Natural Menopause Research Articles

Associations between childhood adversity and age at natural menopause.

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. 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. 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). 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.

Factors predicting age at menopause among Iranian women in the Bandare-Kong cohort study (a cross-sectional survey of PERSIAN cohort study)

BackgroundMenopause is a natural period in women’s life and can be affected by several factors. The aim of this study was to identify the associated factors for age of natural menopause and among women with early and premature menopause based on a cohort study in Iran.MethodsThis population-based study was conducted on 894 post menopause women between 35 and 70 years old who participated in the Bandare-Kong Non-Communicable Diseases (BKNCD) Cohort Study, a part of Prospective Epidemiological Research Studies in Iran (PERSIAN) from March 2016 to February 2019. All women completed a standard self-reported questionnaire. Data were analyzed using chi-square test, independent t test, and ANOVA as well as a multivariable linear regression model.ResultsThe mean age at natural menopause was 48.31 ± 6.34 years. After adjusting other variables, gravida, history of cardiac disease, socioeconomic status and residence status were predictive of age at menopause (P < 0.001). Among the premature menopause group, the mean age at menopause was significantly higher among women with diabetes compared to women without diabetes group (35.68 ± 2.92 vs. 33.82 ± 3.06; P = 0.043), while the mean age at menopause was significantly lower in women with infertility compared to women without infertility (29.13 ± 5.22 vs. 34.84 ± 2.826; P = 0.048).ConclusionsThis study suggests that the predictors of menopausal age differed in women with premature menopause compared to overall menopause age. Prospective studies are needed to evaluation the effects of these factors on menopausal age.

Reproductive factors in the risk of bladder cancer and upper urinary tract cancer: The Japan Public Health Center-based Prospective Study.

Reproductive factors are hypothesized to play a role in the incidence of bladder cancer (BC) and upper urinary tract cancer (together, urothelial cancer (UC)). However, evidence regarding these associations is limited, particularly in Asian populations. We analyzed data from 55,882 females aged 40-69 years, and performed Cox proportional hazards regression analyses with three types of adjustment, namely age; reproductive factor of interest and covariates in addition to age (conventional model); and other reproductive factors in addition to the multivariable adjusted model (reproductive model). During an average of 20.2 years of follow-up, 194 UC cases (145 BC cases and 49 UUTC cases) were identified. Early age at natural menopause (<44 years, compared to 49-51 years) increased BC risk in the reproductive model (HR=2.09 (95% CI=1.04-4.20)). An association between UC/BC and age at menopause, including both natural and surgical/induced, was significant in the reproductive model [HR=1.74 (95% CI=1.09-2.77), and HR=1.94 (95% CI=1.15-3.28), respectively]. Early age at natural menopause was suggested to increase UC risk in the reproductive model (HR=1.78 (95% CI=0.93-3.42)). Our findings suggest a significant association between age at menopause and incidence of UC/BC among Asian populations. This study aids understanding the role of reproductive factors in UC/BC incidence. In Japanese populations, age at menopause is suggested to be associated with UC/BC incidence, especially regarding early natural menopause.

Quality of life in heterosexual menopausal women: The indirect effect of sexual and marital satisfaction, menopause representations, and psychological morbidity

Menopause may negatively impact Quality of Life (QoL). Our study used a cross-sectional design and research participants were 99 women in natural menopause. In our study, we analyzed the relationship between age at menopause onset, hormone therapy use, duration of couple relationship, menopause duration, psychological morbidity, marital satisfaction, menopause representations, and QoL following the Wilson and Cleary Health-Related QoL conceptual model. The authors found that negative representations, lower marital satisfaction, psychological morbidity, and shorter duration of menopause contributed to lower QoL. Moreover, the authors found that psychological morbidity and menopause representations (identity and control/cure dimensions) had an indirect effect between marital satisfaction and vasomotor, psychosocial, and sexual QoL. Also, we found that age at the onset of menopause showed a moderating effect in the final model. Future studies should replicate these results in a longitudinal design and analyze how the variables that showed a moderating role and indirect effects will function as moderators and mediators, respectively, over time.

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.

Reproductive period duration and cognitive function in postmenopausal Latina women in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

A shorter reproductive period, a marker of estrogen exposure, has been related to cognitive impairment among older (>65years) non-Hispanic White women. We explored whether reproductive period duration, age at menarche, and age at menopause are related to cognitive function among postmenopausal Hispanic/Latina women. This cross-sectional analysis used baseline (Visit 1: 2008-2011) data from 3630 postmenopausal women in the Hispanic Community Health Study/Study of Latinos. Reproductive period duration, age at menarche, and age at menopause were assessed by self-report. Cognitive function variables included global cognition, verbal learning, memory, verbal fluency, and processing speed. Associations between each reproductive event and cognitive function were examined using multivariable linear and logistic regression analyses accounting for the complex survey design of the study and adjusting for socio-demographics, parity, and cardiovascular risk factors. We assessed whether associations differed by type of menopause (natural versus surgical) and hormone therapy use. The study population was on average aged 59years, with a mean reproductive period duration of 35years. Older age at menopause and a longer reproductive period were related to higher verbal learning (β=0.04, SE=0.02; p<0.05) and processing speed (ß=0.16, SE=0.04; p<0.001); associations were more pronounced for women with natural menopause. Older age at menarche was associated with lower scores on the digit symbol substitution test (ß=-0.62, SE=0.15; p<0.0001). There were no associations with global cognition. Among postmenopausal Hispanic/Latinas, a longer reproductive period was related to more favorable cognitive measures of verbal learning and processing speed. Our findings support the hypothesis that greater lifetime exposure to estrogens may be associated with higher cognitive performance.

Genetic liability to multiple factors and uterine leiomyoma risk: a Mendelian randomization study.

Uterine leiomyoma is the most common benign tumor in females of reproductive age. However, its causes have never been fully understood. The objective of our study was to analyze the causal association between various factors and uterine leiomyoma using Mendelian randomization (MR). Genetic variables associated with risk factors were obtained from genome-wide association studies. Summary-level statistical data for uterine leiomyoma were obtained from FinnGen and the UK Biobank (UKB) consortium. We used inverse variance weighted, MR-Egger, and weighted median methods in univariate analysis. Multivariable MR analysis was used to identify independent risk factors. A fixed-effect model meta-analysis was used to combine the results of the FinnGen and UKB data. In the FinnGen data, higher genetically predicted age at natural menopause, systolic blood pressure (SBP), diastolic blood pressure (DBP), and fasting insulin were associated with an increased risk of uterine leiomyoma, while higher age at menarche was associated with a reduced risk of uterine leiomyoma. Multivariable MR analysis of SBP and DBP showed that higher DBP might be an independent risk factor of uterine leiomyoma. In the UKB data, the results for age at natural menopause, SBP, DBP, and age at menarche were replicated. The result of the meta-analysis suggested that uterine leiomyoma could also be affected by polycystic ovary syndrome (PCOS), endometriosis, and 2-hour glucose level. Our MR study confirmed that earlier menstrual age, hypertension, obesity, and elevated 2-hour glucose post-challenge were risk factors for uterine leiomyoma, and the causal relationship between smoking and uterine leiomyoma was ruled out. In addition, later age of menopause and endometriosis were found to increase the risk of uterine leiomyoma, while PCOS was found to decrease the risk.

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

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. 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. 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. 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.

Molecular mechanisms regulating natural menopause in the female ovary: a study based on transcriptomic data.

Natural menopause is an inevitable biological process with significant implications for women's health. However, the molecular mechanisms underlying menopause are not well understood. This study aimed to investigate the molecular and cellular changes occurring in the ovary before and after perimenopause. Single-cell sequencing data from the GTEx V8 cohort (30-39: 14 individuals; 40-49: 37 individuals; 50-59: 61 individuals) and transcriptome sequencing data from ovarian tissue were analyzed. Seurat was used for single-cell sequencing data analysis, while harmony was employed for data integration. Cell differentiation trajectories were inferred using CytoTrace. CIBERSORTX assessed cell infiltration scores in ovarian tissue. WGCNA evaluated co-expression network characteristics in pre- and post-perimenopausal ovarian tissue. Functional enrichment analysis of co-expression modules was conducted using ClusterprofileR and Metascape. DESeq2 performed differential expression analysis. Master regulator analysis and signaling pathway activity analysis were carried out using MsViper and Progeny, respectively. Machine learning models were constructed using Orange3. We identified the differentiation trajectory of follicular cells in the ovary as ARID5B+ Granulosa -> JUN+ Granulosa -> KRT18+ Granulosa -> MT-CO2+ Granulosa -> GSTA1+ Granulosa -> HMGB1+ Granulosa. Genes driving Granulosa differentiation, including RBP1, TMSB10, SERPINE2, and TMSB4X, were enriched in ATP-dependent activity regulation pathways. Genes involved in maintaining the Granulosa state, such as DCN, ARID5B, EIF1, and HSP90AB1, were enriched in the response to unfolded protein and chaperone-mediated protein complex assembly pathways. Increased contents of terminally differentiated HMGB1+ Granulosa and GSTA1+ Granulosa were observed in the ovaries of individuals aged 50-69. Signaling pathway activity analysis indicated a gradual decrease in TGFb and MAPK pathway activity with menopause progression, while p53 pathway activity increased. Master regulator analysis revealed significant activation of transcription factors FOXR1, OTX2, MYBL2, HNF1A, and FOXN4 in the 30-39 age group, and GLI1, SMAD1, SMAD7, APP, and EGR1 in the 40-49 age group. Additionally, a diagnostic model based on 16 transcription factors (Logistic Regression L2) achieved reliable performance in determining ovarian status before and after perimenopause. This study provides insights into the molecular and cellular mechanisms underlying natural menopause in the ovary. The findings contribute to our understanding of perimenopausal changes and offer a foundation for health management strategies for women during this transition.

Comparison of plasma oxytocin level in women with natural and surgical menopause.

We aimed to investigate plasma oxytocin level in women with natural and surgical menopause and its relation with other metabolic parameters. This study included 89 postmenopausal women admitted to menopausal outpatient clinics and gave written consent to participate. Participants were allocated into natural (Group 1; n = 61) and surgical (Group 2; n = 28) menopause groups based on causative process for the onset of menopause. After the clinical evaluation and physical examination, blood samples are collected for biochemical profile and plasma oxytocin levels. The complete blood count, lipid profile, thyroid panel, blood glucose concentration, vitamin D and liver enzymes were measured by autoanalyzer, plasma oxytocin level was measured spectrophotometrically by ELISA method. The groups were comparable for age, body mass index, menopause duration, gravity and blood parameters measured except significantly different plasma oxytocin levels between the two groups as 6.8 (3.2-20.6) ng/ml in natural menopause group and 4.2 (2.9-18.2) ng/ml in surgical menopause group (p < 0.001). Plasma oxytocin level was also negatively correlated with age (r = -0.245, p = 0.022) and menopausal duration (r = -0.275, p = 0.01). Our results point out that oxytocin might be a target hormone to manage menopause associated disorders and/or it should be considered for its role in the differences in the incidences of postmenopausal diseases and quality of life in the course of natural and surgical menopausal transition.

Association of infertility with type and timing of menopause: a prospective cohort study.

What is the association between past infertility and the type and timing of menopause in midlife women? Women with a history of infertility were more likely to experience surgical menopause overall and had elevated risk of earlier surgical menopause until age 43 years but experienced no differences in the timing of natural menopause. Infertility is experienced by 12-25% of women and is thought to reveal a propensity for poor health outcomes, such as chronic illness, later in life. However, little is known about whether infertility is linked with characteristics of the menopausal transition as women age, despite possible shared underlying pathways involving ovarian function and gynecologic disease. Secondary analysis of a prospective cohort study of 13 243 midlife females recruited in Phase 1 of the Alberta's Tomorrow Project (Alberta, Canada) and followed approximately every 4 years (2000-2022). Data were collected through standardized self-report questionnaires. History of infertility, defined as ever trying to become pregnant for more than 1 year without conceiving, was measured at baseline. Menopause characteristics were measured at each study follow-up. Menopause type was defined as premenopause, natural menopause, surgical menopause (bilateral oophorectomy), or indeterminate menopause (premenopausal hysterectomy with ovarian conservation). Timing of natural menopause was defined as the age at 1 full year after the final menstrual period, and timing of surgical and indeterminate menopause was defined as the age at the time of surgery. We used flexible parametric survival analysis for the outcome of menopause timing with age as the underlying time scale and multinomial logistic regression for the outcome of menopause type. Multivariable models controlled for race/ethnicity, education, parity, previous pregnancy loss, and smoking. Sensitivity analyses additionally accounted for birth history, menopausal hormone therapy, body mass index, chronic medical conditions, and age at baseline. Overall, 18.2% of women reported a history of infertility. Past infertility was associated with earlier timing of surgical menopause exclusively before age 43 years (age 35: adjusted hazard ratio 3.13, 95% CI 1.95-5.02; age 40: adjusted hazard ratio 1.83, 95% CI 1.40-2.40; age 45: adjusted hazard ratio 1.13, 95% CI 0.87-1.46) as well as greater odds of experiencing surgical menopause compared to natural menopause (adjusted odds ratio 1.40, 95% CI 1.18-1.66). Infertility was not associated with the timing of natural or indeterminate menopause. Information on the underlying cause of infertility and related interventions was not collected, which precluded us from disentangling whether associations differed by infertility cause and treatment. Residual confounding is possible given that some covariates were measured at baseline and may not have temporally preceded infertility. Women with a history of infertility were more likely to experience early surgical menopause and may therefore benefit from preemptive screening and treatment for gynecologic diseases to reduce bilateral oophorectomy, where clinically appropriate, and its associated health risks in midlife. Moreover, the lack of association between infertility and timing of natural menopause adds to the emerging knowledge that diminishing ovarian reserve does not appear to be a primary biological mechanism of infertility nor its downstream implications for women's health. Alberta's Tomorrow Project is only possible due to the commitment of its research participants, its staff and its funders: Alberta Health, Alberta Cancer Foundation, Canadian Partnership Against Cancer and Health Canada, and substantial in-kind funding from Alberta Health Services. The views expressed herein represent the views of the author(s) and not of Alberta's Tomorrow Project or any of its funders. This secondary analysis is funded by Project Grant Priority Funding in Women's Health Research from the Canadian Institutes of Health Research (Grant no. 491439). N.V.S. is supported by a Banting Postdoctoral Fellowship from the Canadian Institutes of Health Research. H.K.B. is supported by the Canada Research Chairs Program. E.A.B. is supported by an Early Career Investigator Award in Maternal, Reproductive, Child and Youth Health from the Canadian Institutes of Health Research. A.K.S. has received honoraria from Pfizer, Lupin, Bio-Syent, and Eisai and has received grant funding from Pfizer. N.V.S., H.K.B., and E.A.B. have no conflicts of interest to report. N/A.

Association between Menopause, Postmenopausal Hormone Therapy and Metabolic Syndrome.

(1) Background: We aimed to explore the associations between menopause, postmenopausal hormone therapy, and metabolic syndrome in a large community-based group of Asian women. (2) Methods: This is a cross-sectional study in which we enrolled women aged 30 to 70 years with sufficient information about menopausal status from the Taiwan Biobank. The definition for metabolic syndrome used in this study aligns with the Bureau of Health Promotion's (Taiwan) proposed definition. (3) Results: A total of 17,460 women were recruited. The postmenopausal group had a higher metabolic syndrome prevalence (30% vs. 14%) and 1.17 times higher odds ratio (OR) than the premenopausal group (95% confidence interval [CI] = 1.02 to 1.33). Regarding the types of menopause, surgical menopause was associated with metabolic syndrome (OR = 1.40; 95% CI = 1.20 to 1.63); however, natural menopause was not associated with metabolic syndrome. Interestingly, postmenopausal hormone therapy was associated with a lower risk of metabolic syndrome in the women with natural menopause (OR = 0.79; 95% CI = 0.70 to 0.89), but not in those with surgical menopause. (4) Conclusions: Our results suggest that menopause is associated with an increased prevalence of metabolic syndrome, while postmenopausal hormone therapy is associated with a lower prevalence of metabolic syndrome in women with natural menopause.

Frequency of Thyroid Disorder in Pre- and Postmenopausal Women and Its Association With Menopausal Symptoms.

Background Thyroid hormone has a significant effect on women's life. Its dysfunction is widespread, particularly among women over 50. Understanding how thyroid disease's clinical symptoms change with aging is crucial when treating peri-and postmenopausal women. Considering that 30% of India's population is female, the thyroid disease epidemic appears to affect Indian women more than any other ailment. Therefore, the main aim of the study was the detection of the frequency of thyroid disorder in pre and postmenopausal women and its association with menopausal symptoms. Methodology An analytical cross-sectional study was conducted at a tertiary care centre. All premenopausal and postmenopausal women attending the obstetrics and gynaecology department above 40 years of age, achieving natural menopause, and willing to participate were included in the study. Results A total of 150 women above 40 years of age were included in the study out of which 61 females were premenopausal age and 89 females were postmenopausal age. It was found that 53.3% were euthyroid, 13.3% had hypothyroidism, 3.4% had hyperthyroid, 23.3% had subclinical hypothyroidism, and 6.7% had subclinical hyperthyroidism. Menopausal symptoms when compared to thyroid disorder demonstrated that somatic symptoms did not differ significantly across different thyroid disorder, psychological symptoms consisting of depressive mood was more prevalent among hypothyroid and hyperthyroid female (P<0.05), and urogenital symptoms consisting of sexual problems and bladder dysfunction did not differ significantly (P>0.05) in different thyroid disorder. Conclusion The present study concludes that thyroid disorder is common among pre- and postmenopausal age group women. Therefore, timely detection and intervention should be taken into consideration, and even if the thyroid level is found to be normal still lifestyle modification and counselling can help in improving the quality of life.

P-676 Bone health in Australian women with early menopause: a 23-year longitudinal analysis

Abstract Study question What is the frequency of osteoporosis, fractures, and osteoporosis management in women with early menopause (menopause &amp;lt;45years; EM)? What factors influence osteoporosis, screening, and treatment? Summary answer Osteoporosis risk is 80% higher in women with early versus natural age menopause. Despite higher screening and treatment, gaps persist in managing EM bone health. What is known already A treatment gap in osteoporosis care exists, with low diagnosis (using dual X-ray absorptiometry, DXA), and primary or secondary fracture prevention. Women with EM have increased rates of osteoporosis. Clinical guidelines recommend screening with DXA and menopause hormone therapy (MHT) for most women with EM to reduce osteoporosis and fracture risk. However, studies suggest osteoporosis knowledge, guideline uptake and management adherence by clinicians and women is limited. Study design, size, duration The Australian Longitudinal Study on Women’s Health is a prospective longitudinal study of Australian women. This study uses the cohort of women born between 1946 – 1951, surveyed nine times between 1996 – 2019. Data from Australian administrative health records including the Pharmaceutical Benefits Scheme (PBS) (MHT, Bone specific agents; BSA) and Medicare benefits schedule (DXA) was linked to survey data. Participants/materials, setting, methods Respondents with self-reported age of menopause were included. EM defined as above. T-test/chi-square used for comparisons at baseline (p &amp;lt; 0.05 indicates significance). Generalised estimating equations (GEE) for panel data explored longitudinal outcomes of osteoporosis, fractures, DXA rates, MHT use and BSA (in women with osteoporosis/fracture). Univariable regression was performed, and variables retained where p &amp;lt; 0.2, to form the multivariable model, and bootstrapping with 100 repetitions at 95% sampling of the original dataset to ensure robustness of results. Main results and the role of chance 8,603 women were included: 610 (7.1%) with EM. Mean (SD) baseline age was 47.6 (1.45) years in the entire cohort, and mean (SD) age of menopause was 38.2 (7.95) and 51.3 (3.04) years in women with EM and natural age menopause, respectively (P &amp;lt; 0.001). Overall, 421 (69.0%) women with EM had DXA screening, 305 (50%) had a fracture/osteoporosis, 474 ever used MHT (77.7%) and 142 (46.6%) used BSA. Using the multivariable model, women with EM had increased risk of osteoporosis (Odds Ratio (OR) 1.80; 95%CI 1.43,2.26), fractures (OR 1.48; 1.18,1.85), MHT use (OR 6.98; 5.78,8.43) and BSA use (OR 1.69; 1.24,2.32). In EM women, increasing age was associated with greater risk of osteoporosis / fracture (OR 1.09; 1.08,1.11), and MHT use did not significantly reduce this risk (OR 0.78; 0.55,1.11). In EM women, age (OR 1.32; 1.12,1.15), BMI (OR 0.94; 0.91,0.96), current smoking (OR 0.51; 0.35,0.74) and inner (OR 0.69; 0.52,0.91) or outer regional (OR 0.66; 0.46,0.95) residential location were associated with DXA screening. In EM women, increasing age (OR 1.15; 1.13,1.18) and lower BMI (OR 0.91; 0.86,0.95) were associated with BSA use. Limitations, reasons for caution Survey data were self-reported by participants, and fracture questions were not included in the 2001 survey. PBS data was only available from 2004, and hospital admissions data for all of Australia was only available from 2007. Wider implications of the findings Osteoporosis and fractures affect a significant number of women with EM. Focus must be made on improving screening and treatment of these women. Trial registration number N/A

P-477 Bidirectional association between ovarian reserve and spontaneous miscarriage: findings from the clinical IVF data to epidemiological evidence and genetic links

Abstract Study question To determine whether the association between ovarian reserve and spontaneous miscarriage risk is bidirectional and caused by shared genetic risk loci. Summary answer Bidirectional association between ovarian reserve and spontaneous miscarriage was observed. This may be attributed to five shared risk genes (SYCP2L, TP63, GSPT1, RIF1, and PRRC2A). What is known already Previous studies have shown that women with lower serum anti-Müllerian hormone (AMH) had an increased risk of embryo aneuploidy or spontaneous miscarriage risk, compared to women with higher AMH concentration, although not all studies agree. The most recent meta-analysis postulated that the association between diminished ovarian reserve (DOR) and miscarriage may be not causal, but that the two occurrences merely share a common cause, such as other systematic clinical conditions or past exposure. Inspired by this hypothesis, we conducted the present analyses to clarify this bidirectional association between DOR and miscarriage and further elucidate plausible mechanisms by using genetic data. Study design, size, duration There were four data sources. 1) The Clinical IVF data were retrospectively collected from an academically affiliated Reproductive Medicine Center (17,786 cycles included). 2) We further analyzed data from the UK Biobank (UKB) which is a large-scale, population-based, prospective cohort study (35,316 white women included). 3) The GWAS summary statistics for age at natural menopause (ANM) and spontaneous miscarriage were obtained from published GWAS studies. 4) The individual-level genotype data were also extracted from UKB. Participants/materials, setting, methods There were four analysis modules, 1) IVF data to test the association of ovarian reserve and miscarriage risk by using logistic regression models, 2) UKB data to test the association of spontaneous miscarriage history and ANM by using linear regression models, 3) GWAS summary data to test the overall genetic enrichment between miscarriage and ANM by plotting Q-Q plot, and 4) individual-level genotype data to identify specific shared genes by using ‘pleio’ R package. Main results and the role of chance In the analysis of clinical data, the risk of miscarriage was 1.5 (95% CI: 1.22-1.85, p &amp;lt; 0.001) times in the group with AMH&amp;lt;1.1 ng/ml, compared to the group with AMH &amp;gt; =1.1 ng/ml after adjustment. In the analysis of UK Biobank data, one more spontaneous miscarriage history would lead to 0.02 (95% CI: 0.00-0.03, p = 0.032) years earlier in the standardized ANM after adjustment. Participants with &amp;gt; =2 spontaneous miscarriage history would have 0.05 (95% CI:0.01-0.08, p = 0.011) years earlier in standardized ANM, compared with participants with &amp;lt; =1 spontaneous miscarriage. In the analysis of GWAS summary statistics, we found that there were 11,736,532 single nucleotide polymorphisms (SNPs) tested by both GWAS studies of ANM and miscarriage. In the stratified conditional Q-Q plot, successive leftward deflections did not show which suggested that an overall genetic overlap between miscarriage and ANM was not observed. In the analysis of the individual-level genotype data, we identified five shared genetic risk loci that affect both miscarriage and menopause. They were all novel risk genes for spontaneous miscarriage. Of these five genes, SYCP2L, TP63, GSPT1, and RIF1 were associated with congenital malformations and PRRC2A was associated with autoimmune disease, which are factors that possibly play a role in the occurrence of miscarriage. Limitations, reasons for caution The UKB epidemiology data and genetic data were restricted to participants of European ancestry. Further studies are needed in non-white populations. Second, the predictive value of GWAS summary data for miscarriage may be limited which results in a null finding in the conditional Q-Q plot. Wider implications of the findings Our findings could be of interest to IVF clinicians in patient counseling regarding the prognosis of IVF treatment and genetic counseling for miscarriage. Our findings encourage further research focus on the shared genetic architecture and common pathophysiological basis of diminished ovarian reserve and miscarriage which may bring new therapeutic opportunities. Trial registration number not applicable

Penetrance of pathogenic genetic variants associated with premature ovarian insufficiency.

Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported at natural menopause under the age of 40 years. We found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes, we ruled out even modest penetrance, with 99.9% (13,699 out of 13,708) of all protein-truncating variants found in reproductively healthy women. We found evidence of haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P = 1.59 × 10-6) and SOHLH2 (3.48 years earlier menopause, P = 1.03 × 10-4). Collectively, our results suggest that, for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. Our findings, plus previous studies, suggest that most POI cases are likely oligogenic or polygenic in nature, which has important implications for future clinical genetic studies, and genetic counseling for families affected by POI.

P-642 Estrogen deprivation and related risks in primary ovarian insufficiency with various hormone therapy initiation time points - evaluating 122,785 Asian women

Abstract Study question Does the initiation time point and/or duration of hormone therapy affect the long-term health consequences in primary ovarian insufficiency (POI)? Summary answer POI women with immediate hormone therapy following their diagnosis showed significantly reduced risk of metabolic syndrome and dyslipidemia, and such effect magnified with aging. What is known already POI women are exposed to extended duration of estrogen deficiency and premature aging, consequently associated with higher risks of cardiovascular, metabolic, osteoporotic and neurodegenerative diseases. The first line of treatment is hormone therapy (HT), preferably until the age of natural menopause. “Timing hypothesis” in terms of hormone replacement therapy (HRT) in menopause has globally changed the treatment protocol, but its evidence in POI is scarce. Study design, size, duration This population-based retrospective cohort study included 122,785 women registered to the National Health Insurance in South Korea from 2009 to 2015. The study group with POI diagnosis contained 24,557 women, determined by the International Classification of Disease, tenth revision (ICD-10) code E283 in the database. Women aged more than 40 years with the E283 code were considered being previously-diagnosed POI. The 1:4 age-matching control group with the systematic random-sampling method included 98,228 women. Participants/materials, setting, methods The participants’ demographic data, diagnosis codes, use of inpatient and outpatient services, pharmacy dispensing claims and mortality data were retrieved and statistically analyzed. According to their use of HT, the study group was further divided into two groups: with (n = 13,240) or without HT (n = 11,317); their routine health check-up data collected in the database were then compared. In all analysis, a p-value &amp;lt;0.05 was considered statistically significant. Main results and the role of chance Compared to the control group, POI women had significantly lower body mass index (BMI), blood pressure, serum total cholesterol and triglyceride (TG), but the incidence rate ratio (IRR) was significantly higher in POI regarding thyroid diseases, type 2 diabetes, dyslipidemia, hypertension, osteoporosis and cardiovascular diseases (IRR with 95% confidence interval (CI) of 1.731[1.691; 1.772], 1.300[1.260; 1.342], 1.499[1.470; 1.529], 1.100[1.071; 1.129], 2.449[2.388;2.513] and 1.468[1.392; 1.547], respectively). Among POI women overall, the HT users had significantly lower BMI, lower systolic blood pressure but similar diastolic blood pressure, and lower serum total cholesterol and TG, compared to the non-users. In terms of IRRs for chronic diseases, the HT users under the age of 40 years did not show any statistically significant difference in comparison to the non-users; however, the HT users aged more than 40 years had significantly lower IRRs for type 2 diabetes, dyslipidemia and hypertension compared to the non-users (0.876[0.822; 0.933], 0.873[0.840; 0.907], 0.849[0.805; 0.896], respectively). Such effect became more statistically vivid when the participants grew older (IRR[95% CI] of 0.849[0.749; 0.963] for thyroid diseases; 0.806[0.708; 0.917] for type 2 diabetes; 0.652[0.592; 0.718] for dyslipidemia; 0.739[0.662; 0.825] for hypertension; 0.835[0.752; 0.928] for osteoporosis; and 0.890[0.728; 1.089] for cardiovascular disease, respectively). Limitations, reasons for caution The current study relied on the health insurance claim data which did not include detailed patient medical record including menstruation pattern and obstetrical/gynecological histories. Also, critical biochemical assay results such as anti-mullerian hormone or pituitary hormones were not available because they were not covered by the national health insurance program. Wider implications of the findings Agreeing with the previous literature, the immediate use of HT is associated with the reduced incidence of chronic diseases in POI women, and its extended use exerts more significant results with aging. If acknowledged early and initiated with HT, previously-inevitable health risks with POI could be conceivably compensated. Trial registration number The current study was supported by Biomedical Research Institute Grant (#202201970001), Pusan National University Hospital.

Age at menopause and all-cause and cause-specific dementia: a prospective analysis of the UK Biobank cohort.

Are there associations between natural or surgical menopause and incident dementia by age at menopause? Compared to age at menopause of 46-50 years, earlier natural menopause (≤40 and 41-45 years) was related to higher risk of all-cause dementia, while a U-shape relationship was observed between age at surgical menopause and risk of dementia. Menopause marks the end of female reproductive period. Age at menopause reflects the length of exposure to endogenous estrogen. Evidence on the association between age at natural, surgical menopause, and risk of dementia has been inconsistent. A population-based cohort study involving 160080 women who participated in the UK Biobank study. Women with no dementia at baseline, and had no missing data on key exposure variables and covariates were included. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs on the association of categorical menopause age with incident all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VD). Restricted cubic splines were used to model the non-linear relationship between continuous age at natural, surgical menopause, and risk of dementia. In addition, we analyzed the interaction effect of ever-used menopausal hormone therapy (MHT) at baseline, income level, leisure activities, and age at menopause on risk of dementia. Compared to women with age at menopause of 46-50 years, women with earlier natural menopause younger than 40 years (1.36, 1.01-1.83) and 41-45 years (1.19, 1.03-1.39) had a higher risk of all-cause dementia, while late natural menopause >55 years was linked to lower risk of dementia (0.83, 0.71-0.98). Compared to natural menopause, surgical menopause was associated with 10% higher risk of dementia (1.10, 0.98-1.24). A U-shape relationship was observed between surgical menopause and risk of dementia. Women with surgical menopause before age 40 years (1.94, 1.38-2.73) and after age 55 years (1.65, 1.21-2.24) were both linked to increased risk of all-cause dementia. Women with early natural menopause without ever taking MHT at baseline had an increased risk of AD. Also, in each categorized age at the menopause level, higher income level or higher number of leisure activities was linked to a lowers risk of dementia. Menopausal age was based on women's self-report, which might cause recall bias. Women who experienced natural menopause or had surgical menopause at an earlier age need close monitoring and engagement for preventive health measures to delay the development of dementia. This work was supported by the Start-up Foundation for Scientific Research in Shandong University (202099000066), Science Fund Program for Excellent Young Scholars of Shandong Provence (Overseas) (2022HWYQ-030), and the National Natural Science Foundation of China (82273702). There are no competing interests. N/A.

Managing Early Onset Osteoporosis: The Impact of Premature Ovarian Insufficiency on Bone Health.

Premature ovarian insufficiency is a reproductive endocrine disorder characterized by the cessation of ovarian function before the age of 40 years. Although the etiopathology of POI remains largely unknown, certain causative factors have been identified. Individuals affected by POI are at an increased risk of experiencing bone mineral density (BMD) loss. Hormonal replacement therapy (HRT) is recommended for patients with POI to mitigate the risk of decreased BMD, starting from the time of diagnosis until reaching the average age of natural menopause. Various studies have compared the dose-effect relationship of estradiol supplementation, as well as different HRT formulations on BMD. The impact of oral contraception on reduced BMD or the potential benefits of adding testosterone to estrogen replacement therapy are still subjects of ongoing discussion. This review provides an overview of the latest advancements in the diagnosis, evaluation, and treatment of POI as it relates to BMD loss.

Association of Early Hysterectomy With Risk of Cardiovascular Disease in Korean Women

Women who undergo surgical hysterectomy before natural menopause may have an earlier increase in hematocrit and storage iron levels than those who continue menstruation, thereby increasing the risk of cardiovascular disease (CVD) at ages younger than usually seen. Examining this issue may provide important implications for women's cardiovascular health to both physicians and patients. To evaluate the association of hysterectomy with the risk of incident CVD among women before age 50 years. In this Korean population-based cohort study, 135 575 women aged 40 to 49 years were evaluated from January 1, 2011, to December 31, 2014. After propensity score matching in covariates including age, socioeconomic status, region, Charlson Comorbidity Index, hypertension, diabetes, dyslipidemia, menopause, menopausal hormone therapy, and adnexal surgery before inclusion, 55 539 pairs were included in the hysterectomy and nonhysterectomy groups. Participants were followed up until December 31, 2020. Data analysis was conducted from December 20, 2021, to February 17, 2022. The primary outcome was an incidental CVD, a composite of myocardial infarction, coronary artery revascularization, and stroke. The individual components of the primary outcome were also evaluated. A total of 55 539 pairs were included; median age in the combined groups was 45 (IQR, 42-47) years. During median follow-up periods in the hysterectomy group of 7.9 (IQR, 6.8-8.9) years and nonhysterectomy group of 7.9 (IQR, 6.8-8.8) years, the incidence of CVD was 115 per 100 000 person-years for the hysterectomy group and 96 per 100 000 person-years for the nonhysterectomy group. After adjusting for confounding factors, the hysterectomy group had an increased risk of CVD compared with the nonhysterectomy group (hazard ratio [HR], 1.25; 95% CI, 1.09-1.44). The incidences of myocardial infarction and coronary artery revascularization were comparable between the groups, whereas the risk of stroke was significantly higher in the hysterectomy group (HR, 1.31; 95% CI, 1.12-1.53). Even after excluding women who underwent oophorectomy, the hysterectomy group had higher risks of CVD (HR, 1.24; 95% CI, 1.06-1.44). The findings of this cohort study suggest early menopause owing to hysterectomy was associated with increased risks for a composite of CVD, particularly stroke.