284 ng/ml, P  = 0.06). Twenty-nine participants with HIV/HCV completed DAA therapy with sustained virologic response. PCSK9 declined from baseline to posttreatment 1 (median 7.3 weeks after end of therapy [EOT]) and posttreatment 2 (median 43.5 weeks after EOT), reaching levels similar to HIV alone; median within-person reduction was -60.5 ng/ml ( P  = 0.003) and -55.6 ng/ml ( P  = 0.02), respectively. Decline in PCSK9 correlated with decline in soluble (s)E-selectin and sCD163 ( r  = 0.64, P  = 0.002; r  = 0.58, P  = 0.008, respectively), but not with changes in LDL-C or other biomarkers. No significant change in PCSK9 occurred in the HIV alone group over 52 weeks. CONCLUSION: PCSK9 declined with DAA therapy in participants with HIV/HCV, correlating with declines in several inflammatory biomarkers but not LDL-C. Elevated PCSK9 with HCV may be linked to particular HCV-associated inflammatory pathways more so than cholesterol homeostasis.

The relation between excess adiposity and breast cancer in women: Clinical implications and management.

BACKGROUND: Breast cancer (BC) is the most common cancer in women. While the combination of improved screening, earlier detection, and advances in therapeutics has resulted in lower BC mortality, BC survivors are now increasingly dying of cardiovascular disease. Cardiovascular disease in the leading cause of non-cancer related mortality among BC survivors. This situation underscores the critical need to research the role of modifiable cardiometabolic risk factors, such as excess adiposity, that will affect BC remission, long-term survivorship, and overall health and quality of life. PURPOSE: First, this review summarizes the evidence on the connection between adipose tissue and BC. Then we review the data on weight trends after BC diagnosis with a focus on the effect of weight gain on BC recurrence and BC- and non-BC-related death. Finally, we provide a guide for weight management in BC survivors, considering the available data on the effect of weight loss interventions on BC.

Assisted reproductive technology: what are the cardiovascular risks for women?

INTRODUCTION: Infertility affects 15% of women of reproductive age in the United States. The use of assisted reproductive technology (ART) has been rising globally, as well as a growing recognition of reproductive factors that increase risk for cardiovascular disease (CVD). AREAS COVERED: Women with infertility who use ART are more likely to have established CVD risk factors, such as obesity, dyslipidemia, hypertension, and diabetes. They are also more likely to experience adverse pregnancy outcomes, which are associated with both peripartum and long-term cardiovascular complications. ART may lead to increased cardiometabolic demands due to ovarian stimulation, pregnancy itself, and higher rates of multifetal gestation. Preeclampsia risk appears greater with frozen rather than fresh embryo transfers. EXPERT OPINION: The use of ART and its association with long term CVD has not been well-studied. Future prospective and mechanistic studies investigating the association of ART and CVD risk may help determine causality. Nevertheless, CVD risk screening is critical pre-pregnancy and during pregnancy to reduce pregnancy complications that elevate future CVD risk. This also offers a window of opportunity to connect patients to longitudinal care for early management of cardiometabolic risk profile and initiation of preventive lifestyle and pharmacotherapy interventions tailored toward patient-specific risk factors.

Functional Hypothalamic Amenorrhea: Recognition and Management of a Challenging Diagnosis.

Functional hypothalamic amenorrhea is responsible for approximately a third of the cases of secondary amenorrhea. The condition is a result of disturbances in gonadotropin-releasing hormone pulsatile secretion at the level of the hypothalamus, which in turn disrupts gonadotropin secretion. It is due to psychosocial stress, disordered eating, and/or excessive exercise. Often, however, it is a combination of more than one etiology, with a possible role for genetic or epigenetic predisposition. The dysfunctional gonadotropin-releasing hormone release leads to the cessation of ovarian function, resulting in amenorrhea, infertility, and a long-term impact on affected women's bone health, cardiovascular risk, cognition, and mental health. Functional hypothalamic amenorrhea is a diagnosis of exclusion, and treatment involves identifying and reversing the underlying cause(s). The aim of this concise review is to summarize the current knowledge of functional hypothalamic amenorrhea, review its pathophysiology and the adverse health consequences, and provide recommendations for diagnosis and management of this condition. Furthermore, this review will emphasize the gaps in research on this common condition impacting women of reproductive age all over the world.

History of infertility and sexual dysfunction in midlife women: Is there a link?

BACKGROUND: Infertility has been linked with an increased risk of sexual dysfunction in reproductive-aged women, with longer periods of infertility associated with a greater risk. AIM: The study's aim was to examine whether a history of infertility treatment in women is linked to sexual dysfunction during midlife. METHODS: The cross-sectional study was conducted among sexually active women, between the ages of 45 and 65 years, who sought consultation at the women's health clinics at a US tertiary care center. History of infertility treatment was assessed with a single question that asked participants if they were treated for infertility in the past. The association between a history of infertility treatment and sexual dysfunction-which was diagnosed by a combination of Female Sexual Function Index score ≤26.55 and Female Sexual Distress Scale-Revised score ≥11-was assessed in a multivariable logistic regression model that adjusted for multiple confounders. OUTCOMES: The primary outcome was sexual dysfunction in midlife women. RESULTS: The analysis included 5912 women, with a mean age of 54.1 years. Nearly 16% of women reported receiving treatment for infertility. More than half the women (55%) had sexual dysfunction: 56.3% of those with previous fertility treatments and 54.4% of those without any fertility treatment (P = .3). Receiving treatment for infertility in the younger years did not significantly increase the odds of sexual dysfunction in midlife in univariate (odds ratio, 1.08; 95% CI, 0.94-1.24; P = .3) and multivariable analyses (odds ratio, 1.11; 95% CI, 0.96-1.29; P = .17). CLINICAL IMPLICATIONS: While infertility is known to be predictive of sexual dysfunction in women during their reproductive years, there was no association between a history of infertility treatment and sexual dysfunction in midlife women in the current study. STRENGTHS AND LIMITATIONS: The study used validated questionnaires accounting for sexual complaints and distress and adjusted for multiple confounding factors. Limitations include the selection bias introduced by the study of women presenting for evaluation of sexual dysfunction, which may have been a result of factors stronger than the influence of infertility. Other limitations include the study's cross-sectional nature with suboptimal racial and ethnic representation. CONCLUSION: Although infertility is commonly associated with female sexual dysfunction in women of reproductive age, the association was not present in midlife women in the current study.

Functional Hypothalamic Amenorrhea and Preclinical Cardiovascular Disease.

CONTEXT: Endothelial dysfunction is a preclinical cardiovascular disease (CVD) marker. Due to various neuroendocrine aberrations, functional hypothalamic amenorrhea (FHA) may be a sex-specific risk factor for CVD in young women. OBJECTIVE: To investigate endothelial function in women with FHA, compared with eumenorrheic controls and recently menopausal women. METHODS: We performed a cross-sectional analysis among women with FHA (n = 30), eumenorrheic controls (n = 29), and recently menopausal women (n = 30). FHA was defined as amenorrhea ≥3 consecutive months, estradiol <50 pg/mL, follicle-stimulating hormone (FSH) < 10 mIU/mL, and luteinizing hormone (LH) < 10 mIU/mL, excluding other etiologies. Participants were recruited through obstetrics and gynecology referrals, social media advertising, and review of electronic health records. Preclinical CVD was measured using EndoPAT 2000 to calculate reactive hyperemic index (RHI). RHI ≤1.67 indicates endothelial dysfunction. RESULTS: Mean estradiol levels in women with FHA, as compared with eumenorrheic controls and recently menopausal women, were 29.0 ± 18.1, 46.4 ± 15.7, and 10.9 ± 14.4 pg/mL (P < .0001), respectively. Women with FHA had lower insulin (P = .0095) and higher cortisol (P = .0004) compared with controls. RHI was significantly lower in women with FHA compared with eumenorrheic controls and recently menopausal women (1.8 ± 0.5 vs 2.2 ± 0.5 vs 2.2 ± 0.6, respectively; P = .008), and 35% of women with FHA had RHI ≤1.67, consistent with endothelial dysfunction. CONCLUSION: These results demonstrate endothelial dysfunction in 1 out of 3 young women with FHA. FHA may be a contributor to preclinical CVD, and it is not explained by hypoestrogenemia alone.

Associations between childhood adversity and age at natural menopause.

OBJECTIVE: Adverse childhood experiences (ACEs) are reported in more than half of the women in the United States and have been shown to negatively impact the menopause experience. The objective of this study was to evaluate the association between ACEs and age at natural menopause. METHODS: This is a cross-sectional study conducted among participants of the Data Registry on the Experiences of Aging, Menopause, and Sexuality (DREAMS). The registry included women who were seen for consultations in the women's health clinic at Mayo Clinic, Rochester, between May 2015 and December 2016. Only postmenopausal women were included in this analysis. Childhood adversity was assessed with the validated ACE questionnaire. Age at natural menopause was self-reported. The association between ACEs and age at menopause was evaluated using a multivariable linear regression model adjusting for multiple confounders. RESULTS: A total of 350 women were evaluated. The mean age was 59.2 years, and a majority were White (92.9%), married/partnered (82%), and educated (91.2% with at least some college education). Women with a history of at least four ACEs were estimated to reach natural menopause 1.3 years sooner than women with no ACE in multivariable analysis, but the results were not statistically significant (95% confidence interval, -3.2 to 0.6; P = 0.18). CONCLUSIONS: Although stressful life experiences such as ACEs may negatively influence health for midlife women, this study did not find an association with the age at natural menopause.

Case report: Repeat coronary function testing in women with ischemia and no obstructive coronary artery disease.

Women with signs and symptoms of ischemia and no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD). It can be diagnosed by coronary function testing (CFT), which is an invasive coronary angiogram procedure. Frequently, these women have persistent angina despite medical therapy, but it is not clear whether it is due to worsening or persistent CMD or inadequate therapy. In this brief report, we describe findings of repeat CFT in a case series of 12 women undergoing repeat CFT for the assessment of persistent angina in order to better understand the evolving pathology.

Age at Menopause, Leukocyte Telomere Length, and Coronary Artery Disease in Postmenopausal Women.

BACKGROUND: Premature menopause is a risk factor for accelerated cardiovascular aging, but underlying mechanisms remain incompletely understood. This study investigated the role of leukocyte telomere length (LTL), a marker of cellular aging and genomic instability, in the association of premature menopause with cardiovascular disease. METHODS: Participants from the UK Biobank and Women's Health Initiative with complete reproductive history and LTL measurements were included. Primary analyses tested the association between age at menopause and LTL using multivariable-adjusted linear regression. Secondary analyses stratified women by history of gynecologic surgery. Mendelian randomization was used to infer causal relationships between LTL and age at natural menopause. Multivariable-adjusted Cox regression and mediation analyses tested the joint associations of premature menopause and LTL with incident coronary artery disease. RESULTS: This study included 130 254 postmenopausal women (UK Biobank: n=122 224; Women's Health Initiative: n=8030), of whom 4809 (3.7%) had experienced menopause before age 40. Earlier menopause was associated with shorter LTL (meta-analyzed ß=-0.02 SD/5 years of earlier menopause [95% CI, -0.02 to -0.01]; P=7.2×10-12). This association was stronger and significant in both cohorts for women with natural/spontaneous menopause (meta-analyzed ß=-0.04 SD/5 years of earlier menopause [95% CI, -0.04 to -0.03]; P<2.2×10-16) and was independent of hormone therapy use. Mendelian randomization supported a causal association of shorter genetically predicted LTL with earlier age at natural menopause. LTL and age at menopause were independently associated with incident coronary artery disease, and mediation analyses indicated small but significant mediation effects of LTL in the association of menopausal age with coronary artery disease. CONCLUSIONS: Earlier age at menopause is associated with shorter LTL, especially among women with natural menopause. Accelerated telomere shortening may contribute to the heightened cardiovascular risk associated with premature menopause.

Autoimmune rheumatic diseases in women with coronary microvascular dysfunction: a report from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) project.

Background: While autoimmune rheumatic diseases (ARDs) have been linked with coronary microvascular dysfunction (CMD), the relationship between ARD and CMD in women with signs and symptoms of ischemia and no obstructive arteries (INOCA) are not well described. We hypothesized that among women with CMD, those with ARD history have greater angina, functional limitations, and myocardial perfusion compromise compared to those without ARD history. Methods: Women with INOCA and confirmed CMD by invasive coronary function testing were included from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) project (NCT00832702). Seattle Angina Questionnaire (SAQ), Duke Activity Status Index (DASI), and cardiac magnetic resonance myocardial perfusion reserve index (MPRI) were collected at baseline. Chart review was performed to confirm self-reported ARD diagnosis. Results: Of the 207 women with CMD, 19 (9%) had a confirmed history of ARD. Compared to those without ARD, women with ARD were younger (p = 0.04). In addition, they had lower DASI-estimated metabolic equivalents (p = 0.03) and lower MPRI (p = 0.008) but similar SAQ scores. There was a trend towards increased nocturnal angina and stress-induced angina in those with ARD (p = 0.05 for both). Invasive coronary function variables were not significantly different between groups. Conclusions: Among women with CMD, women with a history of ARD had lower functional status and worse myocardial perfusion reserve compared to women without ARD. Angina-related health status and invasive coronary function were not significantly different between groups. Further studies are warranted to understand mechanisms contributing to CMD among women with ARDs with INOCA.

Association of Migraine and Vasomotor Symptoms.

OBJECTIVE: To further examine a potential link between migraine and vasomotor symptoms as well as hypertension as a cardiovascular disease risk factor, potentially explaining the association in midlife women. PATIENTS AND METHODS: We conducted a cross-sectional analysis from the Data Registry on Experiences of Aging, Menopause, and Sexuality using questionnaire data from women aged 45 to 60 years seen in women's clinics at a tertiary care center from May 15, 2015, through January 31, 2022. A history of migraine was self-reported; menopause symptoms were assessed with the Menopause Rating Scale. Associations between migraine and vasomotor symptoms were evaluated utilizing multivariable logistic regression models adjusting for multiple factors. RESULTS: Of 5708 women included in the analysis, 1354 (23.7%) reported a migraine history. The total cohort had a mean age of 52.8 years, most (5184 [90.8%]) were White, and 3348 (58.7%) were postmenopausal. In adjusted analysis, women with migraine were significantly more likely to have severe/very severe hot flashes vs no hot flashes compared with women without migraine (odds ratio, 1.34; 95% CI, 1.08 to 1.66; P=.007). Migraine was associated with a diagnosis of hypertension in adjusted analysis (odds ratio, 1.31; 95% CI, 1.11 to 1.55; P=.002). CONCLUSION: This large cross-sectional study confirms an association between migraine and vasomotor symptoms. Migraine also was associated with hypertension, potentially providing a link with cardiovascular disease risk. Given the high prevalence of migraine in women, this association may help identify those at risk for more severe menopause symptoms.

Impact of Menopause Symptoms on Women in the Workplace.

OBJECTIVE: To evaluate the impact of menopause symptoms on work outcomes and to assess the estimated economic impact. PATIENTS AND METHODS: Women aged 45 to 60 years receiving primary care at 1 of the 4 Mayo Clinic sites were invited to participate in a survey study (Hormones and ExpeRiences of Aging) from March 1 through June 30, 2021. A total of 32,469 surveys were sent, with 5219 responses (16.1% response rate). Of the 5219 respondents, 4440 (85.1%) reported current employment information and were included in the study. The primary outcome was self-reported adverse work outcomes related to menopause symptoms assessed by the Menopause Rating Scale (MRS). RESULTS: The mean age of the 4440 participants was 53.9±4.5 years, with the majority being White (4127 [93.0%]), married (3398 [76.5%]), and educated (2632 [59.3%] college graduate or higher); the mean total MRS score was 12.1, signifying moderate menopause symptom burden. Overall, 597 women (13.4%) reported at least one adverse work outcome due to menopause symptoms; 480 women (10.8%) reported missing work in the preceding 12 months (median, 3 days missed). The odds of reporting an adverse work outcome increased with increasing menopause symptom severity; women in the highest quartile of total MRS scores were 15.6 (95% CI, 10.7 to 22.7; P<.001) times more likely to have an adverse work outcome vs those in the first quartile. Based on workdays missed due to menopause symptoms, we estimate an annual loss of $1.8 billion in the United States. CONCLUSION: This large cross-sectional study identified a major negative impact of menopause symptoms on work outcomes and the need to improve medical treatment for these women and make the workplace environment more supportive. Additional studies are needed to confirm these findings in larger and more diverse groups of women.