Natural Menopause Research Articles

A Lifecourse Perspective on Female Sex-Specific Risk Factors for Later Life Cognition.

The prevalence of Alzheimer's disease and related dementias is greater in women compared to men. We provide a review of female sex-specific risk factors across the lifecourse for cognition in older adulthood, highlighting areas that need further study. Pregnancy may affect late-life cognition, with adverse pregnancy outcomes associated with an increased risk of cognitive decline but parity providing a protective effect. Cumulative estrogen exposure, influenced by age of menarche, menopause, and exogenous estrogen use, may modify a woman's risk for dementia. Menopause transition-associated symptoms may impact cognitive health at the time of the symptoms, but long-term effects remain unknown. As compared to natural menopause, surgical menopause seems to increase the risk for cognitive impairment. Studies that have assessed the association between women's reproductive health and cognition have produced conflicting results. Future studies that address these inconsistencies among diverse populations are needed to better care for women throughout their lives.

Polymorphisms of the TNF, LTA, and TNFRSF1B genes are associated with onsets of menarche and menopause in US women of European ancestry

Background The TNF, LTA and TNFRSF1B genes have been implicated in various traits related to menarche and menopause. Aim To analyse the TNF, LTA and TNFRSF1B genes for their association with ages at menarche (AM) and natural menopause (ANM). Subjects and methods The study sample consisted of 314 unrelated females of European ancestry. Twenty SNPs located in and near the genes were analysed using various statistical methods. In addition, the functional significance of the loci associated with AM and ANM was analysed in silico. Results Locus rs2229094 of the LTA gene was associated with AM according to the additive (β = −0.295, p perm = 0.016) and recessive (β = −0.940, p perm = 0.016) genetic models. Haplotype GG rs1148459-rs590368 of the TNFRSF1B gene was associated with AM (β = 0.307, p perm = 0.023). Haplotype GCA rs2844484-rs2229094-rs1799964 was associated with ANM after adjustment for covariates (β = −1.020, p perm = 0.035). All studied loci were associated with ANM after adjustment for breastfeeding (raw p < 0.05). In addition, eight of the most significant models of interlocus interactions were associated with AM and five with ANM. Conclusion The results of the present study suggest that the TNF, LTA and TNFRSF1B genes are associated with AM and ANM.

Prevalence and Associates of Natural Menopause and Surgical Menopause Among Indian Women Aged 30 to 49 Years: An Analysis of the National Family Health Survey

This study estimates the prevalence of natural and surgical menopause among Indian women aged 30 to 49 years, examines the secular trend in prevalence, and identifies different correlates of menopause in India based on multiple rounds of nationally representative samples. The age-adjusted prevalence of menopause significantly declined from 17.3% in 2005–2006 to 15.7% in 2015–2016. The current prevalence of natural menopause and surgical menopause were 9.5% and 6.2%, respectively. The determinants and trends in menopause in India are different for natural and surgical menopause, which require separate attention for the planning and implementation of reproductive and postreproductive health services.

Is Alcohol Consumption Associated With Risk of Early Menopause?

Earlier age at menopause is associated with increased long-term health risks. Moderate alcohol intake has been suggested to delay menopause onset, but it is unknown whether alcohol subtypes are associated with early menopause onset at age 45 years. Therefore, we aimed to evaluate risk of early natural menopause among 107,817 members of the Nurses' Health Study II who were followed from 1989 to 2011. Alcohol consumption overall and by subtypes, including beer, red wine, white wine, and liquor, was assessed throughout follow-up. We estimated hazard ratios in multivariable models that were adjusted for age, body mass index, parity, smoking, and other potential confounders. Women who reported moderate current alcohol consumption had lower risks of early menopause than did nondrinkers. Those who reported consuming 10.0-14.9 g/day had a lower risk of early menopause than did nondrinkers (hazard ratio=0.81, 95% confidence interval: 0.68, 0.97). Among specific beverages, evidence of lower early menopause risk was confined to consumption of white wine and potentially red wine and liquor, but not to beer. Data from this large prospective study suggest a weak association of moderate alcohol intake with lower risk of early menopause, which was most pronounced for consumption of white and red wine and liquor. High consumption was not related to lower risk of early menopause.

Reproductive period and preclinical cerebrospinal fluid markers for Alzheimer disease: a 25-year study.

Objective:The aim of the study was to examine the association between reproductive period, as an indicator of endogenous estrogen, and levels of cerebrospinal fluid (CSF) biomarkers for Alzheimer disease (AD).Methods:A population-based sample of women from Gothenburg, Sweden was followed from 1968 to 1994 (N = 75). All women had natural menopause and were free from dementia. Information on reproductive period (age at menarche to age at menopause) was obtained from interviews from 1968 to 1980. Lumbar puncture was performed from 1992 to 1994 and CSF levels of Aβ42, Aβ40, P-tau, and T-tau were measured with immunochemical methods. Linear regression models adjusted for potential confounders were used to analyze the relationship between reproductive period and CSF biomarkers for AD.Results:Longer reproductive period was associated with lower levels of Aβ42 (β = −19.2, P = 0.01), higher levels of P-tau (β = 0.03, P = 0.01), and lower ratio of Aβ42/Aβ40 (β = −0.02, P = 0.01), while no association was observed for T-tau (β = 0.01, P = 0.46). In separate analyses, examining the different components of reproductive period, earlier age at menarche was associated higher levels of P-tau (β = −0.07, P = 0.031) and lower ratio of Aβ42/Aβ40 (β = 0.05, P = 0.021), whereas no association was observed with Aβ42 (β = 31.1, P = 0.11) and T-tau (β = −0.001, P = 0.98). Furthermore, no association was observed between age at menopause and CSF biomarkers for AD.Conclusions:Our findings suggest that longer exposure to endogenous estrogen may be associated with increased levels of AD biomarkers in the preclinical phase of AD. These findings, however, need to be confirmed in larger samples.Video Summary:.

Impact of premature natural menopause on body composition and physical function in elderly women: A Korean frailty and aging cohort study.

Induced premature menopause accelerates the rate of body composition changes (decrease in skeletal muscle mass and increase in fat mass) and deteriorating physical function. However, few studies have focused on the impact of premature natural menopause. This study aimed to investigate the impact of age at natural menopause (ANM) on body composition and physical function in elderly women.Using data from the Korean Frailty and Aging Cohort Study, 765 community-dwelling elderly women aged 70 to 85 years who experienced natural menopause were recruited in this study. Body composition was measured using dual-energy X-ray absorptiometry. Physical function was evaluated by grip strength, the timed up and go test (TUG), and the short physical performance battery (SPPB). Participants were categorized into 4 groups according to their ANM: <40 (premature natural menopause, PNM), 40 to 44 (early natural menopause, ENM), 45 to 54 (normal menopause, NM), and ≥55 (late menopause, LM) years.There were no significant differences in the body composition parameters, such as the appendicular skeletal muscle mass index (PNM: 5.90 ± 0.90 vs ENM: 5.91 ± 0.70 vs NM: 5.85 ± 0.73 vs LM: 5.90 ± 0.75, kg/m2, P = .75) and trunk fat mass index (PNM: 19.4 ± 3.9 vs ENM: 19.9 ± 4.4 vs NM: 19.9 ± 3.9 vs LM: 20.0 ± 3.8, %, P = .87) between the groups. In the physical function evaluation, there was no significant difference between the groups in grip strength (PNM: 19.8 ± 0.6 vs ENM: 20.3 ± 0.4 vs NM: 20.6 ± 0.2 vs LM: 20.6 ± 0.4, kg, P = .53). However, in the TUG (PNM: 11.8 ± 0.4 vs ENM: 10.3 ± 0.3 vs NM: 10.6 ± 0.1 vs LM: 10.2 ± 0.3, seconds, P < .01) and SPPB (PNM: 10.0 ± 0.2 vs ENM: 10.5 ± 0.2 vs NM: 10.6 ± 0.1 vs LM: 10.8 ± 0.2, points, P < .05), the PNM group showed significantly lower values than the other groups did. There was no difference in physical function between the groups except the PNM.Premature natural menopause did not affect the body composition in elderly women but was associated with physical function deterioration. Therefore, more attention should be paid to the prevention of the physical function deterioration caused by premature natural menopause in elderly women.

Age at Menopause and Risk of Ischemic and Hemorrhagic Stroke.

The few epidemiological studies that addressed the association between age at menopause and ischemic and hemorrhagic stroke risk in women had conflicting findings. We aimed to investigate whether age at (natural and surgical) menopause is a risk factor for total, ischemic, and hemorrhagic stroke in women. We analyzed data from 16 244 postmenopausal women, aged 26 to 70 years at recruitment who were enrolled in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort between 1993 and 1997. Participants were followed for the occurrence of stroke until January 1, 2011. At baseline, participants filled in questionnaires about health, reproductive history including age at menopause, diet, and lifestyle. Cox regression was used to investigate the association between age at menopause and stroke. All analyses were adjusted for age, smoking, systolic blood pressure, and body mass index. Mean age of menopause was 46.4 (7.0) years. A total of 830 strokes (571 ischemic, 162 hemorrhagic, 97 unclassified) were identified. Earlier menopause was associated with an increased risk of total stroke. Compared with women who experienced menopause between 50 and 54 years old, women who underwent menopause before age 40 years had 1.48× higher risk (95% CI, 1.19-1.85) of total stroke. In continuous analyses, we observed a 2% lower total stroke risk for each year menopause was delayed (hazard ratio, 0.98 [95% CI, 0.97-0.99]). The risk between earlier menopause and stroke was confined to ischemic stroke, earlier menopause was not associated with hemorrhagic stroke. The association with age at menopause was stronger for natural menopause (hazard ratio <40 versus 50-54 years, 1.74 [95% CI, 1.12-2.70]) than for surgical menopause (hazard ratio <40 versus 50-54 years, 1.26 [95% CI, 0.84-1.89]). The risk of total and ischemic stroke decreased with an increase in age at menopause. Whether this should have clinical consequences such as intensified risk factor control should be subject of further studies.

Associations of long-term exposure to environmental noise and outdoor light at night with age at natural menopause in a US women cohort.

Premenopausal women from the Nurses' Health Study II (NHS II) were followed from age 40 through 2015. Median daytime and nighttime anthropogenic noise and outdoor LAN exposure were measured from a geospatial prediction model and satellite images, respectively, at residential addresses throughout the follow-up. Time-varying Cox proportional hazard models were used to calculate the hazard ratios and 95% confidence intervals, adjusting for individual lifestyle, reproductive history, and neighborhood socioeconomic factors. Possible effect modification by region, smoking status, body mass index, race/ethnicity, history of rotating shift work, and census tract population density and median income was examined. A total of 63,380 of 105,326 women self-reported natural menopause during 1,043,298 person-years of follow-up. No associations were found for noise (both daytime and nighttime) and outdoor LAN exposure with age at natural menopause (hazard ratios = 0.99-1.00) in the fully adjusted models. Sensitivity analyses showed similar null associations. No meaningful effect modification was found for region, smoking status, body mass index, race/ethnicity, history of rotating shift work, and census tract socioeconomic measures in stratified analyses. No associations were found between environmental noise and outdoor LAN exposure in mid-adulthood and menopausal age in this cohort of US women.

1052-P: Clinical Characteristics of Osteoporosis in Postmenopausal Women with Type 2 Diabetes Mellitus

Objective: To investigate clinical characteristics and risk factors of osteoporosis in postmenopausal women with type 2 diabetes mellitus. Method: A total of 410 postmenopausal women with type 2 diabetes of natural menopause with no history of fracture were collected from outpatients of Beijing Hospital (Oct 2017 - Nov 2019). Bone mineral density (BMD) at lumbar spine L1-L4 and hip was measured using dual-energy X-ray absorptiometry. Biochemical markers of bone and glucose metabolism were evaluated. Patients were divided into three groups based on BMD: A (osteoporosis): T ≤-2.5 SD; B (osteopenia) -2.5 &amp;lt; T ≤ -1 SD; C (normal bone mineral density) T &amp;gt; -1 SD. Statistical differences of age, menopausal age, diabetes age, BMI and biochemical indexes were compared between groups. Result: 1. Case number based on lumbar spine BMD: 189 in A (46.1%), 147 in B (35.9%), and 74 in C (18.0%). ANOVA analysis showed group A patients had the highest age (F 5.698, p 0.004), age of diabetes onset (F 7.596, p 0.001), ALP (F 3.231, p 0.041) and menopausal duration (F 7.596, p 0.001), but the lowest BMI (F 11.456, p 0.000). Logistic multivariate regression showed body mass index is an independent risk factor for osteoporosis in postmenopausal women with type 2 diabetes [A vs. C: OR1.224 (95% CI 1.106-1.355, p 0.000); A vs. B: OR1.172 (95% CI 1.079-1.274, p 0.000].2. Case number based on femoral neck BMD: 159 in A (38.8%), 188 in B (45.9%), 63 in C (15.3%). ANOVA analysis showed group A patients had the highest age (F 21.484, p 0.000), age of diabetes onset (F 10.125, p 0.000) and PTH (F3.691, 0.026), but the lowest BMI (F 11.456, p 0.000). Logistic multivariate regression showed body mass index is an independent risk factor for osteoporosis in postmenopausal women with type 2 diabetes [A vs. C: OR1.267 (95% CI 1.120-1.433, p 0.000); A vs. B: OR1.195 (95% CI1.099-1.301, p 0.000)]. Conclusion: Osteoporosis in postmenopausal women with type 2 diabetes is associated with older age, longer menopause duration, older age of diabetes onset and lower BMI. Disclosure Y. Wang: None. Z. Lina: None. L. Guo: Consultant; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., BD, Eli Lilly and Company, Merck &amp; Co., Inc., Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk, Sanofi China.

Joint Genome-Wide Association Analyses Identified 49 Novel Loci For Age at Natural Menopause.

Age at natural menopause (ANM) is an important index for women's health. Either early or late ANM is associated with a series of adverse outcomes later in life. Despite being an inheritable trait, its genetic determinant has not yet been fully understood. Aiming to better characterize the genetic architecture of ANM, we conducted genome-wide association study (GWAS) meta-analyses in European-specific as well as trans-ancestry samples by using GWAS summary statistics from the following 3 large studies: the Reproductive Genetics Consortium (ReproGen; N = 69 626), the UK Biobank cohort (UKBB; N = 111 593) and the BioBank Japan Project (BBJ; N = 43 861), followed by a series of bioinformatical assessments and functional annotations. By integrating the summary statistics from the 3 GWAS of up to 225 200 participants, this largest meta-analysis identified 49 novel loci and 3 secondary signals that were associated with ANM at the genome-wide significance level (P < 5 × 10-8). No population specificity or heterogeneity was observed at most of the associated loci. Functional annotations prioritized 90 candidate genes at the newly identified loci. Among the 26 traits that were genetically correlated with ANM, hormone replacement therapy (HRT) exerted a causal relationship, implying a causal pattern by which HRT was determined by ANM. Our findings improved our understanding of the etiology of female menopause, as well as shed light on potential new therapies for abnormal menopause.

Search of ways to menopausal hormonal therapy and correction of bacterial vaginosis against the climacteric syndrome

Study objective: optimization of the treatment of climacteric syndrome (CS) and improvement of the life quality in women with bacterial vaginosis (BV) during menopause. Materials and methods. 58 women with natural menopause were examined, 38 of whom were diagnosed with BV. To correct the CS patient used the drug 17β-estradiol Divigel transdermal in combination with micronized progesterone orally. Patients with BV were divided into 2 subgroups: 15 women received standard treatment with metronidazole gel (comparison subgroup), 23 women additionally used Lactagel (main subgroup). The control group included 20 patients with CS without BV. The severity of CS was assessed with MRS scale. Microscopic and bacteriological examination of vaginal discharge was performed to determine the infectious agent, and the species composition of pathogens was determined with a polymerase chain reaction. BV was diagnosed according to Amsel criteria. CQLS questionnaire was used to assess the quality of life of patients with BV. The treatment effectiveness was assessed after 1 and 3 months from the start of treatment.Results. Divigel in women with uterus in combination with oral micronized progesterone has shown high efficiency in the CS correction within a month from the start of treatment. The most significant was the decrease in neurovegetative and psychoemotional symptoms after 3 months from the start of treatment. Lactagel in the therapy of patients with BV on the background of CS allowed increasing the lactobacilli content to the value in patients without BV, restoring the normal vaginal biotope and preventing of the disease recurrence, in contrast to the subgroup of patients who received standard treatment. Lactagel made it possible to improve the life quality of patients to an average level and to increase the overall level of life satisfaction, in contrast to the subgroup with standard treatment where these levels have remained low.Conclusions. Developed approaches to menopausal hormone therapy and BV therapy against the background of natural menopause allows optimizing treatment, improving the life quality of patients, which allows recommending them for widespread use in clinical practice.

Abstract P219: Association Of Age At Menopause And Reproductive Years With Arterial Stiffness And Its 5-year Change: The Atherosclerosis Risk In Communities - Neurocognitive Study (ARIC-NCS)

Introduction: Early age at menopause is posited to increase cardiovascular disease (CVD) risk. However, studies examining the association with arterial stiffness, a predictor of CVD, are inconsistent and cross-sectional. Hypothesis: Earlier age at menopause and shorter reproductive years in women are associated with higher arterial stiffness and greater 5-year change at later life. Methods: We included 1,084 women in ARIC-NCS (mean 74 years at visit 5) with measures of arterial stiffness (carotid-femoral pulse wave velocity (cfPWV)) at visit 5 (2011-13) and visit 6 or 7 (2016-19). At visits 1-4, women self-reported age at first menses, age at menopause, and hysterectomy with and without bilateral oophorectomy. We defined menopause type as natural, surgical, and unknown, which included women with a hysterectomy, but unknown ovarian status. Multivariable linear regression was used to evaluate associations of age at menopause, early age at menopause (&lt;45 years vs. ≥45 years), and reproductive years (age at menopause - age at first menses) with visit 5 cfPWV and cfPWV change between visit 5 and 6 or 7, adjusting for demographics and cardiometabolic risk factors. Results: The average age at menopause was 46.2 years, and 319 (29.4%) women had early age at menopause. No statistically significant associations were observed for age at menopause and reproductive years with either visit 5 cfPWV or cfPWV change. However, the associations with cfPWV change differed by menopause type (Table). Age at menopause and reproductive years were inversely associated with cfPWV change in women with natural menopause but were positively associated with cfPWV change in women with surgical menopause. Conclusion: At later life, age at menopause and reproductive years are not strongly associated with arterial stiffness, although the change in arterial stiffness differs by menopause type. Longitudinal arterial stiffness measures among women at mid-life is needed to understand the effect of natural versus surgical menopause on arterial stiffness.

Abstract MP31: Early Age At Menopause And The Association With Incident Heart Failure In The Southern Community Cohort Study

Introduction: Reproductive factors might have an effect on the development of heart failure (HF). Early age at menopause has been linked with increased risk of cardiovascular disease; however, there is limited evidence on the relationship between early menopause and HF. Hypothesis: We assessed the hypothesis that earlier age at menopause is associated with increased risk of incident HF among women in the southeastern United States. Methods: The Southern Community Cohort Study enrolled ~86,000 low-income black and white adults in 12 southeastern states (2002-2009). Participants for this analysis were 11,948 women who were postmenopausal at enrollment, had no history of HF, and were using Centers for Medicare or Medicaid Services (CMS). HF events were ascertained using International Classification of Diseases , Ninth Revision, codes 428.x via linkage of the cohort with CMS Research Identifiable Files through December 31, 2016. Early menopause was defined as self-reported age at menopause less than 45 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed from multivariable Cox regression models, overall and by race, adjusting for demographic, lifestyle, and reproductive factors, including reason for menopause. Results: At baseline, median age was 58 years and 65% of participants were black. Among women with early menopause, 76% (n=4,836) had menopause due to hysterectomy or oophorectomy. In women with later menopause, 74% (n=4,102) reported natural menopause. During a median follow-up of 9.5 years (interquartile range 6.0-11.8), 3,808 incident HF events occurred. Compared to women with later onset of menopause, those with early menopause had increased HF risk (HR: 1.13, 95% CI: 1.04-1.23). Risk of HF associated with early menopause differed between white and black women (p-value for interaction: 0.02). In stratified analyses, white women with early menopause had an increased risk of HF compared to those with later onset of menopause (HR: 1.26, 95% CI: 1.11-1.43), although there was no association between early age at menopause and risk of HF in black women (HR: 1.07, 95% CI: 0.98-1.18). Conclusions: In conclusion, in this largely low-income population, early menopause is associated with an increased risk of developing HF and associations differ by race. Women with early menopause represent a potential target population for future interventions aimed to decrease risk of HF and cardiovascular risk factors.

Abstract 012: Association Between Premature Menopause And Lifetime Risk Of Coronary Heart Disease: Lifetime Risk Pooling Project

Introduction: Menopause before the age of 40 years is recognized as a risk enhancer for coronary heart disease (CHD) by the 2019 AHA/ACC Primary Prevention guidelines. Race-specific prevalence of premature menopause and its association with lifetime risk of CHD morbidity and mortality have not been well described in Black and White women, and could inform risk stratification and intensity of prevention efforts. Hypothesis: We hypothesized that Black and White women who experience premature menopause (&lt;40 years) will have similarly elevated lifetime burden of CHD compared with women of the same race who do not have premature menopause. Methods: We pooled individual-level data from Black and White postmenopausal women aged 55-69 years from 6 US population-based cohorts. We included women without CHD at baseline and excluded women who reported surgical menopause. We defined premature menopause as age &lt;40 years. We performed (1) modified Kaplan Meier analysis and (2) competing Cox models to estimate joint cumulative risk for CHD or non-cardiovascular death adjusted for age, smoking, education, obesity, hypertension, and diabetes. Results: Of the 3522 Black women and 6514 White women, mean ages were 61.2 ± 4.3 and 60.0 ± 4.4 years, respectively. Premature menopause (&lt;40 years) occurred more commonly in Black (15.5%) compared with White (4.8%) women. Lifetime risk of CHD was higher in Black and White women with premature menopause ( Figure ). Hazard ratios adjusted for risk factors and accounting for competing risk of death were higher in Black (1.41 [1.04, 1.90]) and White (1.39 [1.03, 1.87]) women with premature menopause compared those Black and White women without premature menopause, respectively. Conclusions: Black women are three times more likely to experience premature natural menopause (&lt;40 years) than White women. Premature menopause is independently associated with 40% higher risk of CHD in both Black and White women and should be assessed as a risk-enhancing feature in clinical prevention decisions.

Analysis of clusters of menopausal disorders associated with a decrease in the quality of life in postovarectomy and climacteric syndromes

The decline in the quality of life due to various menopausal disorders in the early postmenopausal period is actually the main reason that leads a woman to seek medical help. Despite this, not enough attention is paid to this problem. Currently, the concept of the formation of individual menopausal symptoms into clusters is emerging to optimize treatment and diagnostic algorithms for managing this category of patients. The aim was a comparative analysis of the menopausal disorders most associated with a decrease in the quality of life. Included were 230 women with climacteric disorders (95 with bilateral oophorectomy; 135 with natural menopause). The assessment of the severity of climacteric disorders was carried out according to the Kuperman index modified by E.V. Uvarova. The SF-36 Health Status Survey was used to assess the quality of life. The average age of patients with surgical menopause was 47.9±2.2 years, with natural menopause - 53.6±3.5 years (p˂0.05). The duration of the estrogen deficiency state in the groups was comparable - 2.8 ± 0.6 years (p&gt;0.05). All patients had a moderate degree of menopausal syndrome (p&gt;0.05), however, the values of the modified menopausal index differed significantly: with postovarectomy syndrome - 57.8±1.1 points, with menopausal syndrome - 49.7±0.9 points (р &lt;0.05). In both groups, a decrease in the quality of life was observed: the total physical component (with postovarectomy syndrome up to 57.2 (36.6; 72.7), with menopause - up to 68.4 (49.3; 83.5)) and the total psychological component (up to 53.9 (42.9; 76.7) and 64.1 (47.3; 84.5), respectively). In contrast to our approach, the formation of clusters of menopausal symptoms, based on the generally accepted approach to the analysis of climacteric disorders (psychological, vasomotor, somatic), provided a significantly smaller sample coverage (with surgical menopause - 68.5%, with natural - 62.6% variance) With a duration of estrogen deficiency of 2.8 ± 0.6 years, the cluster of menopausal disorders, which has the maximum negative effect on the quality of life, includes symptoms: hot flashes, cognitive disorders, sleep disturbances, anxiety, and covers 80.3% of the variance in postovarectomy syndrome, in menopausal - 73.6%. Knowledge of this fact contributes to the identification of risk groups and allows formulating new algorithms for the management of postmenopausal women.

Preliminary study of ovariectomy and chronic losartan-induced alterations in brain AT1 receptors

Women who undergo oophorectomy prior to the age of natural menopause have a higher risk of neurological and psychological impairment. Treatment with the angiotensin receptor blocker (ARB) losartan for 10 weeks following ovariectomy of Long-Evans rats at 3 months of age reduced the ovariectomy-induced cognitive decrements. Following completion of the behavioral experiments, (Campos et al., 2019), the brains were harvested for preliminary receptor autoradiographic studies of AT1 receptor (AT1R) binding in selected brain regions using quantitative densitometric analysis of autoradiograms of 125I-sarcosine1, isoleucine8 angiotensin II binding. Four of the brain regions (amygdala, ventral subiculum, piriform cortex, and cingulate cortex) are associated with cognitive and emotional behavior while one (lateral hypothalamus) is associated with homeostasis. The density of AT1R varied by region: ventral subiculum > amygdala and cingulate cortex, and piriform cortex > cingulate cortex. Losartan treatment decreased AT1R binding in the ventral subiculum of sham and ovariectomized rats by 41.6%, and 46% in the piriform cortex of the sham rats, but tended to increase AT1R binding in the piriform cortex and cingulate cortex 77% and 107%, respectively, in the ovariectomized rats. AT1R binding did not differ significantly between intact male and sham-vehicle female rats among surveyed brain regions. These results suggest that losartan-induced changes in brain AT1R expression may contribute to the reduced anxiety-like behavior and memory impairments seen in ovariectomized rats, but replication of these observations will be needed to determine the extent to which brain AT1R changes mediate the adverse behavioral effects of ovariectomy.

Predicting the age at natural menopause in middle-aged women.

Objective:To predict the age at natural menopause (ANM).Methods:Cox models with time-dependent covariates were utilized for ANM prediction using longitudinal data from 47 to 55-year-old women (n = 279) participating in the Estrogenic Regulation of Muscle Apoptosis study. The ANM was assessed retrospectively for 105 women using bleeding diaries. The predictors were chosen from the set of 32 covariates by using the lasso regression (model 1). Another easy-to-access model (model 2) was created by using a subset of 16 self-reported covariates. The predictive performance was quantified with c-indices and by studying the means and standard deviations of absolute errors (MAE ± SD) between the predicted and observed ANM.Results:Both models included alcohol consumption, vasomotor symptoms, self-reported physical activity, and relationship status as predictors. Model 1 also included estradiol and follicle-stimulating hormone levels as well as SD of menstrual cycle length, while model 2 included smoking, education, and the use of hormonal contraception as additional predictors. The mean c-indices of 0.76 (95% CI 0.71-0.81) for model 1 and 0.70 (95% CI 0.65-0.75) for model 2 indicated good concordance between the predicted and observed values. MAEs of 0.56 ± 0.49 and 0.62 ± 0.54 years respectively for model 1 and 2 were clearly smaller than the MAE for predicted sample mean (1.58 ± 1.02).Conclusions:In addition to sex hormone levels, irregularity of menstrual cycle, and menopausal symptoms, also life habits and socioeconomic factors may provide useful information for ANM prediction. The suggested approach could add value for clinicians’ decision making related to the use of contraception and treatments for menopausal symptoms in perimenopausal women.Video Summary:.

Age at menarche, age at natural menopause, and risk of rheumatoid arthritis — a Mendelian randomization study

BackgroundHormonal reproductive factors have been suggested to play an important role in the etiology of rheumatoid arthritis (RA), an autoimmune inflammatory disorder affecting primarily women. We conducted a two-sample Mendelian randomization (MR) study examining three relevant exposures, age at menarche (AAM), age at natural menopause (ANM), and age at first birth (AFB) with the risk of RA.MethodsWe collected summary statistics from the hitherto largest GWAS conducted in AAM (N = 329,345), ANM (N = 69,360), AFB (N = 251,151), and RA (Ncase = 14,361, Ncontrol = 43,923), all of European ancestry. We constructed strong instruments using hundreds of exposure-associated genetic variants and estimated causal relationship through different MR approaches including an inverse-variance weighted method, an MR-Egger regression and a weighted median method. We conducted a multivariable MR to control for pleiotropic effect acting in particular through obesity and socioeconomic status. We also performed important sensitivity analyses to verify model assumptions.ResultsWe did not find any evidence in support for a causal association between genetically predicted reproductive factors and risk of RA (ORper-SD increment in AAM = 1.06 [0.98–1.15]; ORper-SD increment in ANM = 1.05 [0.98–1.11], OR per-SD increment in AFB = 0.85 [0.65–1.10]). Results remained consistent after removing palindromic SNPs (ORper-SD increment in AAM = 1.06 [0.97–1.15], ORper-SD increment in ANM = 1.05 [0.98–1.13], ORper-SD increment in AFB = 0.81 [0.61–1.07]) or excluding SNPs associated with potential confounding traits (ORper-SD increment in AAM = 1.03 [0.94–1.12], ORper-SD increment in ANM = 1.04 [0.95–1.14]). No outlying instrument was identified through the leave-one-out analysis.ConclusionsOur MR study does not convincingly support a casual effect of reproductive factors, as reflected by age at menarche, age at menopause, and age at first birth, on the development of RA. Despite the largely augmented set of instruments we used, these instruments only explained a modest proportion of phenotypic variance of exposures. Our knowledge regarding this topic is still insufficient and future studies with larger sample size should be designed to replicate or dispute our findings.

Reproductive Factors and Lung Cancer Risk among Never-Smoking Japanese Women with 21 Years of Follow-Up: A Cohort Study.

Previous studies have reported inconsistent associations between reproductive factors and lung cancer. We used data from the Japan Public Health Center-based Prospective Study, which included 400 incident lung cancer cases (305 adenocarcinoma) among 42,615 never-smoking women followed for a median of 21 years, to examine the associations of reproductive and hormonal factors with lung cancer by histological type using Cox proportional hazards models. Longer fertility span (≥36 years vs. ≤32 years) was associated with increased risk of lung adenocarcinoma (HR, 1.48; 95% CI, 1.07-2.06, P trend = 0.01) but not with all lung cancer or nonadenocarcinoma. Similarly, late age at menopause (≥ 50 years) was associated with increased adenocarcinoma risk (vs. ≤ 47 years, HR, 1.41; 95% CI, 1.01-1.96, P trend 0.04). Compared with premenopausal women, women with natural menopause (HR, 1.99; 95% CI, 1.02-3.88) or surgical menopause (HR, 2.75; 95% CI, 1.33-5.67) were at increased risk of adenocarcinoma. In contrast, breastfeeding was associated with reduced risk of nonadenocarcinoma (HR, 0.51; 95% CI, 0.28-0.92). No significant association with parity, age at first birth, exogenous hormone use, or length of menstrual cycle was detected. Reproductive factors may play a role in lung carcinogenesis. Future studies that include estrogen and progesterone biomarkers may help clarify the role of endogenous hormones in lung carcinogenesis. Fertility span and age at menopause may be useful variables in developing risk prediction models for lung adenocarcinoma among nonsmoking women.

Trends in Age at Natural Menopause and Reproductive Life Span Among US Women, 1959-2018

This national survey study uses the National Health and Nutrition Examination Survey (NHANES) to describe trends in age at natural menopause, age at menarche, and reproductive life span, and variables associated with shorter and longer spans, among US women between 1959-1962 and 2015-2018.