Genetic insights into the age-specific biological mechanisms governing human ovarian aging.

There is currently little evidence that the genetic basis of human phenotype varies significantly across the lifespan. However, time-to-event phenotypes are understudied and can be thought of as reflecting an underlying hazard, which is unlikely to be constant through life when values take a broad range. Here, we find that 74% of 245 genome-wide significant genetic associations with age at natural menopause (ANM) in the UK Biobank show a form of age-specific effect. Nineteen of these replicated discoveries are identified only by our modeling framework, which determines the time dependency of DNA-variant age-at-onset associations without a significant multiple-testing burden. Across the range of early to late menopause, we find evidence for significantly different underlying biological pathways, changes in the signs of genetic correlations of ANM to health indicators and outcomes, and differences in inferred causal relationships. We find that DNA damage response processes only act to shape ovarian reserve and depletion for women of early ANM. Genetically mediated delays in ANM were associated with increased relative risk of breast cancer and leiomyoma at all ages and with high cholesterol and heart failure for late-ANM women. These findings suggest that a better understanding of the age dependency of genetic risk factor relationships among health indicators and outcomes is achievable through appropriate statistical modeling of large-scale biobank data.

X centromeric drive may explain the prevalence of polycystic ovary syndrome and other conditions: Genomic structure of the human X chromosome pericentromeric region is consistent with meiotic drive associated with PCOS and other conditions.

X chromosome centromeric drive may explain the prevalence of polycystic ovary syndrome and contribute to oocyte aneuploidy, menopause, and other conditions. The mammalian X chromosome may be vulnerable to meiotic drive because of X inactivation in the female germline. The human X pericentromeric region contains genes potentially involved in meiotic mechanisms, including multiple SPIN1 and ZXDC paralogs. This is consistent with a multigenic drive system comprising differential modification of the active and inactive X chromosome centromeres in female primordial germ cells and preferential segregation of the previously inactivated X chromosome centromere to the polar body at meiosis I. The drive mechanism may explain differences in X chromosome regulation in the female germlines of the human and mouse and, based on the functions encoded by the genes in the region, the transmission of X pericentromeric genetic or epigenetic variants to progeny could contribute to preeclampsia, autism, and differences in sexual differentiation.

Running the Female Power Grid Across Lifespan Through Brain Estrogen Signaling.

The role of central estrogen in cognitive, metabolic, and reproductive health has long fascinated the lay public and scientists alike. In the last two decades, insight into estrogen signaling in the brain and its impact on female physiology is beginning to catch up with the vast information already established for its actions on peripheral tissues. Using newer methods to manipulate estrogen signaling in hormone-sensitive brain regions, neuroscientists are now identifying the molecular pathways and neuronal subtypes required for controlling sex-dependent energy allocation. However, the immense cellular complexity of these hormone-sensitive brain regions makes it clear that more research is needed to fully appreciate how estrogen modulates neural circuits to regulate physiological and behavioral end points. Such insight is essential for understanding how natural or drug-induced hormone fluctuations across lifespan affect women's health.

Trajectories of Sleep Over Midlife and Incident Cardiovascular Disease Events in the Study of Women's Health Across the Nation.

BACKGROUND: Up to 50% of women report sleep problems in midlife, and cardiovascular disease (CVD) is the leading cause of death in women. How chronic poor sleep exposure over decades of midlife is related to CVD risk in women is poorly understood. We tested whether trajectories of insomnia symptoms or sleep duration over midlife were related to subsequent CVD events among SWAN (Study of Women's Health Across the Nation) participants, whose sleep was assessed up to 16 times over 22 years. METHODS: At baseline, SWAN participants (n=2964) were 42 to 52 years of age, premenopausal or early perimenopausal, not using hormone therapy, and free of CVD. They completed up to 16 visits, including questionnaires assessing insomnia symptoms (trouble falling asleep, waking up several times a night, or waking earlier than planned ≥3 times/week classified as insomnia), typical daily sleep duration, vasomotor symptoms, and depressive symptoms; anthropometric measurements; phlebotomy; and CVD event ascertainment (ie, fatal or nonfatal myocardial infarction, stroke, heart failure, revascularization). Sleep trajectories (ie, insomnia, sleep duration) were determined by means of group-based trajectory modeling. Sleep trajectories were tested in relation to CVD in Cox proportional hazards models (multivariable models: site, age, race and ethnicity, education, CVD risk factors averaged over visits; additional covariates: vasomotor symptoms, snoring, depression). RESULTS: Four trajectories of insomnia symptoms emerged: low insomnia symptoms (n=1142 [39% of women]), moderate insomnia symptoms decreasing over time (n=564 [19%]), low insomnia symptoms increasing over time (n=590 [20%]), and high insomnia symptoms that persisted (n=668 [23%]). Women with persistently high insomnia symptoms had higher CVD risk (hazard ratio, 1.71 [95% CI, 1.19, 2.46], P=0.004, versus low insomnia; multivariable). Three trajectories of sleep duration emerged: persistently short (~5 hours: n=363 [14%]), moderate (~6 hours: n=1394 [55%]), and moderate to long (~8 hours: n=760 [30%]). Women with persistent short sleep had marginally higher CVD risk (hazard ratio, 1.51 [95% CI, 0.98, 2.33], P=0.06, versus moderate; multivariable). Women who had both persistent high insomnia and short sleep had significantly elevated CVD risk (hazard ratio, 1.75 [95% CI, 1.03, 2.98], P=0.04, versus low insomnia and moderate or moderate to long sleep duration; multivariable). Relations of insomnia to CVD persisted when adjusting for vasomotor symptoms, snoring, or depression. CONCLUSIONS: Insomnia symptoms, when persistent over midlife or occurring with short sleep, are associated with higher CVD risk among women.

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.

Impact of sex and reproductive status on the default mode network in early midlife: implications for aging of memory circuitry and function.

Alterations to the resting-state default mode network (rsDMN) are early indicators of memory decline and Alzheimer's disease (AD). Brain regions shared by the rsDMN and memory circuitry are highly sexually dimorphic. However, data are limited regarding the impact of sex and reproductive status on rsDMN connectivity and memory circuitry and function. In the current investigation, rsDMN connectivity was assessed in 180 early midlife adults aged 45 to 55 by sex and reproductive status (87 women; 93 men). Associations between left and right hippocampal connectivity of rsDMN and verbal memory encoding circuitry were examined using linear mixed models, controlled for age and parental socioeconomic status, testing interactions by sex and reproductive status. Relative to men, women exhibited greater rsDMN connectivity between the left and right hippocampus. In relation to rsDMN-memory encoding connectivity, sex differences were revealed across the menopausal transition, such that only postmenopausal women exhibited loss of the ability to decrease rsDMN left-right hippocampal connectivity during memory encoding associated with poorer memory performance. Results demonstrate that sex and reproductive status play an important role in aging of the rsDMN and interactions with memory circuitry/function. This suggests the critical importance of sex and reproductive status when studying early midlife indicators of memory decline and AD risk.

Subclinical Atherosclerosis Across the Menopausal Transition in Women With and Without HIV.

The menopausal transition is a pivotal time of cardiovascular risk, but knowledge is limited in HIV. We studied longitudinal carotid artery intima-media thickness (CIMT) in the Women's Interagency HIV Study (2004-2019; 979 women/3247 person-visits; 72% with HIV). Among women with HIV only, those who transitioned had greater age-related CIMT progression compared to those remaining premenopausal (difference in slope = 1.64 µm/year, P = .002); and CIMT increased over time in the pretransition (3.47 µm/year, P = .002) and during the menopausal transition (9.41 µm/year, P < .0001), but not posttransition (2.9 µm/year, P = .19). In women with HIV, menopause may accelerate subclinical atherosclerosis as measured by CIMT.

Excess body weight and postmenopausal breast cancer: Emerging molecular mechanisms and perspectives.

Postmenopausal, obese women have a significantly higher risk of developing estrogen receptor-positive (ER+) breast tumors, that are resistant to therapies and are associated with higher recurrence and death rates. The global prevalence of overweight/obese women has reached alarming proportions and with postmenopausal ER+ breast carcinoma (BC) having the highest incidence among the three obesity-related cancers in females (i.e., breast, endometrial and ovarian), this is of significant concern. Elucidation of the precise molecular mechanisms underlying the pro-cancerous action of obesity in ER+BC is therefore critical for disease prevention and novel treatment initiatives. Interestingly, accumulating data has shown opposing relationships between obesity and cancer in either pre- or post-menopausal women. Excess body weight is associated with an increased risk of breast cancer in postmenopausal women and a decreased risk in pre-menopausal women. Moreover, excess adiposity during early life appears to be protective against postmenopausal breast cancer, including both ER+ and ER negative BC subtypes. Overall, estrogen-dependent mechanisms have been implicated as the main driving force in obesity-related breast tumorigenesis. In the present review we discuss the epidemiologic and mechanistic aspects of association between obesity and breast tumors after menopause, mainly in the context of hormone dependency. Molecular and cellular events underlying this association present as potential avenues for both therapeutic intervention as well as the prevention of BC-promoting processes linked to excess adiposity, which is proving to be vital in an increasingly obese global population.

Menopause Status and Within-Group Differences in Chronological Age Affect the Functional Neural Correlates of Spatial Context Memory in Middle-Aged Females.

Reductions in the ability to encode and retrieve past experiences in rich spatial contextual detail (episodic memory) are apparent by midlife-a time when most females experience spontaneous menopause. Yet, little is known about how menopause status affects episodic memory-related brain activity at encoding and retrieval in middle-aged premenopausal and postmenopausal females, and whether any observed group differences in brain activity and memory performance correlate with chronological age within group. We conducted an event-related task fMRI study of episodic memory for spatial context to address this knowledge gap. Multivariate behavioral partial least squares was used to investigate how chronological age and retrieval accuracy correlated with brain activity in 31 premenopausal females (age range, 39.55-53.30 years; mean age, 44.28 years; SD age, 3.12 years) and 41 postmenopausal females (age range, 46.70-65.14 years; mean age, 57.56 years; SD age, 3.93 years). We found that postmenopausal status, and advanced age within postmenopause, was associated with lower spatial context memory. The fMRI analysis showed that only in postmenopausal females, advanced age was correlated with decreased activity in occipitotemporal, parahippocampal, and inferior parietal cortices during encoding and retrieval, and poorer spatial context memory performance. In contrast, only premenopausal females exhibited an overlap in encoding and retrieval activity in angular gyrus, midline cortical regions, and prefrontal cortex, which correlated with better spatial context retrieval accuracy. These results highlight how menopause status and chronological age, nested within menopause group, affect episodic memory and its neural correlates at midlife.SIGNIFICANCE STATEMENT This is the first fMRI study to examine how premenopause and postmenopause status affect the neural correlates of episodic memory encoding and retrieval, and how chronological age contributes to any observed group similarities and differences. We found that both menopause status (endocrine age) and chronological age affect spatial context memory and its neural correlates. Menopause status directly affected the direction of age-related and performance-related correlations with brain activity in inferior parietal, parahippocampal, and occipitotemporal cortices across encoding and retrieval. Moreover, we found that only premenopausal females exhibited cortical reinstatement of encoding-related activity in midline cortical, prefrontal, and angular gyrus, at retrieval. This suggests that spatial context memory abilities may rely on distinct brain systems at premenopause compared with postmenopause.

Autonomic nervous system dysfunction throughout menopausal transition: A potential mechanism underpinning cardiovascular and cognitive alterations during female ageing.

Cardiovascular diseases (CVD) and neurodegenerative disorders, such as Alzheimer's disease (AD), are highly prevalent conditions in middle-aged women that severely impair quality of life. Recent evidence suggests the existence of an intimate cross-talk between the heart and the brain, resulting from a complex network of neurohumoral circuits. From a pathophysiological perspective, the higher prevalence of AD in women may be explained, at least in part, by sex-related differences in the incidence/prevalence of CVD. Notably, the autonomic nervous system, the main heart-brain axis physiological orchestrator, has been suggested to play a role in the incidence of adverse cardiovascular events in middle-aged women because of decreases in oestrogen-related signalling during transition into menopause. Despite its overt relevance for public health, this hypothesis has not been thoroughly tested. Accordingly, in this review, we aim to provide up to date evidence supporting how changes in circulating oestrogen levels during transition to menopause may trigger autonomic dysfunction, thus promoting cardiovascular and cognitive decline in women. A main focus on the effects of oestrogen-mediated signalling at CNS structures related to autonomic regulation is provided, particularly on the role of oestrogens in sympathoexcitation. Improving the understanding of the contribution of the autonomic nervous system on the development, maintenance and/or progression of both cardiovascular and cognitive dysfunction during the transition to menopause should help improve the clinical management of elderly women, with the outcome being an improved life quality during the natural ageing process.

Rethinking Menopausal Hormone Therapy: For Whom, What, When, and How Long?

Menopausal hormone therapy (HT) was widely used in the past, but with the publication of seminal primary and secondary prevention trials that reported an excess cardiovascular risk with combined estrogen-progestin, HT use declined significantly. However, over the past 20 years, much has been learned about the relationship between the timing of HT use with respect to age and time since menopause, HT route of administration, and cardiovascular disease risk. Four leading medical societies recommend HT for the treatment of menopausal women with bothersome menopausal symptoms. In this context, this review, led by the American College of Cardiology Cardiolovascular Disease in Women Committee, along with leading gynecologists, women's health internists, and endocrinologists, aims to provide guidance on HT use, including the selection of patients and HT formulation with a focus on caring for symptomatic women with cardiovascular disease risk.

Effect of Menopause Status on Brain Perfusion Hemodynamics.

BACKGROUND: The menopause transition is associated with an increasing risk of cerebrovascular disorders. However, the direct effect of menopause status on brain perfusion hemodynamics remains unclear. This study aimed to explore the influence of menopause status on cerebral blood flow (CBF) using arterial spin labeling magnetic resonance imaging. METHODS: In this cross-sectional study, 185 subjects underwent arterial spin labeling magnetic resonance imaging at a hospital in China between September 2020 and December 2022, including 38 premenopausal women (mean age, 47.74±2.02 years), 42 perimenopausal women (mean age, 50.62±3.15 years), 42 postmenopausal women (mean age, 54.02±4.09 years), and 63 men (mean age, 52.70±4.33 years) of a similar age range. Mean CBF values in the whole brain, gray matter, white matter, cortical gray matter, subcortical gray matter, juxtacortical white matter, deep white matter, and periventricular white matter were extracted. ANCOVA was used to compare mean CBF among the 4 groups, controlling for confounding factors. Student t test was applied to compare mean CBF between the 3 female groups and age-matched males, respectively. Multivariable regression analysis was used to analysis the effect of age, sex, and menopause status on the CBF of the whole brain, gray matter, white matter, and subregions. RESULTS: Perimenopausal and postmenopausal women showed a higher proportion of white matter hyperintensities compared with the other 2 groups (P<0.001). Premenopausal women exhibited higher CBF in the whole brain, gray matter, white matter, and subregions, compared with perimenopausal, postmenopausal women and men (P≤0.001). Multivariable regression analysis demonstrated significant effect of age and insignificant effect of sex on CBF for all participants. In addition, menopause status and the interaction between age and menopause status on CBF of whole brain, gray matter, white matter, and the subregions were observed in female participants, except for the deep and periventricular white matter regions, with premenopausal women exhibited a slight increase in CBF with age, while perimenopausal and postmenopausal women exhibited declines in CBF with age. CONCLUSIONS: The current findings suggest that alterations of brain perfusion hemodynamics begin during the perimenopause period, which may be due to the increased burden of white matter hyperintensities.

Association of female reproductive and hormonal factors with gallbladder cancer risk in Asia: A pooled analysis of the Asia Cohort Consortium.

The female predominance of gallbladder cancer (GBC) has led to a hypothesis regarding the hormone-related aetiology of GBC. We aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women. We conducted a pooled analysis of 331,323 women from 12 cohorts across 4 countries (China, Japan, Korea, and Singapore) in the Asia Cohort Consortium. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess the association between reproductive factors (age at menarche, parity, age at first delivery, breastfeeding, and age at menopause) and GBC risk. We observed that a later age at menarche was associated with an increased risk of GBC (HR 1.4, 95% CI 1.16-1.70 for 17 years and older vs. 13-14 years), especially among the cohort born in 1940 and later (HR 2.5, 95% CI 1.50-4.35). Among the cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC (HR 1.56, 95% CI 1.08-2.24 for 31 years of age and older vs. 20 years of age and younger). Other reproductive factors did not show a clear association with GBC risk. Later ages at menarche and at first delivery were associated with a higher risk of GBC, and these associations varied by birth cohort.

Global burden of 34 cancers among women in 2020 and projections to 2040: Population-based data from 185 countries/territories.

Globally women face inequality in cancer outcomes; for example, smaller improvements in life expectancy due to decreased cancer-related deaths than men (0.5 vs 0.8 years, 1981-2010). However, comprehensive global evidence on the burden of cancer among women (including by reproductive age spectrum) as well as disparities by region, remains limited. This study aimed to address these evidence gaps by considering 34 cancer types in 2020 and their projections for 2040. The cancer burden among women in 2020 was estimated using population-based data from 185 countries/territories sourced from GLOBOCAN. Mortality to Incidence Ratios (MIR), a proxy for survival, were estimated by dividing the age-standardised mortality rates by the age-standardised incidence rates. Demographic projections were performed to 2040. In 2020, there were an estimated 9.3 million cancer cases and 4.4 million cancer deaths globally. Projections showed an increase to 13.3 million (↑44%) and 7.1 million (↑60%) in 2040, respectively, with larger proportional increases in low- and middle-income countries. MIR among women was higher (poorer survival) in rare cancers and with increasing age. Countries with low Human Development Indexes (HDIs) had higher MIRs (69%) than countries with very high HDIs (30%). There was inequality in cancer incidence and mortality worldwide among women in 2020, which will further widen by 2040. Implementing cancer prevention efforts and providing basic cancer treatments by expanding universal health coverage through a human rights approach, expanding early screening opportunities and strengthening medical infrastructure are key to improving and ensuring equity in cancer control and outcomes.

Antidepressant Effect of Enzymatic Porcine Placenta Hydrolysate in Repeated Immobilization Stress-Induced Ovariectomized Female Mice.

When postmenopausal women are under stress conditions, this exacerbates mood disorders and issues with neuroimmune systems. The porcine placenta is known to relieve menopausal depression in clinical trials, but its underlying mechanisms for depression and anti-inflammatory functions remain poorly defined. The present study was designed to examine the anti-inflammatory effects of enzymatic porcine placenta hydrolysate (EPPH) on LPS-induced levels of nitric oxide (NO), prostaglandin E2 (PGE2), corticosterone (CORT), and pro-inflammatory cytokine interleukin-1 beta (IL-1ß) in RAW 264.7 macrophage cells. In addition, the neurite outgrowth of PC12 cells was evaluated to examine the effects of EPPH on neurite growth. To mimic the symptoms of women with menopause-related depression, a stressed ovariectomized (OVX) female mouse model was used to evaluate the antidepressant effects of EPPH. The female mice were randomly divided into five groups: (1) the sham-operated (Sham) group, (2) the OVX + repeated stress + saline-treated (OVX + ST) group, (3) the OVX + repeated stress + estradiol (0.2 mg/kg)-treated (positive control) group, (4) the OVX + repeated stress + EPPH (300 mg/kg)-treated (300) group, and (5) the OVX + repeated stress + EPPH (1500 mg/kg)-treated (1500) group. Female mice were OVX and repeatedly immobilization-stressed for 2 weeks (2 h/day). A tail suspension test was conducted on the 13th day, followed by the forced swimming test on the 14th day to assess the antidepressant effects of EPPH. After the behavioral tests, the levels of CORT, PGE2, and IL-1ß were evaluated. In addition, c-Fos expression in the paraventricular nucleus (PVN) was evaluated using immunohistochemistry. The concentrations of NO, PGE2, and IL-1ß stimulated by LPS were significantly reduced via the addition of EPPH to RAW 264.7 cells. EPPH significantly promoted neurite outgrowth in PC12 cells compared to that of the controls. In the tail suspension test, the duration of immobility was reduced in mice treated with EPPH 1500 compared to the OVX + ST group. The EPPH 1500 group had significantly decreased levels of c-Fos-positive neurons in the PVN and reduced levels of CORT and IL-1ß in the serum of the Sham group. These results suggested that the high dose of EPPH administration induced the antidepressant-like effect in the ovariectomized mice with repeated stress via downregulating the levels of CORT, IL-1ß, and PGE2 in the serum through reducing the expression of c-Fos in the PVN regions.

Cardiometabolic health, menopausal estrogen therapy and the brain: How effects of estrogens diverge in healthy and unhealthy preclinical models of aging.

Research in preclinical models indicates that estrogens are neuroprotective and positively impact cognitive aging. However, clinical data are equivocal as to the benefits of menopausal estrogen therapy to the brain and cognition. Pre-existing cardiometabolic disease may modulate mechanisms by which estrogens act, potentially reducing or reversing protections they provide against cognitive decline. In the current review we propose mechanisms by which cardiometabolic disease may alter estrogen effects, including both alterations in actions directly on brain memory systems and actions on cardiometabolic systems, which in turn impact brain memory systems. Consideration of mechanisms by which estrogen administration can exert differential effects dependent upon health phenotype is consistent with the move towards precision or personalized medicine, which aims to determine which treatment interventions will work for which individuals. Understanding effects of estrogens in both healthy and unhealthy models of aging is critical to optimizing the translational link between preclinical and clinical research.

Polycystic ovary syndrome and endometrial cancer risk: results from a nationwide cohort study.

Most previous studies have found an elevated risk of endometrial cancer among women with polycystic ovary syndrome (PCOS). However, these have highly varying methods for ascertainment of PCOS diagnoses and have limitations such as few exposed women and short follow-up. In this cohort study, we investigated the association between PCOS and endometrial cancer among women born in Denmark between January 1, 1940, and December 31, 1993 (N=1,719,121). Data in this study, including PCOS and endometrial cancer diagnoses and covariates, were derived from nationwide registers. We used cox proportional hazard regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 7862 endometrial cancer cases were identified during 23.7 years of follow-up (inter quartile range 37.7-61.9). We found an increased risk of endometrial cancer among women with PCOS compared with women without PCOS (HR: 3.02, 95% CI; 2.03-4.49). The risk was increased for premenopausal women (HR5.82, 95% CI: 3.64-9.30) whereas no marked association was seen for postmenopausal women. However, for postmenopausal women, results were limited by few cases and young age at end of follow-up. Mounting evidence of an increased risk for endometrial cancer among women with PCOS reinforces the need for prevention and early detection.

Association of parity with the timing and type of menopause: A longitudinal cohort study.

We investigated the time-varying association between parity and timing of natural menopause, surgical menopause, and premenopausal hysterectomy among 23,728 women aged 40-65 years at enrollment in the Alberta's Tomorrow Project cohort study (2000-2022), using flexible parametric survival analysis. Overall, natural menopause was most common by study end (57.2%), followed by premenopausal hysterectomy (11.4%) and surgical menopause (5.3%). Risks of natural menopause before age 50 years were elevated for 0 births (adjusted hazard ratio at age 45: 1.33, 95% CI 1.18-1.49) and 1 birth (age 45: 1.21, 1.07-1.38), but similar for ≥3 births (age 45: 0.95, 0.85-1.06), compared to 2 births (reference). Elevated risks of surgical menopause before age 45 years for 0 births (age 40: 1.37, 1.09-1.69) and 1 birth (age 40: 1.11, 0.85-1.45) attenuated when excluding women with past infertility or recurrent pregnancy loss, and reduced risks were observed over time for ≥3 births (age 50: 0.84, 0.75-0.94). Risks of premenopausal hysterectomy were lower before age 50 years for 0 births (age 45: 0.82, 0.76-0.88) but elevated after age 40 years for ≥3 births (age 50: 1.25, 1.08-1.45). These complex associations necessitate additional research on the sociobiological impacts of childbearing on gynecologic health.

Impact of ovary-intact menopause in a mouse model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) afflicts over half of all patients with heart failure and is a debilitating and fatal syndrome affecting postmenopausal women more than any other demographic. This bias toward older females calls into question the significance of menopause in the development of HFpEF, but this question has not been probed in detail. In this study, we report the first investigation into the impact of ovary-intact menopause in the context of HFpEF. To replicate the human condition as faithfully as possible, vinylcyclohexene dioxide (VCD) was used to accelerate ovarian failure (AOF) in female mice while leaving the ovaries intact. HFpEF was established with a mouse model that involves two stressors typical in humans: a high-fat diet and hypertension induced from the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME). In young female mice, AOF or HFpEF-associated stressors independently induced abnormal myocardial strain indicative of early subclinical systolic and diastolic cardiac dysfunction. HFpEF but not AOF was associated with elevations in systolic blood pressure. Increased myocyte size and reduced myocardial microvascular density were not observed in any group. Also, a broad panel of measurements that included echocardiography, invasive pressure measurements, histology, and serum hormones revealed no interaction between AOF and HFpEF. Interestingly, AOF did evoke a higher density of infiltrating cardiac immune cells in both healthy and HFpEF mice, suggestive of proinflammatory effects. In contrast to young mice, middle-aged "old" mice did not exhibit cardiac dysfunction from estrogen deprivation alone or from HFpEF-related stressors.NEW & NOTEWORTHY This is the first preclinical study to examine the impact of ovary-intact menopause [accelerated ovarian failure (AOF)] on HFpEF. Echocardiography of young female mice revealed early evidence of diastolic and systolic cardiac dysfunction apparent only on strain imaging in HFpEF only, AOF only, or the combination. Surprisingly, AOF did not exacerbate the HFpEF phenotype. Results in middle-aged "old" females also showed no interaction between HFpEF and AOF and, importantly, no cardiovascular impact from HFpEF or AOF.

Sleep disturbance and sympathetic neural reactivity in postmenopausal females.

Sleep disturbance, one of the most common menopausal symptoms, contributes to autonomic dysfunction and is linked to hypertension and cardiovascular risk. Longitudinal studies suggest that hyperreactivity of blood pressure (BP) to a stressor can predict the future development of hypertension. It remains unknown if postmenopausal females who experience sleep disturbance (SDG) demonstrate greater hemodynamic and sympathetic neural hyperreactivity to a stressor. We hypothesized that postmenopausal females with reported sleep disturbance would exhibit increased hemodynamic and sympathetic reactivity to a stressor compared with postmenopausal females without sleep disturbance (non-SDG). Fifty-five postmenopausal females (age, 62 ± 4 yr old; SDG, n = 36; non-SDG; n = 19) completed two study visits. The Menopause-Specific Quality of Life Questionnaire (MENQOL) was used to assess the presence of sleep disturbance (MENQOL sleep scale, ≥2 units). Beat-to-beat BP (finger plethysmography), heart rate (HR; electrocardiogram), and muscle sympathetic nerve activity (MSNA; microneurography; SDG, n = 25; non-SDG, n = 15) were continuously measured during a 10-min baseline and 2-min stressor (cold pressor test; CPT) in both groups. Menopause age and body mass index were similar between groups (P > 0.05). There were no differences between resting BP, HR, or MSNA (P > 0.05). HR and BP reactivity were not different between SDG and non-SDG (P > 0.05). In contrast, MSNA reactivity had a more rapid increase in the first 30 s of the CPT in the SDG (burst incidence, Δ10.2 ± 14.8 bursts/100 hb) compared with the non-SDG (burst incidence, Δ4.0 ± 14.8 bursts/100 hb, time × group, P = 0.011). Our results demonstrate a more rapid sympathetic neural reactivity to a CPT in postmenopausal females with perceived sleep disturbance, a finding that aligns with and advances recent evidence that sleep disturbance is associated with sympathetic neural hyperactivity in postmenopausal females.NEW & NOTEWORTHY This is the first study to demonstrate that muscle sympathetic nerve activity (MSNA) to a cold pressor test is augmented in postmenopausal females with perceived sleep disturbance. The more rapid increase in MSNA reactivity during the cold pressor test in the sleep disturbance group was present despite similar increases in the perceived pain levels between groups. Baseline MSNA burst incidence and burst frequency, as well as blood pressure and heart rate, were similar between the sleep disturbance and nonsleep disturbance groups.