Endogenous Estrogen Exposure Research Articles

Female reproductive factors, exogenous hormone use, and incident chronic kidney disease and end-stage renal disease.

Younger women have a slower progressive loss of kidney function than age-matched men and the sex advantage diminishes after menopause, suggesting a role for female hormones in the development of kidney diseases. To examine the relationships of numerous reproductive factors and exogenous hormone use with long-term risk of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in women. A total of 260,108 women without prevalent CKD and ESRD were included. The relationships of various reproductive factors and exogenous hormone use with incident CKD and ESRD were assessed, with multivariable adjustment for potential confounders. During a median of ∼12.5 years of follow-up, 8,766 CKD and 554 ESRD cases were identified. Younger age at first live birth, hysterectomy or bilateral oophorectomy before 50 years old, menopausal before 45 years old, and menopausal hormone therapy (MHT) initiated before 50 years old was associated with a higher risk of CKD. The relationships of these factors with ESRD were generally consistent with those for CKD. Each 5-year increment in menopausal age was associated with an 11% lower risk of CKD (HR = 0.89; 95% CI: 0.87, 0.91) and a 13% lower risk of ESRD (HR = 0.87; 95% CI: 0.79, 0.95). Each 5-year delay in starting MHT was associated with a 13% lower risk of CKD (HR = 0.87; 95% CI: 0.84, 0.90) and a 15% lower risk of ESRD (HR = 0.85; 95% CI: 0.73, 0.99). Several reproductive characteristics reflecting shorter cumulative exposure to endogenous estrogen or premature exposure to exogenous hormones are associated with a greater risk of CKD and ESRD in women, supporting a potential role of female hormones in renal pathophysiology.

Endogenous estrogen exposure and hypertension risk; a population-based cohort study with about two decades of follow-up.

The impact of endogenous estrogen exposure (EEE) on hypertension (HTN) incidence has not been investigated yet. This study aimed to evaluate HTN incidence in women with different endogenous estrogen durations. Information was gathered from the Tehran Lipid and Glucose Study (TLGS) to conduct current research. At the initiation of the study, 4463 post-menarche normotensive women, including 3599 premenopausal and 864 menopausal women, were included. EEE was calculated for each woman, and they were followed up for the HTN event. According to the EEE, the hazard ratios and 95% confidence intervals (CI) for the HTN event were presented using Cox proportional hazards regression models (unadjusted and adjusted). The median (interquartile range) of follow-up (between menarche and the date of HTN incidence or last follow-up) was 33.2(25.1, 42.3) years. The event of menopause occurred in 31.8% of participants. The unadjusted model's findings illustrated that the EEE z-score was inversely associated with HTN incidence in post-menarcheal women [unadjusted hazard ratio (HR) 0.47, 95% CI 0.44, 0.50], meaning that the risk of HTN decreased by 53% for every 1-SD rise in the EEE z-score. After adjusting for potential confounders, the results showed no statistically significant changes (adjusted HR 0.46, 95% CI 0.43-0.49). In participants with prehypertension at baseline, the hazard of HTN decreased by 56% per 1-SD rise in the EEE z-score. This longitudinal study demonstrated the protective effect of a longer EEE duration on HTN risk, even among those with prehypertension status.

Age at menarche and idiopathic pulmonary fibrosis: a two-sample mendelian randomization study

BackgroundSex difference in the incidence rate of idiopathic pulmonary fibrosis (IPF) indicates that estrogen has a certain protective effect on the disease. Nevertheless, there is a dearth of study investigating the association between factors pertaining to endogenous estrogen exposure level, such as age at menarche (AAM) in women, and IPF. Our study intended to employ Mendelian randomization (MR) method to elucidate the causal association between AAM and IPF.MethodsOur study utilized AAM as a measure of endogenous estrogen exposure and investigated its causal effect on the risk of IPF through MR. We employed the inverse variance weighted (IVW) method to assess the causal relationship between AAM and IPF risk, with supplementary analyses conducted using the weighted median estimator (WME) and MR-Egger method. Several sensitivity analyses were performed to assess the dependability of MR estimates.ResultsA total of 9 selected single nucleotide polymorphisms (SNPs) significantly associated with AAM were selected as instrumental variables. The IVW method showed that genetically later AAM was associated with an increased risk of IPF (odds ratio [OR] = 1.0014, 95%confidence interval [CI] = 1.0005–1.0023, p = 0.001). The median weighting method and the MR-Egger method obtained similar estimates, and no heterogeneity or pleiotropy was found, indicating that the results were robust.ConclusionsOur MR study suggested a causal relationship between a later onset of menarche and a heightened susceptibility to IPF.

Does parity and risk of dementia follow a U‐shaped relationship? Findings from the Cache County Study of Memory and Aging

AbstractBackgroundRecent evidence from the UK Biobank of over 273,000 women indicates a U‐shaped relationship between parity and risk of dementia, with nulliparity and grand multiparity showing increased risk of dementia compared to women having 1‐3 births after adjustment for important sociodemographic and health history factors, but not Apolipoprotein E (ApoE) polymorphism. ApoE4 genotype, a known risk factor for Alzheimer’s disease and Alzheimer’s disease related dementia (AD/ADRD), has been shown to be related to higher potential female fertility due to increased concentrations of progesterone. Our objective was to determine whether a similar U‐shaped relationship is present in the population based Cache County Study of Memory in Aging (CCSMA) cohort, after controlling for important confounding factors including ApoE genotype.MethodsCCSMA was a longitudinal study that investigated risk factors contributing to AD/ADRD and other dementias. CCSMA enrolled 90% (N = 5,092, n = 2928 women) of the Cache County, Utah permanent resident population aged 65 and older as of January 1, 1995. Participants were followed for four triennial waves for AD/ADRD ascertainment. Prior number of live births for CCSMA women was assessed via self‐report and validated via linked Utah Population Database records (99% successful linkage). Adjusted risk ratios using Poisson regression with robust variance were calculated to assess whether parity was associated with later dementia risk, adjusting for important sociodemographic and health history factors (Table 1).ResultsAmong the total sample, 5.6% were nulliparous, 18.4% had 1‐2 births, 54% had 3‐5 births, and 22% had 6+ births. Over the course of the study, 12% were diagnosed with AD and 7% with ADRD. Compared to women with 3‐5 births, women with zero, 1‐2, and ≥6 live births had an aRR of 1.16 (95% CI: 0.80, 1.69), 1.00 (95% CI: 0.76, 1.32), and 1.21 (95% CI: 0.96, 1.53) (Figure 1), respectively. Results were similar for ADRD.ConclusionOur results support a U‐shaped relationship between parity and dementia risk. Whether the relationship between parity and dementia risk is being driven by social and behavioral factors involved in parenting or biological factors associated with childbearing (e.g., total endogenous estrogen exposure) warrants further investigation.

Lifetime cumulative effect of reproductive factors on ischaemic heart disease in a prospective cohort

ObjectiveThis study aimed to examine the association between lifetime oestrogen exposure and ischaemic heart disease (IHD), based on the hypothesis that higher lifetime oestrogen exposure is linked to lower cardiovascular...

THU197 Peripheral Precocious Puberty In A 6-year-old Girl With Extreme Estradiol Elevation With Rapid Normalization: A Case Report

Abstract Disclosure: L. Meller: None. M. Marinkovic: None. M.E. Patterson: None. Background: Peripheral precocious puberty (PPP) in girls is typically associated with ovarian or adrenal tumors, ovarian cysts, McCune-Albright syndrome (MAS), or exogenous hormone exposure. We present an unusual case of PPP with extreme estradiol elevation and rapid normalization. Clinical Case: A 6.5-year-old previously healthy girl presented with two-month history of bilateral breast growth and tenderness, associated with daily cramping. Subsequently, she developed clear, odorless vaginal discharge. Two days prior to the visit she started light vaginal bleeding. Parents denied any medication intake or use of lavender or essential oils. She had no family history of early puberty. On the exam, she was tall for her age (95%) with a recent growth spurt. She had breast buds (Tanner 2) and vaginal bleeding without pubic hair (Tanner 1) or signs of hyperandrogenemia. There were no skin lesions or gross bone abnormalities. Bone age was equal to chronological age. She had an extreme elevation of estradiol of 156pg/mL and 170pg/mL (reference range<=16pg/mL) measured two weeks apart with prepubertal LH/FSH. Thyroid tests were normal. Pelvic ultrasound and abdomen/pelvis CT showed no abnormalities of ovaries and adrenal glands. Nine days after the onset, vaginal bleeding and cramping spontaneously resolved. Estradiol levels measured two days after cessation of vaginal bleeding normalized (7pg/mL) while LH/FSH remained prepubertal. Interestingly, two weeks after the bleeding stopped her pelvic ultrasound showed significantly enlarged ovaries (R 4.1mL, L 4.3mL), while her estradiol remained normal (5pg/mL). Conclusion: We describe an unusual presentation of PPP in a young girl with extreme estradiol elevation causing simultaneous premature breast development and vaginal bleeding. We suspect PPP was secondary to ruptured ovarian cyst that was not captured by imaging. Other differentials include MAS, exogenous hormone exposure, adrenal or ovarian tumors. These were unlikely due to lack of abnormal skin or bone findings, environmental hormone exposure and normal imaging. Her ovarian enlargement could be secondary to high endogenous estrogen exposure, and she may be at risk of developing central precocious puberty. This unique case emphasizes the importance of prompt assessment of children with precocious puberty and discusses the differential diagnosis process for PPP with markedly elevated estradiol with rapid normalization. Presentation: Thursday, June 15, 2023

Number of children and cognitive function among Chinese menopausal women: The mediating role of depressive symptoms and social participation

ObjectivesThis study examined the association between number of children and cognitive function and its possible hormone and psychosocial pathways in Chinese menopausal women. MethodsWe analyzed data from the China Health and Retirement Longitudinal Study (CHALRS), including 4803 menopausal women. Ordinary least squares (OLS) regression modeling and structural equation modeling (SEM) were applied to explore the association between number of children and cognitive function and the potential mechanisms. ResultsOverall, the median number of biological children was three among participants. The cognitive function score decreased significantly with increasing numbers of children [β = −0.547, 95 % confidence interval (CI): −0.677, −0.416]. There was a significant interaction between number of children and residence (P = 0.003). Compared with older women with three or less children, women with more than three children had worse cognitive function (β = −0.798, 95 % CI: −1.081, −0.514). Mediation analysis verified that depressive symptoms and social participation partially mediate the associations between the number of children and cognitive function. LimitationsFirst, because of the cross-sectional design, our study was unable to make causal inferences. Second, information about endogenous estrogen exposure was not collected in CHARLS. Third, recall bias may exist due to the use of self-reported data. ConclusionOur results indicated that a higher number of children is associated with an increased risk for cognitive impairment. We suggest paying special attention to mental and social health among women with multiple children (>3).

Re-Evaluating the Association Between Hormonal Contraception and Breast Cancer Risk.

This review aims to summarize and assess key studies investigating the relationship between hormonal contraception and breast cancer risk. Approximately two-thirds of breast cancers express the estrogen receptor, and long-term exposure to estrogen is a debated risk factor for breast cancer development. This hypothesis is based on prior studies looking at reproductive risk factors (endogenous estrogen exposure) along with hormone replacement therapy (exogenous hormone exposure). Historically accepted reproductive risk factors include age at menarche, age at first delivery, and parity. Exogenous hormone exposure encompasses both receipt of hormonal contraception and menopausal hormone replacement therapy. This review highlights the reported risks associated with the most common hormonal contraception methods including oral, transdermal, and transvaginal routes. Large observational studies of the past and more recent works are summarized highlighting gaps in knowledge. Several themes emerge: difficulty accounting for well-established risk factors in analyses of epidemiologic studies, challenges determining whether associations between hormonal contraception and breast cancer are due to the exogenous hormones themselves or to increased engagement with the medical system, and discrepancies between statistically significant and clinically significant risk, odds, and hazard ratios. Understanding the strengths and limitations of these studies will help providers in and outside of oncology support women making decisions regarding both cancer risk-reduction and family planning.

Lifetime Cumulative Effect of Reproductive Factors on Stroke and Its Subtypes in Postmenopausal Chinese Women: A Prospective Cohort Study.

Multiple reproductive factors are associated with stroke. Little is known about the cumulative effects of reproductive factors during a reproductive life course on stroke and its subtypes, especially among female Chinese individuals. The objective of this study was to assess the associations of lifetime cumulative estrogen exposure due to reproductive factors with stroke and its etiologic subtypes among postmenopausal Chinese women. Postmenopausal women without prior stroke at baseline (2004-2008) were selected from the China Kadoorie Biobank (CKB). Lifetime cumulative estrogen exposure due to reproductive factors was assessed using 3 composite indicators: reproductive lifespan (RLS), endogenous estrogen exposure (EEE), and total estrogen exposure (TEE). Stroke and its subtypes, ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), were identified through linkage to a disease registry system and health insurance data during follow-up (2004-2015). Multivariable-adjusted Cox proportional hazards regression models were applied to estimate the adjusted hazard ratio (aHR) and 95% CIs for the risk of stroke by quartiles of RLS, EEE, and TEE, respectively. A total of 122,939 postmenopausal participants aged 40-79 years without prior stroke at baseline were included. During a median follow-up period of 8.9 years, 15,139 cases with new-onset stroke were identified, including 12,853 cases with IS, 2,580 cases with ICH, and 269 cases with SAH. Compared with the lowest quartile (Q1) of RLS, the highest quartile (Q4) had a lower risk of total stroke (aHR: 0.95, 95% CI 0.92-0.98), IS (aHR: 0.95, 95% CI 0.92-0.98), and ICH (aHR: 0.87, 95% CI 0.81-0.94). Both EEE and TEE displayed a graded association with the subsequent descending risk of total stroke (aHR for Q4 vs Q1: EEE: 0.85, 95% CI 0.82-0.89; TEE: 0.87, 95% CI 0.84-0.90), IS (aHR for Q4 vs Q1: EEE: 0.86, 95% CI 0.83-0.90; TEE: 0.86, 95% CI 0.83-0.89), and ICH (EEE: 0.73, 95% CI 0.65-0.81; TEE: 0.83,95% CI 0.76-0.91), with a p for trend < 0.001 for all these associations. Individuals' cumulative estrogen exposure due to reproductive factors could potentially be a valuable indicator for risk stratification of stroke events after menopause.

Reproductive Lifespan and Motor Progression of Parkinson's Disease.

Objectives: Estrogen not only plays a key role in the decreased risk of Parkinson’s disease (PD) but also influences its severity. We aimed to explore the effect of the reproductive lifespan on the motor progression of PD female patients in a large prospective cohort study. Methods: A competing risk analysis with a Fine and Gray model on 491 female and 609 male patients with PD was conducted. We regarded the chance of faster motor progression (as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) III increasing by ≥16 points during follow-up) and the chance of death as competing risks. The reproductive lifespan was regarded as the variable of interest, while faster motor progression was set as the primary outcome. Results: In the multivariable competing risk analysis, the male sex was not significantly associated with faster motor progression (subdistribution hazard ratio (SHR) 0.888, 95% CI 0.652–1.209, p = 0.450), while a shorter reproductive lifespan was associated with faster motor progression in women (SHR 0.964, 95% CI 0.936–0.994, p = 0.019). Sensitivity analysis indicated that a shorter reproductive lifespan was also significantly associated with faster motor progression in the 48 female patients who reported menopause after the onset of PD (SHR 0.156, 95% CI 0.045–0.542, p = 0.003). A linear mixed model also revealed the significant main effects of a short reproductive lifespan on the higher UPDRS III score in PD female patients at the last visit (p = 0.026). Conclusions: Our study indicates that a short reproductive lifespan contributes to faster motor progression in PD female patients, which has important implications for understanding the role of endogenous estrogen exposure in female PD and is beneficial to select appropriate patients in clinical trials.

Ovarian steroid hormones: A long overlooked but critical contributor to brain aging and Alzheimer's disease.

Ovarian hormones, particularly 17β-estradiol, are involved in numerous neurophysiological and neurochemical processes, including those subserving cognitive function. Estradiol plays a key role in the neurobiology of aging, in part due to extensive interconnectivity of the neural and endocrine system. This aspect of aging is fundamental for women’s brains as all women experience a drop in circulating estradiol levels in midlife, after menopause. Given the importance of estradiol for brain function, it is not surprising that up to 80% of peri-menopausal and post-menopausal women report neurological symptoms including changes in thermoregulation (vasomotor symptoms), mood, sleep, and cognitive performance. Preclinical evidence for neuroprotective effects of 17β-estradiol also indicate associations between menopause, cognitive aging, and Alzheimer’s disease (AD), the most common cause of dementia affecting nearly twice more women than men. Brain imaging studies demonstrated that middle-aged women exhibit increased indicators of AD endophenotype as compared to men of the same age, with onset in perimenopause. Herein, we take a translational approach to illustrate the contribution of ovarian hormones in maintaining cognition in women, with evidence implicating menopause-related declines in 17β-estradiol in cognitive aging and AD risk. We will review research focused on the role of endogenous and exogenous estrogen exposure as a key underlying mechanism to neuropathological aging in women, with a focus on whether brain structure, function and neurochemistry respond to hormone treatment. While still in development, this research area offers a new sex-based perspective on brain aging and risk of AD, while also highlighting an urgent need for better integration between neurology, psychiatry, and women’s health practices.

Exogenous Hormone Factors in Relation to the Risk of Malignant Melanoma in Women: A Systematic Review and Meta-Analysis.

Simple SummaryMany epidemiological studies have examined the relationship between cutaneous malignant melanoma (CMM) and both endogenous oestrogen exposure (e.g., age at menarche and parity) and exogenous hormone use (e.g., oral contraceptives (OCs) and menopausal hormone therapy (MHT)). Though a previous meta-analysis investigating the relationship between characteristics of female endocrine status and CMM risk found no significant association, the potential role of THERAPY AS oral contraceptive (OC) and hormonal replacement therapy (MHT) use still remains controversial. Since then, several studies have been published about the therapy with contrasting results, while CMM incidence continues to increase with a significant gender divergence. The therapy of OC and MHT may play a role in CMM and the removal of this could be useful as emerging therapeutics in melanoma. Therefore, we conducted this systematic review and meta-analysis to summarize the evidence and derive a more accurate estimation of exogenous hormone factors in women and CMM.The influence of exogenous female hormones on the risk of developing malignant melanoma in women remains controversial. The aim of our review and meta-analysis is to summarize the evidence and derive a more accurate estimation of the association between oral contraceptives (OCs) or menopausal hormone therapy (MHT) and the risk of developing malignant melanoma in women. PubMed, Web of Science, and Scopus database were searched for studies published up until October 2021. The PRISMA statement and MOOSE guidelines were followed. Studies were pooled using a random effects model. Heterogeneity was explored with the chi-square-based Cochran’s Q statistic and the I2 statistic. Publication bias was assessed with Begg’s test and Egger’s test. Forty-six studies met the eligibility criteria. The pooled analysis (26 studies) on OC use and the risk of developing cutaneous malignant melanoma (CMM) showed no significant association, but demonstrated significant association for cohort studies (OR 1.08, 95% CI 1.01–1.16; I2 = 0.00%, p = 0.544). The pooled analysis (16 studies) showed a significantly increased risk of CMM in association with MHT (OR 1.15, 95% CI 1.08–1.23; I2 = 25.32%, p = 0.169). Stratifying the results by study design showed that a significant increased risk of CMM was associated with MHT in the cohort studies (OR 1.12; 95% CI 1.04–1.19; I2 = 0%, p = 0.467). No significant publication bias could be detected. Further studies are needed to investigate the potential association with formulation, duration of use, and dosage of use, and to better understand the role of possible confounders.

The Impact of Endogenous Estrogen Exposure Duration on Fracture Incidence: a Longitudinal Cohort Study

Although it is well documented that estrogen hormone is positively associated with bone mineral density and lower risk of fracture, there are limited studies on the association between duration of endogenous estrogen exposure (EEE) and fracture, especially by longitudinal design. This study aimed to investigate the relationship between EEE with fracture incidence by longitudinal design in a community-based study. A total of 5269 eligible postmenarcheal women, including 2411 premenopausal and 2858 menopausal women, were recruited from among the Tehran Lipid and Glucose Study. Cox proportional hazards regression model with adjustment of potential confounders was performed to assess the relationship between duration of EEE and incident of any hospitalized fractures. A total of 26.7% (1409/5269) women were menopausal at the baseline, and 2858 of the remaining participants reached menopause at the end of follow-up. Results of the unadjusted model demonstrated that the EEE z-score was negatively associated with fracture incidence [unadjusted hazard ratio (HR) 0.81, 95% CI 0.68-0.96] in postmenarchal women, indicating that per 1-SD increase of EEE z-score, the hazard of fracture reduced by 19%. Results remained statistically unchanged after adjustment for potential confounders (adjusted HR 0.70, 95% CI 0.58-0.86). The findings of this cohort study suggest that a longer duration of EEE has a protective effect on fracture incidence; a point that needs to be considered in fracture risk assessment.

Reproductive factors and the risk of incident dementia: A cohort study of UK Biobank participants.

Women's reproductive factors have been associated with the risk of dementia; however, these findings remain uncertain. This study aimed to examine the risk of incident all-cause dementia associated with reproductive factors in women and the number of children in both sexes and whether the associations vary by age, socioeconomic status (SES), smoking status, and body mass index (BMI) in the UK Biobank. A total of 273,240 women and 228,957 men without prevalent dementia from the UK Biobank were included in the analyses. Cox proportional hazard regressions estimated hazard ratios (HRs) for reproductive factors with incident all-cause dementia. Multiple adjusted models included age at study entry, SES, ethnicity, smoking status, systolic blood pressure, BMI, history of diabetes mellitus, total cholesterol, antihypertensive drugs, and lipid-lowering drugs. Over a median of 11.8 years follow-up, 1,866 dementia cases were recorded in women and 2,202 in men. Multiple adjusted HRs ((95% confidence intervals (CIs)), p-value) for dementia were 1.20 (1.08, 1.34) (p = 0.016) for menarche <12 years and 1.19 (1.07, 1.34) (p = 0.024) for menarche >14 years compared to 13 years; 0.85 (0.74, 0.98) (p = 0.026) for ever been pregnant; 1.43 (1.26, 1.62) (p < 0.001) for age at first live birth <21 compared to 25 to 26 years; 0.82 (0.71, 0.94) (p = 0.006) for each abortion; 1.32 (1.15, 1.51) (p = 0.008) for natural menopause at <47 compared to 50 years; 1.12 (1.01, 1.25) (p = 0.039) for hysterectomy; 2.35 (1.06, 5.23) (p = 0.037) for hysterectomy with previous oophorectomy; and 0.80 (0.72, 0.88) (p < 0.001) for oral contraceptive pills use. The U-shaped associations between the number of children and the risk of dementia were similar for both sexes: Compared with those with 2 children, for those without children, the multiple adjusted HR ((95% CIs), p-value) was 1.18 (1.04, 1.33) (p = 0.027) for women and 1.10 (0.98, 1.23) (p = 0.164) for men, and the women-to-men ratio of HRs was 1.09 (0.92, 1.28) (p = 0.403); for those with 4 or more children, the HR was 1.14 (0.98, 1.33) (p = 0.132) for women and 1.26 (1.10, 1.45) (p = 0.003) for men, and the women-to-men ratio of HRs was 0.93 (0.76, 1.14) (p = 0.530). There was evidence that hysterectomy (HR, 1.31 (1.09, 1.59), p = 0.013) and oophorectomy (HR, 1.39 (1.08, 1.78), p = 0.002) were associated with a higher risk of dementia among women of relatively lower SES only. Limitations of the study include potential residual confounding and self-reported measures of reproductive factors, as well as the limited representativeness of the UK Biobank population. In this study, we observed that some reproductive events related to shorter cumulative endogenous estrogen exposure in women were associated with higher dementia risk, and there was a similar association between the number of children and dementia risk between women and men.

Female Reproductive Factors and Incidence of Nontuberculous Mycobacterial Pulmonary Disease Among Postmenopausal Women in Korea.

There are conflicting results regarding endogenous estrogen exposure and risk of incident nontuberculous mycobacterial pulmonary disease (NTM-PD). In addition, evidence on impact of hormone replacement therapy (HRT) on risk of NTM-PD is lacking. This study aimed to evaluate the impacts of endogenous estrogen exposure and HRT on risk of NTM-PD in postmenopausal women. This population-based cohort study comprised 1400095 postmenopausal women without previous NTM-PD who participated in the 2009 national health screening exam in South Korea. The cohort was followed until the date of incident NTM-PD, death, or December 2018. We evaluated whether lifetime endogenous estrogen exposure and HRT were associated with incident NTM-PD. Endogenous estrogen exposure was evaluated using age at menarche and menopause and reproductive period (duration between age at menarche and age at menopause). During a median of 8.4 (interquartile range, 8.2-8.7) years of follow-up, 0.1% of participants (1818/1400095) developed NTM-PD, with an incidence rate of 0.15/1000 person-years. Multivariable Cox regression analyses showed no significant relationship between endogenous estrogen exposure (age at menarche, age at menopause, and reproductive period) and risk of NTM-PD. In contrast, duration of HRT showed a significant dose-response relationship with incident NTM-PD even after adjustment for demographics and reproductive factors (adjusted hazard ratio [95% CI]: 1.30 [1.12-1.51] in HRT for <2 years; 1.28 [1.03-1.59] in 2-5 years; and 1.65 [1.33-2.05] in ≥5 years). While there was no significant association with endogenous estrogen exposure, HRT was monotonically associated with increased risk of NTM-PD in postmenopausal women.

Female Reproductive Factors and the Risk of Bronchiectasis: A Nationwide Population-Based Longitudinal Study.

Although the oestrogen level is thought to be involved in the occurrence of bronchiectasis, limited data are available on the relationship between female reproductive factors and the risk of bronchiectasis. We performed a population-based retrospective cohort study of 959,523 premenopausal women and 1,362,401 postmenopausal women without a previous history of bronchiectasis who participated in a health screening exam in 2009 in South Korea. In premenopausal women, compared with a later age at menarche (≥16 years), an earlier menarche (<12 years) was associated with a reduced risk of bronchiectasis with an adjusted hazard ratio (aHR) (95% confidence interval (CI)) of 0.74 (0.67–0.81). However, there were no significant associations between other reproductive factors (breastfeeding, parity, or oral contraceptive use) and the risk of bronchiectasis. In postmenopausal women, the risk of bronchiectasis (aHR (95% CI)) was lower in those with an earlier menarche (0.79 (0.72–0.87) for <12 years vs. ≥16 years), a later menopause (0.90 (0.84–0.96) ≥55 years vs. <40 years), and a longer reproductive period (0.90 (0.86–0.94) for ≥40 years vs. <30 years). There was no significant relationship between parity and the risk of bronchiectasis. Although breastfeeding <1 year (aHR (95% CI) = 0.92 (0.87–0.97) for <0.5 years and 0.93 (0.88–0.97) for 0.5–1 years) and oral contraceptive use <1 year (0.97 (0.94–0.99)) reduced the risk of bronchiectasis, hormone replacement therapy ≥5 years increased the risk of bronchiectasis (1.24 (1.18–1.30)). Female reproductive factors are risk factors for developing bronchiectasis, showing a higher risk associated with shorter endogenous oestrogen exposure regardless of the menopausal status.

Association of reproductive factors with dementia: A systematic review and dose-response meta-analyses of observational studies.

SummaryBackgroundAssociations between endogenous estrogen exposure indicators and risk of subtypes of dementia have been unclear.MethodsDatabases (PubMed, EMBASE and Web of Science) were searched electronically on 1st July and updated regularly until 12nd November 2021. Observational studies of English language were selected if reported an effect estimate [e.g., odds ratio (OR), rate ratio (RR) or hazard ratio (HR)] and 95% CI for the association between any exposure (age of menarche, age at menopause, reproductive period, estradiol level) and any endpoint variable [all-cause dementia, Alzheimer's disease (AD), vascular dementia (VD), cognitive impairment (CI)]. Random-effects models and dose-response meta-analyses were used to calculate estimates and to show the linear/nonlinear relationship. PROSPERO CRD42021274827.FindingsWe included 22 studies (475 9764 women) in this analysis. We found no clear relationship between late menarche (≥14 vs <14 years) and dementia, CI in categorical meta-analysis compared to a J-shape relationship in dose-response meta-analyses. Later menopause (≥45 vs <45 years) was consistently associated with a lower risk of all-cause dementia (pooled RR: 0.87, 95%CI: 0.78–0.97, I2=56.0%), AD (0.67, 0.44–0.99, I2=78.3%), VD (0.87, 0.80–0.94) and CI (0.82, 0.71–0.94, I2=19.3%) in categorical meta-analysis, showing similar results in dose-response meta-analyses. An inverse relationship between longer reproductive duration (≥35 vs <35 years) and dementia was observed in dose-response meta-analysis. In addition, estradiol levels after menopause were inversely correlated with the risk of AD and CI.InterpretationIn this study, later menopause and longer reproductive period were associated with a lower risk of dementia, while the relationship for menarchal age was J-shaped. There was an inverse relationship between higher postmenopausal estrogen levels and risk of AD and CI. Longitudinal study are needed to further explore the association between life-time estrogen exposure and risk of subtypes of dementia.FundingStart-up Foundation for Scientific Research in Shandong University.

Cardiovascular mortality after bilateral oophorectomy: a prospective cohort study.

Bilateral oophorectomy permanently reduces endogenous estrogen exposure and may increase cardiovascular mortality in women. This study aimed to investigate the association between bilateral oophorectomy and cardiovascular mortality and whether this association was conditional on hysterectomy or on the use of hormone therapy at the time of study entry. A prospective cohort study of 25,338 female nurses aged ≥ 45 years within the Danish Nurse Cohort. Nurses were enrolled in 1993 or 1999 and followed until death, emigration, or end of follow-up on December 31, 2018, whichever came first. Exposure was bilateral oophorectomy. Outcome was cardiovascular mortality. Associations were estimated using Poisson regression models with log person-years as the offset. A total of 2,040 (8.1%) participants underwent bilateral oophorectomy. During a mean follow-up of 21.2 (SD: 5.6) years, 772 (3.0%) nurses died from cardiovascular disease. In adjusted analyses, a 31% higher rate of cardiovascular mortality was observed after bilateral oophorectomy (aMRR 1.31; 95% CI, 0.88-1.96) compared with women who retained their ovaries. No evidence of effect modification by use of hormone therapy at baseline or by hysterectomy on the association between bilateral oophorectomy and cardiovascular mortality was observed. Bilateral oophorectomy may be associated with cardiovascular mortality in women, but the estimate was not statistically significant. Additionally, we were unable to make firm conclusions regarding the possible modifying role of hormone therapy and hysterectomy on this potential association. Additional studies are needed to replicate this work.

Adrenal-permissive HSD3B1 genetic inheritance and risk of estrogen-driven postmenopausal breast cancer.

BACKGROUNDGenetics of estrogen synthesis and breast cancer risk has been elusive. The 1245A→C missense-encoding polymorphism in HSD3B1, which is common in White populations, is functionally adrenal permissive and increases synthesis of the aromatase substrate androstenedione. We hypothesized that homozygous inheritance of the adrenal-permissive HSD3B1(1245C) is associated with postmenopausal estrogen receptor–positive (ER-positive) breast cancer.METHODSA prospective study of postmenopausal ER-driven breast cancer was done for determination of HSD3B1 and circulating steroids. Validation was performed in 2 other cohorts. Adrenal-permissive genotype frequency was compared between postmenopausal ER-positive breast cancer, the general population, and postmenopausal ER-negative breast cancer.RESULTSProspective and validation studies had 157 and 538 patients, respectively, for the primary analysis of genotype frequency by ER status in White female breast cancer patients who were postmenopausal at diagnosis. The adrenal-permissive genotype frequency in postmenopausal White women with estrogen-driven breast cancer in the prospective cohort was 17.5% (21/120) compared with 5.4% (2/37) for ER-negative breast cancer (P = 0.108) and 9.6% (429/4451) in the general population (P = 0.0077). Adrenal-permissive genotype frequency for estrogen-driven postmenopausal breast cancer was validated using Cambridge and The Cancer Genome Atlas data sets: 14.4% (56/389) compared with 6.0% (9/149) for ER-negative breast cancer (P = 0.007) and the general population (P = 0.005). Circulating androstenedione concentration was higher with the adrenal-permissive genotype (P = 0.03).CONCLUSIONAdrenal-permissive genotype is associated with estrogen-driven postmenopausal breast cancer. These findings link genetic inheritance of endogenous estrogen exposure to estrogen-driven breast cancer.FUNDINGNational Cancer Institute, NIH (R01CA236780, R01CA172382, and P30-CA008748); and Prostate Cancer Foundation Challenge Award.

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

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. 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. 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. Our study suggests that female hormonal factors, including endogenous and exogenous estrogen exposure, may be associated with migraine occurrence in spontaneous menopausal women.