Association of Reproductive History With Brain MRI Biomarkers of Dementia Risk in Midlife

Objective.To examine associations between indicators of estrogen exposure from women’s reproductive history and brain MRI biomarkers of Alzheimer’s disease (AD) in midlife.Methods.We evaluated 99 cognitively normal women ages 52+6 years, and 29 men ages 52+7 years, with reproductive history data, neuropsychological testing, and volumetric MRI scans. We used multiple regressions to examine associations between reproductive history indicators, voxel-wise gray matter volume (GMV), memory and global cognition scores, adjusting for demographics and midlife health indicators. Exposure variables were menopause status, age at menarche, age at menopause, reproductive span, hysterectomy status, number of children and pregnancies, use of menopause hormonal therapy (HT) and hormonal contraceptives (HC).Results.All menopausal groups exhibited lower GMV in AD-vulnerable regions as compared to men, with peri-menopausal and post-menopausal groups also exhibiting lower GMV in temporal cortex as compared to the pre-menopausal group. Reproductive span, number of children and pregnancies, use of HT and HC were positively associated with GMV, chiefly in temporal cortex, frontal cortex, and precuneus, independent of age, APOE-4 status, and midlife health indicators. Although reproductive history indicators were not directly associated with cognitive measures, GMV in temporal regions was positively associated with memory and global cognition scores.Conclusions.Reproductive history events signaling more estrogen exposure, such as pre-menopausal status, longer reproductive span, higher number of children, use of HT and HC, were associated with larger GMV in midlife women. Further studies are needed to elucidate sex-specific biological pathways through which reproductive history influences cognitive aging and AD-risk.

Shared Genetics Between Age at Menopause, Early Menopause, POI and Other Traits

Reproductive ageing leading to menopause is characterized by depletion of follicles and its regulating mechanisms are only partly understood. Early age at menopause and premature ovarian insufficiency (POI) are associated with several other traits such as cardiovascular disease, dyslipidemia, osteoporosis and diabetes. In large cohorts of Northern European women hundreds of Single Nucleotide Polymorphisms (SNPs) have been identified to be associated with age at menopause. These SNPs are located in genes enriched for immune and mitochondrial function as well as DNA repair and maintenance processes. Genetic predisposition to earlier menopause might also increase the risk of other associated traits. Increased risk for cardiovascular disease in women has been associated with age at menopause lowering SNPs. Pleiotropy between early age at menopause and increased mortality from coronary artery disease has been observed, implicating that genetic variants affecting age at menopause also affect the risk for coronary deaths. This review will discuss the shared genetics of age at menopause with other traits. Mendelian Randomization studies implicate causal genetic association between age at menopause and age at menarche, breast cancer, ovarian cancer, BMD and type 2 diabetes. Although the shared biological pathways remain to be determined, mechanisms that regulate duration of estrogen exposure remain an important focus.

The influence of endogenous and exogenous hormonal factors on migraine in spontaneous postmenopausal women: A nationwide population-based study in South Korea

Background Hormonal and menstrual factors are known to influence migraines in women. However, studies in the postmenopausal period are relatively insufficient for clinical translation. This study investigated the influence of endogenous and exogenous hormonal factors on migraines in spontaneous menopausal women. Methods We obtained and analyzed the data related to hormonal factors from the Korean Health Examination database. A migraine diagnosis was identified using the Korean National Health Insurance Service database between 2009 and 2018. We observed migraine occurrence in spontaneous postmenopausal women. Study populations were divided into two groups depending on new diagnosis of migraine during the follow up periods. We investigated the association between endogenous and exogenous hormonal factors and migraine. Results 1,114,742 spontaneous postmenopausal women were enrolled. Migraine risk tended to increase in the shorter lifetime number of years of menstruation group compared to the group with lifetime number of years of menstruation ≥40 years. All of the hormone replacement therapy (HRT) groups showed higher risk compared with the non-HRT group. Migraine risk tends to increase with greater postmenopausal years compared to the postmenopausal <5 years group. Conclusion Our study suggests that female hormonal factors, including endogenous and exogenous estrogen exposure, may be associated with migraine occurrence in spontaneous menopausal women.

RISK FACTORS FOR ESTROGEN EXPOSURE IN VARIOUS GRADES OF ENDOMETRIOID CARINOMA

Background: Incidence endometrial cancer in Southeast Asia it is estimated that 41% of new cases emerge. The incidence of endometrial cancer in Dr. Soetomo General Hospital has increased every year. In 2016 there were 119 new cases of endometrial cancer and in 2017 there were 160 cases. 75%-80% is type I endometrial cancer (endometrioid carcinoma). Risk factors for estrogen exposure (early menarche, parity, obesity) are risk factors for endometrial cancer. The prognosis of endometrial cancer depends on the grade. This study aims to determine differences in risk factors for estrogen exposure in various grades of type I endometrial cancer (endometrioid carcinoma) in the Poli Onkologi Satu Atap Dr. Soetomo General Hospital Surabaya. Methods: the research method was analytic observational with cross-sectional design. Sample size of 40 medical records was taken by total sampling technique. Research variables include age of menarche, parity, BMI, and grade of endometrial cancer. The instrument used was a data collection sheet and medical records. Data analysis using chi-square test. Results: The results showed 52% patients were grade 1-2, there were 95% of menarche patients in the age range of 12-14 years, 62.5% patients had parity of 1-2 and 52% patients, BMI was underweight-normal category. Test results based on early menarche did not show significant differences between grades 1-2 and grade 3 in endometrioid carcinoma (p = 0.168). Likewise, parity in various grades of endometrial cancer type I (endometrioid carcinoma) there was no significant difference (p = 0.220) and BMI also no significant difference (p = 0.987). Conclusions: risk factors for estrogen exposure which include menarche, parity, obesity do not make a significant differences to the grades of endometrioid carcinoma.

Estrogen and COVID-19 symptoms: Associations in women from the COVID Symptom Study

It has been widely observed that adult men of all ages are at higher risk of developing serious complications from COVID-19 when compared with women. This study aimed to investigate the association of COVID-19 positivity and severity with estrogen exposure in women, in a population based matched cohort study of female users of the COVID Symptom Study application in the UK. Analyses included 152,637 women for menopausal status, 295,689 women for exogenous estrogen intake in the form of the combined oral contraceptive pill (COCP), and 151,193 menopausal women for hormone replacement therapy (HRT). Data were collected using the COVID Symptom Study in May-June 2020. Analyses investigated associations between predicted or tested COVID-19 status and menopausal status, COCP use, and HRT use, adjusting for age, smoking and BMI, with follow-up age sensitivity analysis, and validation in a subset of participants from the TwinsUK cohort. Menopausal women had higher rates of predicted COVID-19 (P = 0.003). COCP-users had lower rates of predicted COVID-19 (P = 8.03E-05), with reduction in hospital attendance (P = 0.023). Menopausal women using HRT or hormonal therapies did not exhibit consistent associations, including increased rates of predicted COVID-19 (P = 2.22E-05) for HRT users alone. The findings support a protective effect of estrogen exposure on COVID-19, based on positive association between predicted COVID-19 with menopausal status, and negative association with COCP use. HRT use was positively associated with COVID-19, but the results should be considered with caution due to lack of data on HRT type, route of administration, duration of treatment, and potential unaccounted for confounders and comorbidities.

The Impact of Exogenous Estrogen Exposure on the Characteristics and Outcome of Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early-Stage Breast Cancer

<b><i>Introduction:</i></b> The impact of exogenous estrogen exposure on breast cancer characteristics and outcomes is not well described. We aimed to investigate the effect of prior treatment with oral contraceptives (OCT), hormone replacement therapy (HRT), and fertility treatments on early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. <b><i>Methods:</i></b> This is a single-center retrospective cohort study comprising all women with ER-positive, HER2-negative, early breast cancer whose tumors were sent to Oncotype DX analysis between 2005 and 2012. Data on prior exposures to OCT, HRT, and fertility treatments were collected. The impact of these exposures on prespecified histopathological features was assessed including tumor size, nodal status, intensity of the hormonal receptors, grade, Oncotype recurrence score, Ki67, and lymphovascular and perineural invasion. The impact of these exposures on disease-free survival (DFS) and overall survival (OS) was also evaluated. <b><i>Results:</i></b> A total of 620 women were included, of which 19% had prior exposure to OCT, 30% to HRT, and 11% to fertility treatments. OCT use was associated with smaller (≤1 cm) tumors (<i>p</i> = 0.023) and were less likely to have grade 3 disease (<i>p</i> = 0.049). No other associations were found between exogenous estrogen exposure and tumor characteristics. Median follow-up was 10.4 years. Ten-year DFS was 85.7%, and it was not influenced by exogenous exposure. Ten-year OS was 90.2%, and OCT was associated with improved OS in univariate analysis (HR = 0.31, 95% CI: 0.11–0.85), but this difference did not remain significant in multivariate analysis (<i>p</i> = 0.275). <b><i>Conclusion:</i></b> The impact of exogenous estrogen exposure on ER-positive, HER2-negative early breast cancer characteristics is limited. In the long term, none of the evaluated exposures had negative effect on DFS and OS.

Using different surgical techniques and ideas to reduce post-operative adhesion formation: a systematic review and meta-analysis

Adhesion development is the most common sequelae of intra-abdominal and pelvic surgery. Using a good surgical technique is advocated as a first step in preventing adhesions. However, the evidence for different surgical techniques to reduce adhesion formation needs confirmation. This review contributed to the growing knowledge pool by elucidating factors that potentially predispose to the development of adhesions. A literature search was performed using the PubMed database for all relevant English language articles and were reviewed with particular attention to predisposing factors to post-operative adhesion development. In addition, the reference lists of each article were reviewed to identify additional relevant articles. Various factors have been shown to directly increase the risk of post-operative adhesion development; namely, certain genetic polymorphisms in the interleukin-1 receptor antagonist, increased estrogen exposure, and endometriosis. There were 28 papers with 27 studies included for a systematic review. Of these, 17 studies were eligible for meta-analysis and 11 for qualitative assessment only. None of the techniques that were compared significantly reduced the incidence of adhesive small bowel obstruction. In a small low-quality trial, the pregnancy rate increased after subserous fixation of suture knots. However, the incidence of adhesions was lower after laparoscopic compared with open surgery (relative risk (RR): 0.14; 95% confidence interval (CI): 0.03-0.61) and when the peritoneum was not closed (RR: 0.36; 95% CI: 0.21-0.63). None of the specific techniques that were compared reduced the two main adhesion-related clinical outcomes, small bowel obstruction and infertility.

Endogenous estrogen exposure and chronic kidney disease; a 15-year prospective cohort study

Background Despite strong evidence demonstrating the role of estrogen as a protective factor for kidney function in women, limited data are available regarding the influence of endogenous estrogen exposure (EEE) on chronic kidney disease (CKD). The present study aimed to assess the incidence of CKD in women with various levels of EEE. Methods In a prospective population-based study over a 15-year follow-up, a total of 3043 eligible women aged 30–70 years, participating in Tehran-Lipid and Glucose-Study were recruited and divided into two groups (EEE < 11 and EEE ≥ 11 years). EEE calculated based on age at menarche, age at menopause, number and duration of pregnancies, lactation, and duration of oral contraceptive use after excluding the progesterone dominant phase of the menstrual cycle. Cox’s proportional hazards model was applied to estimate the hazard ratio of CKD between the study groups, after adjusting for confounders. Results The total cumulative incidence rate of CKD was 50.1 per 1000 person years; 95% CI: 47.7–52.6); this was 53.9 (95%CI, 50.2–57.8) and 47.1 (95%CI, 44.0–50.4) per 1000 person years in women with EEE < 11 and EEE ≥ 11 years, respectively. The model adjusted for age, BMI, smoking, hypertension, and diabetes showed that the hazard ratio (HR) of incidence CKD in women with EEE < 11 compare to those with EEE ≥ 11 years in the subgroup of women aged< 45 years was 2.66(95% CI, 2.2, 3.2), whereas, in the subgroup aged ≥45 years, it was 1.22 (95% CI, 1.04, 1.4). Conclusion This study shows a higher HR of CKD incidence in women with low EEE levels in their later life. Screening of these women for CKD may be recommended.

Reproductive History and Age of Onset for Women Diagnosed with Amyotrophic Lateral Sclerosis: Data from the National ALS Registry: 2010–2018

<b><i>Background:</i></b> Amyotrophic lateral sclerosis (ALS) is a neurological disease of largely unknown etiology with no cure. The National ALS Registry is a voluntary online system that collects demographic and reproductive history (females only) data from patients with ALS. We will examine the association between demographic and reproductive history among female patients aged &#x3e;18 years and various ages of onset for ALS. <b><i>Methods:</i></b> Data from a cross-sectional study were collected and examined for 1,018 female ALS patients. Patient characteristics examined were demographics including race, BMI, and familial history of ALS. Among patients, information on reproductive history, including age at menopause, ever pregnant, and age at first pregnancy was collected. Unadjusted and adjusted logistic regression models were used to estimate OR and 95% CI in this study. <b><i>Results:</i></b> Women were more likely to be diagnosed with ALS before age 60 if they were nonwhite (<i>p</i> = 0.015), had attended college (<i>p</i> = 0.0012), had a normal BMI at age 40 (<i>p</i> &#x3c; 0.0001), completed menopause before age 50 (<i>p</i> &#x3c; 0.0001), and had never been pregnant (<i>p</i> = 0.046) in the univariate analysis. Women diagnosed with ALS before age 60 were also more likely to have limb site of onset (<i>p</i> &#x3c; 0.0001). In the multivariate analysis, those who completed menopause before age 50 were more likely to be diagnosed with ALS before age 60 (OR = 1.8, 95% CI: 1.4–2.3) compared with women who completed menopause at or after age 50, after controlling for race, ever pregnant, age at first pregnancy, family history of ALS, education status, smoking history, and BMI at age 40. For women who were diagnosed with ALS before age 50, the odds of them entering menopause before age 50 climb to 48.7 (95% CI: 11.8, 200.9). The mean age of ALS diagnosis for women who completed menopause before age 50 was 58 years and 64 years for women who entered menopause after age 50 (<i>p</i> &#x3c; 0.0001). <b><i>Conclusion:</i></b> Women who reported completing menopause before age 50 were significantly more likely to be diagnosed with ALS before age 60 compared with those who reported entering menopause after age 50. More research is needed to determine the relationship between female reproductive history, especially regarding endogenous estrogen exposure and early-onset ALS.