Type Of Menopause Research Articles

Association of lifetime lactation and characteristics of menopause: a longitudinal cohort study.

Lactation has many established benefits for women's long-term health; however, its influence on menopause is less clear. This study investigated the association between lifetime duration of lactation and the timing and type of menopause in midlife women. We analyzed survey data on 19,783 parous women aged 40 to 65 years at enrollment in the Alberta's Tomorrow Project (2000-2022), a prospective community-based cohort study in Alberta, Canada. Duration of lifetime lactation across all births was categorized as: <1 month (reference group; 19.8% of women), 1-3 months (12.1%), 4-6 months (11.7%), 7-12 months (18.8%), and ≥ 13 months (37.7%). Women were classified as premenopause, natural menopause (age at 1 year after the final menstrual period), surgical menopause (age at bilateral oophorectomy), or indeterminate menopause (age at premenopausal hysterectomy with ovarian preservation). Flexible parametric survival analysis and multinomial logistic regression were used to analyze menopause timing and type, respectively, according to lactation status and controlling for birth year, education, parity, hormonal contraceptive use, and smoking. In a dose-response manner, longer lactation was associated with reduced risk of natural menopause before age 50 (for ≥ 13 months of lactation, adjusted hazard ratio at age 45: 0.68, 95% CI 0.59-0.78), surgical menopause before age 55 (age 45: 0.56, 0.50-0.63), and indeterminate menopause before age 50 (age 45: 0.75, 0.69-0.82). Longer lactation was associated with lower odds of surgical (adjusted odds ratio 0.54, 95% CI 0.45-0.66) and indeterminate menopause (0.63, 0.55-0.73), compared to natural menopause. Optimizing the timing of natural menopause and reducing risks of early surgical and indeterminate menopause may be novel maternal benefits of breastfeeding.

Multiomic profiling reveals timing of menopause predicts prefrontal cortex aging and cognitive function.

A new case of dementia is diagnosed every 3 s. Beyond age, risk prediction of dementia is challenging. There is growing evidence of underlying processes that connect aging across organ systems and may provide insight for early detection, and there is a need to identify early biomarkers at an age when action can be taken to mitigate cognitive decline. We hypothesized that timing of menopause, a marker of ovarian aging, predicts brain age decades later. We used 2086 subjects with multiple "omics" measurements from post-mortem brain samples. Age at menopause (AAM) is positively correlated with cognitive function and negatively correlated with pre-frontal cortex aging acceleration (calculated as estimated biological age from DNA methylation minus chronological age). Genetic correlations showed that at least part of these associations is derived from shared heritability. To dissect the mechanism linking AAM to cognitive decline, we turned to transcriptomic data which confirmed that later AAM was associated with gene expression in pre-frontal cortex consistent with better cognition, and among those who reached menopause naturally, decreased gene expression of pathways implicated in aging. Those with surgical menopause displayed different molecular changes, including perturbed nicotinamide adenine dinucleotide (NAD+) activity, validated by metabolomics. Bile acid metabolism was perturbed in both groups, although different bile acid ratios were associated with AAM in each. Together, our data suggest that AAM is predictive of brain aging and cognition, with potential mediation by the gut, although through different mechanisms depending on the type of menopause.

Associated risk and resilience factors of Alzheimer's disease in women with early bilateral oophorectomy: Data from the UK Biobank.

Bilateral oophorectomy (BO) confers immediate estradiol loss. We examined prevalence and predictors of Alzheimer's disease (AD) in women with early BO comparing their odds ratios of AD to those of women with spontaneous menopause (SM). A cohort from UK Biobank (n = 34,603) included women aged 60 + at baseline with and without AD who had early BO or SM. AD was determined based on AD related ICD-10 or ICD-9 code. We used logistic regression to model the association of menopause type with AD. Model predictors included age, education, age at menopause, hormone therapy (HT), APOE4, body mass index (BMI), cancer history, and smoking history. Those with early BO had four times the odds of developing AD (OR = 4.12, 95% CI [2.02, 8.44]) compared to those with SM. APOE4 (OR = 4.29, 95% CI [2.43, 7.56]), and older age (OR = 1.16, 95% CI [1.05, 1.28]) were associated with increased odds of AD in the BO group. Greater years of education were associated with reduced odds of AD for both BO (OR = 0.91, 95% CI [0.85, 0.98]), and SM (OR = 0.95, 95% CI [0.90, 0.99]), while ever use of HT was associated with decreased odds of AD only for the BO group (OR = 0.43, 95% CI [0.23, 0.82]). Women with early BO, particularly with an APOE4 allele, are at high risk of AD. Women with early BO who use HT and those with increased education have lower odds of developing AD.

8648 Association of isoflavone intake and age at natural menopause

Abstract Disclosure: M. Mitsunami: None. E.R. Bertone-Johnson: None. A. Eliassen: None. J.E. Chavarro: None. Introduction: Isoflavones, a type of phytoestrogens found mainly in soy and legumes, are structurally similar to estrogens and are consumed at a relatively high rate by Asian populations with an average intake of approximately 15-40 mg/d for isoflavone. They have been reported to alleviate menopausal symptoms, such as hot flashes, suggesting that isoflavones may be biologically active in a low-estrogen environment. Previous studies have reported inconsistent associations between the intake of soy and isoflavones and age at natural menopause. Therefore, our aim was to test the hypothesis that higher isoflavone intake is related to higher age at natural menopause. Methods: We followed 85,810 premenopausal women (mean [SD], 36.5 [4.7] year) who completed a previously validated food frequency questionnaire, had not been diagnosed with cancer, and did not undergo any menopausal hormone therapy as of 1991. Diet was assessed every 4 years. Isoflavone intake was estimated from these reports. Participants self-reported their menopausal status and the type of menopause (natural, surgical, and radiation or chemotherapy) every 2 years. We used proportional hazard regression models with age in months to evaluate the relation of isoflavone intake with age at natural menopause where natural menopause was the study outcome and menopause due to surgery, radiation, or chemotherapy were censoring events. We used restricted cubic splines to assess the possibility of non-linear relations between isoflavone intake and age at menopause using the U.S. average isoflavone intake (0.8mg/d) as a reference while adjusting for potential confounders, including age at menarche, BMI, race/ethnicity, smoking status, physical activity, parity, breastfeeding, time to regular menstrual cycle, energy intake, and two dietary factors identified by principal component analysis. Results: Over 1,079,608 person-years, we observed 37,438 cases of natural menopause. Soy products contributed approximately half of isoflavone intake. There was a non-linear association between isoflavone intake and age at natural menopause (p&amp;lt;0.001). Women with isoflavone intakes below the U.S. national average were more likely to experience earlier onset menopause. Conversely, in women with intakes above the national average, the risk of menopause decreased with increasing isoflavone intakes, albeit plateauing at intakes of approximately 3-4mg/d (90-95th percentile of observed distribution). There was a suggestion of a positive association between isoflavone intake and earlier onset menopause for intakes above the 99th percentile of the observed distribution (∼14 mg/d). Conclusion: This study suggests a non-linear relation between isoflavone intake and age at natural menopause with a potential later onset of menopause at intake levels higher than typical in the US diet but lower than those typically observed in East Asia. Presentation: 6/2/2024

A descriptive study on quality of life among menopausal women residing in selected rural areas of Udupi district, Karnataka

Background: Menopause is defined as the period of time when ovarian function stops, resulting in permanent amenorrhea, or as the cessation of periods for a period of time equal to three prior cycles. Materials and Methods: A descriptive study conducted among 100 menopausal women, by using The Menopause-specific Quality of Life (MENQOL) Questionnaire, The data is collected by administering a semi structured socio-demographic proforma, residing at rural area in cherkady village of udupi district. Results: The data in Table 1 depicts the majority of the menopausal women 30 (30%) were in the age group of (46 to 50) years. The maximum percentage of the menopausal women 100(100%) were married. The maximum percentage of the menopausal women 62(62%) belong to the Hindu religion. The majority of the menopausal women with educational status 66(66%) were primary (1st std-7th std). Regarding the menopausal women occupation status 100 (100%) were unskilled workers. The majority of the menopausal women with educational status of husband 70(70%) were primary (1st std-7th std). Regarding the menopausal women occupation status of husband 55(55%) were semi-skilled worker. The majority of the primigravida women with place of residence 100(100%) were from rural area. Regarding the menopausal women type of family 53(53%) belonged to nuclear family. The highest percentage of menopausal women 100 (100%) had a monthly income ranging from Rs.2391-7101.A maximum of 34 (34%) attained menarche at the age of 12 years and 49(49%) of them were of61-70 kg weight. A maximum of menopausal women 100(100%) were doing exercise twice a week. About the majority of 99(99%) menopausal women were anemic. About the majority of 88(88%) menopausal women perceived adequate social support. None of them had habit of smoking and alcoholism.

Reproductive Factors and Thyroid Cancer Risk: The Multiethnic Cohort Study.

Background: Women are three times more likely to be diagnosed with thyroid cancer than men, with incidence rates per 100,000 in the United States of 20.2 for women and 7.4 for men. Several reproductive and hormonal factors have been proposed as possible contributors to thyroid cancer risk, including age at menarche, parity, age at menopause, oral contraceptive use, surgical menopause, and menopausal hormone therapy. Our study aimed to investigate potential reproductive/hormonal factors in a multiethnic population. Methods: Risk factors for thyroid cancer were evaluated among female participants (n = 118,344) of the Multiethnic Cohort Study. The cohort was linked to Surveillance, Epidemiology, and End Results cancer incidence and statewide death certificate files in Hawaii and California, with 373 incident papillary thyroid cancer cases identified. Exposures investigated include age at menarche, parity, first pregnancy outcome, birth control use, and menopausal status and type. Multivariable Cox proportional hazards models were used to obtain relative risk (RR) of papillary thyroid cancer and their 95% confidence intervals (CI). Covariates included age, race and ethnicity, reproductive history, body size, smoking, and alcohol consumption. Results: We observed a statistically significant increased risk of papillary thyroid cancer for oophorectomy (adjusted RR 1.58, 95% CI: 1.26, 1.99), hysterectomy (adjusted RR 1.65, 95% CI: 1.33, 2.04), and surgical menopause (adjusted RR 1.55, 95% CI: 1.22, 1.97), and decreased risk for first live birth at ≤20 years of age versus nulliparity (adjusted RR 0.66, 95% CI: 0.46, 0.93). These associations did not vary by race and ethnicity (p het > 0.44). Conclusion: The reproductive risk factors for papillary thyroid cancer reported in the literature were largely confirmed in all racial and ethnic groups in our multiethnic population, which validates uniform obstetric and gynecological practice.

Association between type of menopause and mild cognitive impairment: The REDLINC XII study

ObjectiveTo evaluate the association between type of menopause (spontaneous or surgical) and mild cognitive impairment (MCI). Study designThis study was a cross-sectional, observational, and sub-analytical investigation conducted within gynecological consultations across nine Latin American countries. MethodWe assessed sociodemographic, clinical, and anthropometric data, family history of dementia, and the presence of MCI using the Montreal Cognitive Assessment (MoCA) tool. ResultsThe study involved 1185 postmenopausal women with a mean age of 55.3 years and a body mass index of 26.4 kg/m2. They had an average of 13.3 years of education, and 37 % were homemakers. Three hundred ninety-nine experienced menopause before 40, including 136 with surgical menopause (bilateral oophorectomy). Out of the 786 women who experienced menopause at 40 or more years, 110 did so due to bilateral oophorectomy. There were no differences in MoCA scores among women who experienced menopause before or after the age of 40. However, lower MoCA scores were observed in women with surgical menopause than in those with spontaneous menopause (23.8 ± 4.9 vs. 25.0 ± 4.3 points, respectively, p < 0.001). Our logistic regression model with clustering of patients within countries found a significant association between MCI and surgical menopause (OR 1.47, 95 % CI: 1.01–2.16), use (ever) of menopausal hormone therapy (OR 0.33, 95 % CI: 0.21–0.50), and having >12 years of education (OR 0.21, 95 % CI: 0.14–0.30). ConclusionWhen comparing women who experience spontaneous menopause over the age of 40 with those who undergo it before this age, there was no observed increased risk of developing MCI, while those with surgical menopause, independent of age, are more prone to cognitive decline. Women who have ever used menopausal hormone therapy have a lower MCI risk. Further research is warranted to delve deeper into this topic.

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.

Pregnancy history and estradiol influence spatial memory, hippocampal plasticity, and inflammation in middle-aged rats

Pregnancy and motherhood can have long-term effects on cognition and brain aging in both humans and rodents. Estrogens are related to cognitive function and neuroplasticity. Estrogens can improve cognition in postmenopausal women, but the evidence is mixed, partly due to differences in age of initiation, type of menopause, dose, formulation and route of administration. Additionally, past pregnancy influences brain aging and cognition as a younger age of first pregnancy in humans is associated with poorer aging outcomes. However, few animal studies have examined specific features of pregnancy history or the possible mechanisms underlying these changes. We examined whether maternal age at first pregnancy and estradiol differentially affected hippocampal neuroplasticity, inflammation, spatial reference cognition, and immediate early gene activation in response to spatial memory retrieval in middle-age. Thirteen-month-old rats (who were nulliparous (never mothered) or previously primiparous (had a litter) at three or seven months) received daily injections of estradiol (or vehicle) for sixteen days and were tested on the Morris Water Maze. An older age of first pregnancy was associated with impaired spatial memory but improved performance on reversal training, and increased number of new neurons in the ventral hippocampus. Estradiol decreased activation of new neurons in the dorsal hippocampus, regardless of parity history. Estradiol also decreased the production of anti-inflammatory cytokines based on age of first pregnancy. This work suggests that estradiol affects neuroplasticity and neuroinflammation in middle age, and that age of first pregnancy can have long lasting effects on hippocampus structure and function.

Linking menopause-related factors, history of depression, APOE ε4, and proxies of biological aging in the UK biobank cohort

In a subset of females, postmenopausal status has been linked to accelerated aging and neurological decline. A complex interplay between reproductive-related factors, mental disorders, and genetics may influence brain function and accelerate the rate of aging in the postmenopausal phase. Using multiple regressions corrected for age, in this preregistered study we investigated the associations between menopause-related factors (i.e., menopausal status, menopause type, age at menopause, and reproductive span) and proxies of cellular aging (leukocyte telomere length, LTL) and brain aging (white and gray matter brain age gap, BAG) in 13,780 females from the UK Biobank (age range 39–82). We then determined how these proxies of aging were associated with each other, and evaluated the effects of menopause-related factors, history of depression (= lifetime broad depression), and APOE ε4 genotype on BAG and LTL, examining both additive and interactive relationships. We found that postmenopausal status and older age at natural menopause were linked to longer LTL and lower BAG. Surgical menopause and longer natural reproductive span were also associated with longer LTL. BAG and LTL were not significantly associated with each other. The greatest variance in each proxy of biological aging was most consistently explained by models with the addition of both lifetime broad depression and APOE ε4 genotype. Overall, this study demonstrates a complex interplay between menopause-related factors, lifetime broad depression, APOE ε4 genotype, and proxies of biological aging. However, results are potentially influenced by a disproportionate number of healthier participants among postmenopausal females. Future longitudinal studies incorporating heterogeneous samples are an essential step towards advancing female health.

Magnitude and Temporal Variations of Socioeconomic Inequalities in the Quality of Life After Early Breast Cancer: Results From the Multicentric French CANTO Cohort.

Socioeconomic status (SES) influences the survival outcomes of patients with early breast cancer (EBC). However, limited research investigates social inequalities in their quality of life (QoL). This study examines the socioeconomic inequalities in QoL after an EBC diagnosis and their time trends. We used data from the French prospective multicentric CANTO cohort (ClinicalTrials.gov identifier: NCT01993498), including women with EBC enrolled between 2012 and 2018. QoL was assessed using the European Organisation for Research and Treatment of Cancer QoL Core 30 questionnaire (QLQ-C30). summary score at diagnosis and 1 and 2 years postdiagnosis. We considered three indicators of SES separately: self-reported financial difficulties, household income, and educational level. We first analyzed the trajectories of the QLQ-C30 summary score by SES group. Then, social inequalities in QLQ-C30 summary score and their time trends were quantified using the regression-based slope index of inequality (SII), representing the absolute change in the outcome along socioeconomic gradient extremes. The analyses were adjusted for age at diagnosis, Charlson Comorbidity Index, disease stage, and type of local and systemic treatment. Among the 5,915 included patients with data on QoL at diagnosis and at the 2-year follow-up, social inequalities in QLQ-C30 summary score at baseline were statistically significant for all SES indicators (SIIfinancial difficulties = -7.6 [-8.9; -6.2], SIIincome = -4.0 [-5.2; -2.8]), SIIeducation = -1.9 [-3.1; -0.7]). These inequalities significantly increased (interaction P < .05) in year 1 and year 2 postdiagnosis, irrespective of prediagnosis health, tumor characteristics, and treatment. Similar results were observed in subgroups defined by menopausal status and type of adjuvant systemic treatment. The magnitude of preexisting inequalities in QoL increased over time after EBC diagnosis, emphasizing the importance of considering social determinants of health during comprehensive cancer care planning.

Abstract PO2-09-12: The magnitude and temporal variations of socioeconomic inequalities in quality of life after early breast cancer: results from the multicentric French CANTO cohort

Abstract Objective Previous studies showed that various outcomes in patients with early breast cancer (EBC), from incidence to survival, were influenced by social factors. However, there is limited research on the socioeconomic inequalities in quality of life (QoL) after treatment for EBC, and the magnitude and changes over time of these inequalities have not been quantified. This study examines the socioeconomic inequalities in QoL and their time trends among a large cohort of patients with EBC. Methods We conducted a comprehensive longitudinal analysis using data from the prospective multicentric CANTO study (CANcer TOxicity, NCT01993498), which included participants with EBC enrolled between 2012 and 2018. QoL was assessed using the summary score of the EORTC QLQ-C30 questionnaire at the time of diagnosis and 1 and 2 years post-diagnosis. We included patients with complete QoL data at diagnosis and 2 years post-diagnosis. Analyses were conducted for three indicators of socioeconomic status separately: self-reported financial difficulties, household income and educational level. We first analyzed trajectories of QoL by socioeconomic status from diagnosis to Year 1 and Year 2. Then, social inequalities in QoL were estimated using the regression-based slope indexes of inequality (SII) and compared across the follow-up periods. The SII represents the absolute change in the QLQ-C30 summary score along the two extremes of the socioeconomic gradient, taking into account the intermediate groups and their relative sizes. The analyses were adjusted for age at diagnosis, Charlson comorbidity index, disease stage, use and type of endocrine therapy, use and type of chemotherapy, breast surgery, radiotherapy use, and lymph node management. Results In the 5915 analyzed patients, compared to those with higher socioeconomic status, those reporting a high level of financial difficulty, lower income, or lower education were younger, most often premenopausal, with comorbidities, diagnosed with stage III BC, and treated with mastectomy and axillary lymph node dissection. There were no differences between socioeconomically-defined groups concerning BC histology, grade and IHC-defined subtype. Social inequalities in QoL at baseline were statistically significant for all socioeconomic status indicators (SIIfinancial difficulties = -7.6 [-8.9;-6.2], SIIincome= -4.0 [-5.2;-2.8]) and SIIeducation= -1.9 [-3.1;-0.7]). In multivariable analyses, social inequalities significantly increased (interaction p&amp;lt; 0.05) in Year 1 (SIIfinancial difficulties = -11.1 [-12.8;-9.4], SIIincome= -6.5 [-8.0;-5.0] and SIIeducation= -5.0 [-6.6;-3.5]) and Year 2 (SIIfinancial difficulties = -10.7 [-12.2;-9.1], SIIincome= -6.7 [-8.0;-5.3] and SIIeducation= -4.7 [-6.1;-3.3]) suggesting a widening socioeconomic gap in QoL outcomes irrespective of pre-diagnosis health, tumor characteristics and treatment. Similar results were observed in subgroups defined by menopausal status (pre/postmenopausal) and type of systemic treatment (chemotherapy, endocrine therapy). Conclusion Our study highlights and quantifies the association of several individual socioeconomic indicators with the QoL of patients with EBC in France. The magnitude of socioeconomic inequalities in QoL increased over time after EBC diagnosis in a country with a strong welfare system and universal healthcare coverage. In the era of precision medicine, these results underscore the importance of developing interventions to improve precision care, considering the conditions in which people are born, grow, work, live and age and the wider set of forces and systems shaping the conditions of daily life. Citation Format: José Luis Sandoval, Antonio Di Meglio, Arlindo Ferreira, Maria Alice Franzoi, Fabrice André, Barbara Pistilli, Christelle Jouannaud, Marion Fournier, Philippe Rouanet, Asma Dhaini Mermeche, Paul Cottu, Sibille Everhard, Anne-Laure Martin, Silvia Stringhini, Idris Guessous, Ines Vaz Luis, Gwenn Menvielle. The magnitude and temporal variations of socioeconomic inequalities in quality of life after early breast cancer: results from the multicentric French CANTO cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-09-12.

Association of muscle disorders in late postmenopausal women according to the type of experienced menopause.

Musculoskeletal disorders frequently affect postmenopausal women. This study aims to compare muscle disorders between women according to the type of experienced menopause: premature (PM) or normal age of menopause (NAM). This was a cross-sectional study conducted in nine Latin American countries in which late postmenopausal women (55 to 70 years) were surveyed with a general questionnaire, the Menopause Rating Scale (MRS: item #4 exploring musculoskeletal discomfort), and strength, assistance with walking, rising from a chair, climbing stairs, and falling questionnaire (risk of sarcopenia). A total of 644 women were included: 468 who had NAM, and 176 who had PM (116 spontaneous and 60 surgical). The overall mean age of the participants was 60.9 ± 4.2 years. Women who had PM experienced more musculoskeletal discomfort (33.5% vs 20.9%, P < 0.001) and a higher likelihood of sarcopenia (35.2% vs 19.9%, P < 0.001) than women who had a NAM. Women who had surgical PM exhibited a higher prevalence of severe musculoskeletal discomfort (46.7% vs 29.3%, P < 0.02) and a higher likelihood of sarcopenia (45.0% vs 27.6%, P < 0.02) than women who had a NAM. After adjusting for covariates (age, body mass index, menopausal hormone therapy use, physical activity, education, cigarette consumption, use of antidepressants, sexual activity, comorbidities, and having a partner), our logistic regression model determined that spontaneous PM was not associated with higher odds of musculoskeletal discomfort and higher odds of sarcopenia. On the other hand, women who had surgical PM were more likely to experience musculoskeletal discomforts (odds ratio: 2.26; 95% confidence interval: 1.22-4.17) and higher odds for sarcopenia (odds ratio: 2.05; 95% confidence interval: 1.16-3.65) as compared to women who experienced a NAM. Women experiencing surgical PM have a higher likelihood of developing muscle disorders. This underscores the potential significance of hormonal levels in influencing musculoskeletal health during postmenopause.

Abstract 1072: The EsomiR project: A case control study to assess the role of exosomal miRNAs in breast cancer cancerogenesis

Abstract Introduction: One of the unmet needs in Breast Cancer (BC) prevention is how to identify women at higher risk of developing this disease, who might benefit from periodic surveillance and/or from chemoprevention. The goal of this retrospective study is to assess the role miRNAs isolated from extracellular vesicles (EV-miRNAs) as possible early biomarkers for identifying patients with higher risk of developing BC, in order to personalize their screening programme. To this goal, EV-miRNAs from cyst fluid derived from women with Gross Cyst Disease of the Breast (GCDB - a benign disease of the mammary gland associated with a 2-4-fold increase in the risk of developing BC) have been analysed. Methodology: Cyst fluids have been selected among samples from a cohort of 600 patients diagnosed with GCDB between 1985 and 1993, some of whom developed BC during follow-up. EV-miRNAs have been extracted from cyst fluid using the exoRNeasy midi kit (Qiagen), qualitatively evaluated by Bioanalyzer (Agilent) and quantified by Qubit™ using the microRNA Assay Kit (Thermo Fisher Scientific). The MiRNome profiles have been assessed by microarray using an optimised protocol on Agilent platform (labelling and hybridization on SurePrint Human miR Microarrays 8 × 60 K and images acquisition by G2565CA scanner). Results: A total of 117 samples (58 cases and 59 controls, paired on the bases of clinical and pathological variables) have been analysed. Single variable logistic regression analysis on the most expressed EV-miRNAs (logFC &amp;gt;= 6 (n=329)), selected six EV-miRNAs (miR-6076, miR-202-3p, miR-6872-3p, miR-769-3p, miR-5195-3p, miR-4443) and one (miR-4713-3p) negatively and positively associated with BC development, respectively (raw p-value &amp;lt;0.05). A risk score combining the seven EV-miRNAs was derived by multivariable logistic regression modelling and reported an AUC=0.73 (95% [CI] 0.6427-0.8231). The model was refined including clinical variables and applying step-wise logistic regression analysis. The combination of 3 EV-miRNAs (miR-6076, miR-6872-3p, miR-5195-3p) with menopausal status, familiarity and type of cyst yielded an AUC of 0.8 (95% [CI] 0.7015-0.8847). Logistic regression was also performed on Type I cysts (n=78), that are correlated with a higher risk of developing BC, pointing in evidence 3 EV-miRNAs with a negative (miR-6076, miR-6872-3p) or positive (miR-4515) correlation with BC development risk (AUC = 0.74, 95% [CI] 0.6278-0.8475). In the model comprehensive of clinical variables, two of those EV-miRNAs (miR-6872-3p, miR-4515) together with familiarity and menopausal status were selected, giving an AUC of 0.8 (95% [CI] 0.6961-0.8991). Conclusion: This study allowed the identification of a EV-miRNA-based BC risk signature obtained by liquid biopsy on cyst fluid. The final purpose of this project is to transfer this signature in the clinic by testing it prospectively on plasma samples. Citation Format: Barbara Cardinali, Patrizia Piccioli, Francesco Boccardo, Alessandra Rubagotti, Linda Zinoli, Andrea Sciutto, Simona Coco, Giovanna Chiorino, Paola Ostano, Emir Sehovic, Zita Cavalieri, Cristina Bruzzo, Silvia Marconi, Roberta Tasso, Rodolfo Quarto, Davide Ceresa, Paolo Malatesta, Lucia Del Mastro. The EsomiR project: A case control study to assess the role of exosomal miRNAs in breast cancer cancerogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1072.

Age at natural or surgical menopause, all-cause mortality, and lifespan among postmenopausal women in the United States.

This study investigated the association of age at natural menopause with or without undergoing hysterectomy and/or bilateral oophorectomy after menopause and age at surgical menopause with all-cause mortality and lifespan in postmenopausal women. The data stemmed from the National Health and Nutrition Examination Survey (NHANES) (1999-2018) and NHANES III (1988-1994), including 14,161 postmenopausal women over 40. Cox proportional hazard models were used to estimate unadjusted and adjusted hazard ratios (HRs) (95% confidence intervals [CIs]). We also used Cox proportional hazard models with penalized splines to depict the association between continuous age at menopause and all-cause mortality and nonparametric regression with smoothing splines to illustrate the association between age at menopause and lifespan in deceased participants. The adjusted HRs (95% CIs) for age at natural menopause of <40, 40 to 44, and 55+ years in women without undergoing hysterectomy or bilateral oophorectomy after menopause were 1.48 (1.15-1.91), 1.16 (1.00-1.35), and 0.91 (0.77-1.07) compared with age at natural menopause of 45 to 54, respectively. The respective HRs (95% CIs) for age at surgical menopause were 1.39 (1.11-1.75), 1.09 (0.86-1.38), and 0.83 (0.53-1.32). However, no significant association was found between age at natural menopause and all-cause mortality among women undergoing hysterectomy and/or bilateral oophorectomy after menopause. When treated as continuous variables, age at natural menopause without undergoing hysterectomy or bilateral oophorectomy after menopause presented inverse and nonlinear associations with all-cause mortality, whereas age at surgical menopause was linearly inversely associated with all-cause mortality. The association between age at menopause and lifespan was linearly positive regardless of menopausal type. Young age at menopause was associated with increased risks of all-cause mortality. The later menopause age was related to a longer lifespan.

Natural vs. Surgical Postmenopause and Psychological Symptoms Confound the Effect of Menopause on Executive Functioning Domains of Cognitive Experience.

The menopause transition is associated with difficulties in executive function. However, it is unclear whether these difficulties persist past perimenopause. This study investigated whether potential confounders, including natural vs. surgical postmenopause and menopause-related psychological symptoms, influence whether executive dysfunction persists into postmenopause. A cross-sectional sample of women aged 35-65 years (N = 1971) in one of four groups, premenopause, perimenopause, natural postmenopause, and surgical postmenopause, were surveyed. Participants self-reported executive functioning with the Brown Attention Deficit Disorder Scale (BADDS), anxiety symptom severity with the Generalized Anxiety Disorder Questionnaire (GAD-7), and depression symptom severity with the Center for Epidemiologic Studies Depression Scale (CES-D). We analyzed the association between group and BADDS scores using linear regression models - first, by controlling for age, education, and self-reported attention deficit hyperactivity disorder (ADHD) diagnosis (Model #1) and, second, by further controlling for current difficulty sleeping, anxiety, and depression (Model #2). In both models, BADDS scores were significantly elevated (indicating more difficulties in executive function) among women in the perimenopausal and surgical postmenopausal groups compared with those in the premenopausal group. Likewise, the perimenopausal and surgical postmenopausal groups had the highest proportions of participants who reported difficulty sleeping and clinical levels of anxiety and depression. BADDS scores were significantly higher in natural postmenopausal vs. premenopausal women without controlling for difficulty sleeping, anxiety, and depression (Model #1), but not when adjusting for these variables (Model #2). The type of menopause and psychological symptoms are important confounders of the relationship between the menopause transition and executive dysfunction, and help explain whether executive dysfunction persists or recovers in postmenopause.Reprinted from Maturitas 2023; 170:64-73, with permission from Elsevier. Copyright © 2023.

EPIDEMIOLOGIC GEROSCIENCE INNOVATIONS AT THE NEXUS OF REPRODUCTIVE AGING AND WOMEN’S HEALTH

Abstract Signs of reproductive aging in women usually begin in women’s 30s and co-occur with declining circulating estrogen concentrations and irregular menstrual cycle onset. Menopause, defined by cessation in menstruation for ≥1 year, occurs on average at age 51 years, but about 1% experience menopause before age 40. Menopause and reproductive aging contribute to multiple health conditions such as certain cancers; however, a less studied condition is the genitourinary syndrome of menopause (GSM). GSM signs and symptoms include vulvovaginal atrophy, vaginal dryness, urinary tract infections, and more. Additionally, menopause leads to increased risk of osteoporosis, dementia, and other aging-related conditions. Given the multifactorial implications of reproductive aging in women’s health, an interdisciplinary geroscience-guided framework for epidemiology of aging is needed to identify biological contributors and consequences of reproductive aging to develop healthspan-enhancing interventions. In this symposium, we present five new developments across multiple stages of reproductive aging, consistent with meeting theme “Building Bridges. Catalyzing Research. Empowering All Ages”. Among women aged 35-60 years, we assess the role of cervical “inflamm-aging” in GSM; diabetes and vaginal dysbiosis associations with GSM; and vaginal microbial and metabolic signatures of urinary conditions/dysfunction. Among women aged ≥65 years, we examine associations of post-hip fracture sex hormones with physical recovery and links between age and type of menopause with Alzheimer’s disease. Building on the 2021 Journals of Gerontology Series A special issue on intersections of reproductive and aging biology, we discuss opportunities to advance reproductive aging and women’s health research by combining molecular assessment with rigorous epidemiology. This is a collaborative symposium between the Epidemiology of Aging, Geroscience, and Women’s Issues Interest Groups.

Abstract B125: Reproductive factors and thyroid cancer risk: The multiethnic cohort study

Abstract Background : Thyroid cancer is the most common endocrine cancer worldwide, with the incidence in women being three times that of men. Several reproductive and hormonal factors have been proposed as possible contributors to thyroid cancer risk, including age at menarche, parity, age at menopause, oral contraceptive use, surgical menopause, and hormone replacement therapy. Our study aimed to investigate potential reproductive/hormonal factors in a multiethnic population. Methods : A prospective cohort study of women of diverse racial and ethnic groups in the Multiethnic Cohort Study (n=118,344) was used. Included were 373 papillary thyroid cancer cases, linked to SEER cancer incidence and statewide death certificate files in Hawaii and California. Exposures investigated include age at menarche, parity, menopausal status and type, birth control use, and outcomes of first pregnancy. Cox proportional hazards models of papillary thyroid cancer were used to obtain relative risk (RR) and 95% confidence intervals (CI) to examine the associations with reproductive/hormonal factors. Results : We observed a statistically significant increased risk of papillary thyroid cancer for hysterectomy, oophorectomy, surgical menopause, and not having a child by age 20. The adjusted estimates for oophorectomy RR 1.66 (95% CI: 1.31, 2.11) and hysterectomy RR 1.82 (95% CI: 1.42, 2.34). Menopause due to surgery was associated with a 55% increase in risk (RR 1.55, 95% CI: 1.22, 1.97) and nulliparity vs ≤ 20 years of age at first livebirth was related to a 51% increased risk (adjusted RR 1.51, 95% CI: 1.07, 2.15). Adjustment factors included age and race/ethnicity and menopausal status, menopausal type, and oral contraception where appropriate. Former use of estrogen menopausal hormone therapy was associated with a 35% increased risk (adjusted RR: 1.35, 95% CI: 1.02, 1.79). No significant heterogeneity was seen in these associations by race/ethnicity (p het &amp;gt;0.48). Conclusion : The reproductive risk factors for papillary thyroid cancer reported in the literature were largely confirmed in our multiethnic population. Our analysis finds having a hysterectomy or oophorectomy and the use of MHT are associated with an increased risk of papillary thyroid cancer, and having a child at a younger age is associated with a reduction in thyroid cancer risk. Citation Format: Janine V. Abe, Song-Yi Park, Christopher A. Haiman, Loïc Le Marchand, Brenda Y. Hernandez, Lynne R. Wilkens. Reproductive factors and thyroid cancer risk: The multiethnic cohort study [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B125.

Association of Infertility With Type and Timing of Menopause: A Prospective Cohort Study

(Abstracted from Hum Reprod 2023;38(9):1843–1852) Up to 25% of women experience infertility in their lifetime, with a variety of possible causes including dysfunction in the endocrine system, immune system, or reproductive anatomic structures. Research has found that infertility is associated with propensity for poor health outcomes later in life, including reproductive cancer, cardiovascular disease, stroke, and diabetes mellitus.

Elevated gonadotropin levels are associated with increased biomarker risk of Alzheimer's disease in midlife women.

In preclinical studies, menopausal elevations in pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), trigger Alzheimer's disease (AD) pathology and synaptic loss in female animals. Herein, we took a translational approach to test whether gonadotropin elevations are linked to AD pathophysiology in women. We examined 191 women ages 40-65 years, carrying risk factors for late-onset AD, including 45 premenopausal, 67 perimenopausal, and 79 postmenopausal participants with clinical, laboratory, cognitive exams, and volumetric MRI scans. Half of the cohort completed 11C-Pittsburgh Compound B (PiB) amyloid-β (Aβ) PET scans. Associations between serum FSH, LH and biomarkers were examined using voxel-based analysis, overall and stratified by menopause status. Associations with region-of-interest (ROI) hippocampal volume, plasma estradiol levels, APOE-4 status, and cognition were assessed in sensitivity analyses. FSH levels were positively associated with Aβ load in frontal cortex (multivariable adjusted P≤0.05, corrected for family wise type error, FWE), an effect that was driven by the postmenopausal group (multivariable adjusted PFWE ≤ 0.044). LH levels were also associated with Aβ load in frontal cortex, which did not survive multivariable adjustment. FSH and LH were negatively associated with gray matter volume (GMV) in frontal cortex, overall and in each menopausal group (multivariable adjusted PFWE ≤ 0.040), and FSH was marginally associated with ROI hippocampal volume (multivariable adjusted P = 0.058). Associations were independent of age, clinical confounders, menopause type, hormone therapy status, history of depression, APOE-4 status, and regional effects of estradiol. There were no significant associations with cognitive scores. Increasing serum gonadotropin levels, especially FSH, are associated with higher Aβ load and lower GMV in some AD-vulnerable regions of midlife women at risk for AD. These findings are consistent with preclinical work and provide exploratory hormonal targets for precision medicine strategies for AD risk reduction.