Estrogen Use Research Articles

Longitudinal associations of reproductive factors and exogeneous estrogens with neuroimaging biomarkers of Alzheimer's disease and cerebrovascular disease.

Female-specific reproductive factors and exogeneous estrogen use are associated with cognition in later life. However, the underlying mechanisms are not understood. The present study aimed to investigate the effect of reproductive factors on neuroimaging biomarkers of Alzheimer's disease (AD) and cerebrovascular pathologies. We evaluated 389 females (median age of 71.7 years) enrolled in the Mayo Clinic Study of Aging with reproductive history data and longitudinal magnetic resonance imaging (MRI) scans. We used linear mixed effect models to examine the associations between reproductive factors and changes in neuroimaging measures. Ever hormonal contraception (HC) use was longitudinally associated with higher fractional anisotropy across the corpus callosum, lower white matter hyperintensity (WMH) volume, and greater cortical thickness in an AD meta-region of interest (ROI). The initiation of menopausal hormone therapy (MHT)>5 years post menopause was associated with higher WMH volume. HC use and initiation of MHT>5 years post menopause were generally associated with neuroimaging biomarkers of cerebrovascular pathologies. Hormonal contraception use was associated with better brain white matter (WM) integrity. Initiation of menopausal hormone therapy>5 years post menopause was associated with worsening brain WM integrity. Hormonal contraception use was associated with greater cortical thickness. Ages at menarche and menopause and number of pregnancies were not associated with imaging measures. There were few associations between reproductive factors or exogenous estrogens and amyloid or tau PET.

Oral Hormone Replacement Therapy and Uterine Volume in Korean Adolescents with Turner Syndrome: A Retrospective Case-Control Study

Study ObjectiveWe aimed to identify critical factors for uterine development by comparing uterine volume (UV) among patients with Turner syndrome (TS) who underwent pubertal induction (PI), patients with TS who had natural menarche (NM), and patients in a non-TS control group. MethodsThis retrospective case-control study included patients with TS who had undergone PI with oral estrogen in a PI group(n=31) and a NM group(n=7). The control group included patients without TS with spontaneous puberty who underwent pelvic ultrasound at 16 years of age. For TS patients, both the UV from the first ultrasound performed at age 16 or older (1st-UV) and the UV from the most recent final ultrasound (final-UV) were obtained. ResultsThe 1st-UV was larger for patients in the NM group than those in the PI group (p<0.001), but did not differ significantly between the NM and control groups (p=0.375). The final-UV of the PI group was larger than their 1st-UV (p<0.001), but still smaller than the NM group (p=0.021). HRT duration and 1st-UV of PI group were positively correlated (p=0.048). There were no variables that were significantly correlated with final-UV of PI group. ConclusionPatients with TS who experienced NM showed normal uterine development, but TS patients who underwent PI showed significantly smaller, undeveloped UV. While HRT duration and UV are positively correlated at the beginning of HRT, it is unclear what determines the final UV; however, late PI initiation and use of oral estrogen probably contributed to the lack of UV development.

Operative Complications, Vaginal Bleeding, and Practice Considerations for Patients on Testosterone Undergoing Gender-Affirming Hysterectomy

Study ObjectiveTo evaluate operative complications and healthcare utilization in transgender patients on testosterone undergoing minimally invasive gender-affirming hysterectomy compared to control patients. DesignWe performed a retrospective cohort study. Operative reports were used to gather information on intraoperative complications. We collected information on postoperative complications, electronic medical record (EMR) messages, phone calls, emergency department utilization, and clinic visits through a 90-day postoperative period. Healthcare utilization reasons were categorized as vaginal bleeding, pain, vaginal discharge, dysuria, urinary retention, bowel concern, incision concern, or other. SettingTertiary care academic medical center. PatientsPatients aged 18 to 55 who underwent a benign minimally invasive hysterectomy with or without oophorectomy performed between January 2014 and December 2022. The testosterone-using cohort consisted of patients who had a gender identity of male, transgender male, genderqueer, or nonbinary with documented testosterone use prior to surgery (n = 88). The control cohort consisted of patients who identified as female, genderqueer, or nonbinary with no documented testosterone use (n = 242). InterventionsNot applicable. Measurements and Main ResultsPatients using testosterone were younger, had a lower body mass index, lower American Society of Anesthesiologists class, and were more likely to be nulliparous. The median time patients used testosterone was 2.5 years (1.5–5.0). Patients on testosterone are at increased risk of intraoperative perineal lacerations requiring repair (RR 3.3, CI 95% [1.03–10.5]). A higher number of patients on testosterone reported vaginal bleeding via EMR message or phone call (RR 1.74 CI 95% [1.1–2.7]) compared to controls. No difference in reasons for emergency department visits was noted. The use of postoperative vaginal estrogen started at the postoperative visit was more frequent in the testosterone-using patients (7 [8.0%] vs 4 [1.7%], p = .01). ConclusionThis study demonstrates that testosterone use preoperatively may increase risk of intraoperative vaginal laceration requiring repair. Testosterone use also correlates with increased reports of vaginal bleeding through EMR message, phone call, and clinic visit. These results contribute new evidence to include in preoperative counseling and support existing evidence surrounding the safety of gender-affirming hysterectomy.

#1936 Investigating genetic and environmental modifiers of autosomal dominant polycystic kidney disease through a distinct PKD2-founder variant (p.Arg803*)

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is among the most common hereditary diseases that lead to kidney failure [1]. Apart from progressive, cystic enlargement of the kidneys, classic ADPKD is inevitably associated with polycystic liver disease (PLD) and arterial hypertension [2] due to mutated PKD1 (78%) or PKD2 (15%) [3]. Despite knowledge of the diagnostic PKD1 or PKD2 variant, there is great intrafamilial variability in terms of disease progression and organ involvement. Therefore, there is an unmet medical need to establish better genotype-phenotype correlations. In 2022, Taiwanese colleagues identified a PKD2 founder variant (NM_000297.4 (PKD2): c.2407C&amp;gt;T (p.Arg803*)) which accounts for 17.8% of all ADPKD cases in Taiwan [4]. As we also detected patients with PKD2-Arg803* in our European center, we hypothesize that p.Arg803* constitutes a recurrent mutation. The established Taiwanese cohort provides the unique opportunity to build up a sister cohort of patients with this specific mutation. This novel approach can aid in identifying genetic and environmental modifiers of ADPKD, which in turn is essential in elucidating the pathogenesis, as well as the adequate classification, prognosis and treatment of ADPKD patients. Method For patient recruitment, the search was carried out simultaneously in a multi-pronged approach. First, the European Rare Kidney Disease Network (ERKNet), relevant registries and biobanks were searched to identify patients. In addition, authors of ClinVar entries and published literature with specific mentions of the variant were contacted. Lastly, clinical and genetic ADPKD specialists were reached out to directly. Deep phenotyping was performed by a specific clinical questionnaire that was sent to the respective treating physicians via Microsoft Forms. This included baseline information about patients as well as clinical parameters. Specifically, a detailed analysis of kidney, liver, CNS and further manifestations of ADPKD was performed. In addition to the main mutation, additional findings in relevant ADPKD genes were documented. Environmental factors such as smoking, estrogen use, diets and exercise were also been explicitly recorded. Results Through systematic search, 545 institutions or clinicians were contacted in 47 countries. Thus far, about 170 patients with PKD2-p.Arg803* have been identified in 25 centers from 15 countries outside of Taiwan. The process of deep phenotyping is ongoing (completed on 20 patients as of 01/2024). A preliminary analysis of this smaller cohort showed a mean age of 62 (range: 38–90) years and a sex distribution (F:M) of 11: 9. The median total kidney volume was 1437 ml (IQR 2525.5) mL and three patients had reached kidney failure at age 70, 72 and 69. Eighteen out of the 20 patients had three or more liver cysts with a median total liver volume of 1849 (IQR 822.5) mL. Conclusion We are continuing to expand the cohort, aiming to reach full datasets in about 80 international patients for joint analysis with the Taiwanese founder cohort. Detailed statistical analysis of the joint cohort will allow us to better characterize modifiers on the genetic and environmental level. We hope our project can contribute to further understanding disease variability in ADPKD.

Abstract 2006: Estrogen Therapy Is Associated With A Greater Risk Of Cardiovascular-kidney-metabolic Syndrome And Thrombosis In Cisgender Women, But Spares Transgender Women: A Global Retrospective Study

Despite the use of estrogen-based therapies in cisgender- and transgender-women, and the presumed cardioprotective effect of endogenous estrogen, there are no comprehensive studies investigating the risk of cardiovascular-kidney-metabolic (CKM) syndrome in patients taking exogenous estrogen. CKM syndrome is a health disorder attributable to connections among obesity, type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and cardiovascular disease, including heart failure (HF), ischemic heart disease (IHD), and stroke. We hypothesized that cis- and trans-women would have decreased risk of CKM syndrome. We conducted a retrospective analysis using the TriNetX database, which contains patient information from 83 healthcare organizations worldwide. We identified 9,271,702 cis-women +/- estrogen and 17,729 trans-women on estrogen matched 1:1 with cis-men and separated patients into age deciles from 20-69 years. Cis-women taking estrogen showed a significantly increased risk of CKM comorbidities including dyslipidemia, HTN, T2DM, overweight/obesity (OB), HF, IHD, and CKD (p&lt;0.0001 for all), and an elevated risk of thrombotic outcomes, such as myocardial infarction (MI), stroke, pulmonary embolism (PE), and deep vein thrombosis (DVT) compared to cis-women not taking estrogen (p&lt;0.0001 for all). In contrast, the use of estrogen in trans-women compared to cis-men was not associated with a greater risk of MI, stroke, PE, or DVT, (except in the 60-69 year-aged cohort for DVT, p=0.0056). Trans-women taking estrogen also had a lower risk of HTN, T2DM, HF, IHD, and CKD, despite a higher risk of dyslipidemia, and OB compared to cis-men (p=0.02-&lt;0.0001). This is the first comprehensive study revealing a significant association between exogenous estrogen use and CKM syndrome in cis-women. Additionally, our novel findings indicate that estrogen use in trans-women is associated with dyslipidemia, and OB, but is not associated with a greater overall risk for CKM syndrome or thrombosis. Given these findings, additional prospective studies are needed to confirm the risks or protections provided by estrogen therapy in cisgender and transgender women.

Prediction of Postoperative Urinary Tract Infection Following Benign Gynecologic Surgery.

The objective was to develop a prediction model for urinary tract infection (UTI) after pelvic surgery. We utilized data from three tertiary care centers of women undergoing pelvic surgery. The primary outcome was a UTI within 8weeks of surgery. Additional variables collected included procedural data, severity of prolapse, use of mesh, anti-incontinence surgery, EBL, diabetes, steroid use, estrogen use, postoperative catheter use, PVR, history of recurrent UTI, operative time, comorbidities, and postoperative morbidity including venous thromboembolism, surgical site infection. Two datasets were used for internal validation, whereas a third dataset was used for external validation. Algorithms that tested included the following: multivariable logistic regression, decision trees (DTs), naive Bayes (NB), random forest (RF), gradient boosting (GB), and multilayer perceptron (MP). For the training dataset, containing both University of British Columbia and Mayo Clinic Rochester data, there were 1,657 patients, with 172 (10.4%) UTIs; whereas for the University of Calgary external validation data, there were a total of 392 patients with a UTI rate of 16.1% (n = 63). All models performed well; however, the GB, DT, and RF models all had an area under the curve (AUC) > 0.97. With external validation the model retained high discriminatory ability, DT: AUC = 0.88, RF: AUC = 0.88, and GB: AUC = 0.90. A model with high discriminatory ability can predict UTI within 8weeks of pelvic surgery. Future studies should focus on prospective validation and application of randomized trial models to test the utility of this model in the prevention of postoperative UTI.

Association of endometriosis with asthma: a study of the NHANES database in 1999–2006

ObjectiveAsthma is a chronic inflammatory disease of the airways with a gender differences in the prevalence after puberty. Recent studies have reported a relationship between asthma and endometriosis, possibly related to the immune response mechanisms, but the evidences are limited and inconsistent. Herein, this research aimed to investigate the association of endometriosis with asthma based on the representative population in the United States (U.S.) to provide some reference for further exploration on mechanism of gender difference in asthma.MethodsIn this cross-sectional study, data of women aged ≥ 20 years old were extracted from the National Health and Nutrition Examination Survey (NHANES) database in 1999–2006. Weighted univariate and multivariate logistic regression analyses were utilized to explore the association of endometriosis with asthma. The multivariate models adjusted for covariates including age, race, education level, marital status, poverty income ratio (PIR), body mass index (BMI), waist circumference, smoking, estrogen and progesterone hormones use, uterine fibroids, at least one ovary removed, and birth control pills intake. The evaluation indexes were odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses of age, race, BMI, and pregnancy history were also performed.ResultsAmong 5,556 eligible women, 782 had asthma, and 380 had endometriosis. The average age of participants was 37.19 years old, and more than half of them were non-Hispanic White (68.44%). After adjusting for covariates, endometriosis was associated with higher odds of asthma compared with non-endometriosis [OR = 1.48, 95%CI: (1.10–1.99)]. This relationship was also found in 40–49 years old [OR = 2.26, 95%CI: (1.21–4.23)], BMI of 25-29.9 kg/m2 [OR = 2.87, 95%CI: (1.52–5.44)], and pregnancy history [OR = 1.44, 95%CI: (1.01–2.06)] subgroups.ConclusionEndometriosis had a positive association with asthma in adult women. Females aged 40–49 years old, with BMI of 25-29.9 kg/m2 and had a history of pregnancy should take care about monitoring endometriosis to reduce the potential risk of asthma. Further studies are still needed to clarify the causal association between endometriosis and asthma.

Abstract 97: A E2F6 ceRNA network suppresses dendritic cell function, via PBX1/IL-10 signaling, in ovarian cancer

Abstract It is reported that long-term use of estrogen could increase the risk of ovarian cancer. However, the role of estrogen in immunoevasion is not fully explored. We have previously demonstrated that estrogen-mediated upregulation of E2F6, and, c-Kit, by epigenetic silencing of miR-193a, and a competing endogenous (ceRNA) mechanism. In this study, we found that PBX1, a transcriptional activator of the immunosuppressive cytokine, IL-10, is also a target of miR-193a. Importantly, overexpression of the E2F6 3’UTR upregulates both E2F6 and, PBX1, as well as IL10 in ovarian cancer cell lines, suggesting that ceRNA mechanism exists between E2F6 and PBX1. These phenomena are further supported by our stochastic simulation of the estrogen-mediated E2F6 ceRNA network on the distribution of E2F6 and PBX1 mRNA in cancer cells, which is consistent with the TCGA ovarian cancer RNA-Seq dataset. Importantly, monocyte-derived dendritic cell activation of T-cell function was inhibited by pretreatment of conditioned media derived from ovarian cancer cells overexpressing E2F6 3’UTR; such inhibition was rescueable by an anti-IL-10 antibody. Clinically, IL10 level was higher in ovarian cancer patients with higher E2F6 and PBX1, and in ovarian cancer cell lines overexpressed with E2F6 3’UTR. Taken together, these results showed that E2F6 could suppress anti-tumor immune response of dendritic cell, E2F6 ceRNA network. Epigenetic intervention in restoring the expression of miR-193a may be able to enhance anti-tumor immune response against ovarian cancer. Citation Format: Michael W.Y. Chan, Yin-Chen Chen, Ching-Wen Lin, Frank Cheng, Ching-Cher Sanders Yan, Chao-Ping Hsu, Yu-Min Chuang, Jie-Ting Low, Xiaojing Ma, Yao-Ting Huang, Chia-Bin Chang, Chin Li, Hung-Cheng Lai, Shu-Fen Wu, Shih-Hsun Hung, Je-Chiang Tsai. A E2F6 ceRNA network suppresses dendritic cell function, via PBX1/IL-10 signaling, in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 97.

Abstract 765: Tobacco smoke exposure, hormonal history, and estrogen metabolism in women with EGFR-mutant non-small cell lung cancer (NSCLC)

Abstract Introduction: The factors responsible for NSCLC development in never-smokers remain unclear, thus hindering prevention efforts. Our group is one of the first in the U.S. to build a registry of never-smokers with NSCLC to facilitate research to address this global problem. Given the high prevalence of women among cases, we are investigating the contribution of estrogen metabolism to this disease. CYP1B1 converts parent estrogens to the putative carcinogen 4-hydroxyestrogen (4-OHE), a process further accelerated by tobacco smoke exposure. In contrast, CYP1A1 generates 2-hydroxyestrogen (2-OHE), which may be converted to anti-proliferative derivatives. We determined previously that women with EGFR-mutant NSCLC enrolled in the registry have a 2-fold higher ratio of 4-OHEs to 2-OHEs, as compared to cancer-free controls. While EGFR-mutant NSCLCs are typically thought to be diagnosed in never-smokers, prior data indicate that a fraction of patients report some smoking history. The goal of this current study is to determine the smoking prevalence among women with EGFR-mutant NSCLC in our registry and explore the impact of smoking and hormonal history on estrogen metabolism. Methods: The Lung Cancer in Never-Smokers Risk Registry (LCNS-RR) is recruiting patients with NSCLC who are never-smokers (&amp;lt;100 cigarettes/lifetime) and/or have tumors with oncogenes characteristically present in never-smokers (e.g., EGFR, ALK). In addition to donating biospecimens (e.g., blood, urine), participants complete a survey on tobacco and environmental exposures, hormonal history, and other factors. Using UPLC-MS/MS, profiles of urinary estrogens (E1, E2, E3, 4-OHE1, 4-OHE2, 2-OHE1, 2-OHE2) were determined for 32 women with EGFR-mutant NSCLC in the LCNS-RR. The proportion of each estrogen species over total estrogen and the ratio of 4-OHEs to 2-OHEs were calculated. Medians were compared using the Wilcoxon rank-sum test. Results: Among women in this EGFR-mutant cohort, none were current smokers, 16 were former smokers, and 16 were never-smokers. Among the former smokers, median pack-years was 11.6. The ratio of 4-OHEs to 2-OHEs was comparable in former- vs. never-smokers (0.51 vs. 0.49, p-value = 0.956). Twenty-three women (71.8%) had a history of oral contraception use, and 5 (15.6%) reported early menarche (&amp;lt;12 years of age). However, neither of these factors correlated with 4-OHE production. Among 28 post-menopausal women, 7 (25%) reported estrogen use since menopause, an exposure that was not associated with 4-OHE levels. Conclusion: This preliminary analysis suggests that smoking history, use of hormones, or early menarche do not enhance the production of 4-OHEs in women with EGFR-mutant NSCLC. Recruitment to the LCNS-RR is ongoing and will facilitate future analyses in a larger cohort. (Supported by a Ride Hard Breathe Easy Innovation Award) Citation Format: Ahmad Raza, Joseph Treat, Daniel D. Krzizike, Lisa Vanderveer, Mitchell Cheung, Carolyn Zawislak, Lisa Etkins, Eric Ross, Douglas B. Flieder, Martin J. Edelman, Margie L. Clapper, J Nicholas Bodor. Tobacco smoke exposure, hormonal history, and estrogen metabolism in women with EGFR-mutant non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 765.

Abstract 3442: Factors modifying the association between hormonal contraception and risk of early-onset breast cancer

Abstract Breast cancer rates among women younger than 50 years-old have been steadily increasing since the mid-1990s. There is consistent evidence that use of combination estrogen and progesterone oral contraceptives (OCs)—including contemporary formulations with lower estrogen—increases breast cancer risk. It is unclear, however, if this risk varies by factors such as progestin type in the OC formulation, timing of OC use, histopathologic characteristics of the breast cancer, or individual patient characteristics. This study included premenopausal women aged &amp;lt;50 years and cancer-free when they enrolled in the U.S.-based American Cancer Society Cancer Prevention Study-3 cohort between 2006 and 2013 (n=101,838 women). At enrollment participants responded to a detailed life history questionnaire including questions about type, brand, duration, and recency of OC use. Incident breast cancers diagnosed between 2006-2018 were identified through cancer registry linkages (n=759). Participants were followed until the first of 1) breast cancer diagnosis, 2) age &amp;gt;50 years, or 3) December 31, 2018. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were used to estimate associations between OC use and breast cancer risk. On average, participants were 39.3 years at baseline and were followed for 5.7 years (up to 12.3 years). Current versus never use of OCs for 10+ years was associated with a higher risk of breast cancer (10-&amp;lt;20 years: HR=1.46, 95% CI: 1.03-2.07; 20-&amp;lt;30 years: HR=1.66, 95% CI: 1.14-2.41; 30+ years HR= 2.51, 95% CI: 0.77-8.16). Cessation of OC use progressively attenuated the association down to the null 15 years after discontinuation of use (HR=1.04, 95% CI: 0.73-1.49). Associations with current OC use varied by generation of progestin in the formulation (first generation: HR=1.37, 95% CI: 0.93-2.02; second: HR=1.79, 95% CI: 1.20-2.67; third: HR=1.65, 95% CI: 1.13-2.42; fourth: HR= 0.91, 95% CI: 0.49-1.67). The strongest associations were observed for use of formulations with norgestrel: HR=2.82, 95% CI: 1.54-5.19; norgestimate: HR=1.80, 95% CI: 1.19-2.72; and levonorgestrel: HR=1.56, 95% CI: 1.00-2.43. The OC-breast cancer associations were primarily limited to localized, grade 1 or 2, and ER+ disease. Race, income, body mass index, physical activity, alcohol use, cigarette smoking, parity, and breastfeeding did not appear to modify the associations. There were also no clear differences in the associations based on age at first or last OC use or timing relative to pregnancy. Current, long-term OC use was associated with increased risk of early-onset breast cancer. These data suggest that risks may vary with progestin content, and future studies are needed to define formulations that minimize breast cancer risk while still maximizing protection against other female cancers. Citation Format: Lauren R. Teras, Emily L. Deubler, Mark E. Sherman, Clara Bodelon, Lauren E. McCullough, James M. Hodge, Sicha Chantaprasopsuk, Alpa V. Patel. Factors modifying the association between hormonal contraception and risk of early-onset breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3442.

Use of menopausal hormone therapy beyond age 65 years and its effects on women's health outcomes by types, routes, and doses.

The study aims to assess the use of menopausal hormone therapy beyond age 65 years and its health implications by types of estrogen/progestogen, routes of administration, and dose strengths. Using prescription drug and encounter records of 10 million senior Medicare women from 2007-2020 and Cox regression analyses adjusted for time-varying characteristics of the women, we examined the effects of different preparations of menopausal hormone therapy on all-cause mortality, five cancers, six cardiovascular diseases, and dementia. Compared with never use or discontinuation of menopausal hormone therapy after age 65 years, the use of estrogen monotherapy beyond age 65 years was associated with significant risk reductions in mortality (19% or adjusted hazards ratio, 0.81; 95% CI, 0.79-0.82), breast cancer (16%), lung cancer (13%), colorectal cancer (12%), congestive heart failure (CHF) (5%), venous thromboembolism (3%), atrial fibrillation (4%), acute myocardial infarction (11%), and dementia (2%). For the use of estrogen and progestogen combo-therapy, both E+ progestin and E+ progesterone were associated with increased risk of breast cancer by 10%-19%, but such risk can be mitigated using low dose of transdermal or vaginal E+ progestin. Moreover, E+ progestin exhibited significant risk reductions in endometrial cancer (45% or adjusted hazards ratio, 0.55; 95% CI, 0.50-0.60), ovarian cancer (21%), ischemic heart disease (5%), CHF (5%), and venous thromboembolism (5%), whereas E+ progesterone exhibited risk reduction only in CHF (4%). Among senior Medicare women, the implications of menopausal hormone therapy use beyond age 65 years vary by types, routes, and strengths. In general, risk reductions appear to be greater with low rather than medium or high doses, vaginal or transdermal rather than oral preparations, and with E2 rather than conjugated estrogen.

Migraines, vasomotor symptoms, and cardiovascular disease in the Coronary Artery Risk Development in Young Adults study.

To examine whether vasomotor symptoms (VMS) and migraine headaches, hypothesized to be vasoactive conditions, are associated with greater risk for cardiovascular disease (CVD) events including strokes. We performed a secondary data analysis of a subset of women (n = 1,954) in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based cohort, which began data collection at 18 to 30 y of age. We examined whether migraine headaches and VMS trajectories (characterized as minimal, increasing, and persistent) at CARDIA year 15 examination were associated with higher risk of CVD events and stroke (both ischemic and hemorrhagic) using Cox proportional hazards regression models and adjustment for traditional CVD risk factors (age, cigarette use, and levels of systolic and diastolic blood pressure, fasting glucose, high- and low-density cholesterol, and triglycerides) and reproductive factors. Among women with minimal VMS (n = 835), increasing VMS (n = 521), and persistent VMS (n = 598), there were 81 incident CVD events including 42 strokes. Women with histories of migraine and persistent VMS had greater risk of CVD (hazard ratio [HR], 2.25; 95% CI, 1.15-4.38) after adjustment for age, race, estrogen use, oophorectomy, and hysterectomy compared with women without migraine histories and with minimal/increasing VMS. After adjustment for CVD risk factors, these associations were attenuated (HR, 1.51; 95% CI, 0.73-3.10). Similarly, women with histories of migraine and persistent VMS had greater risk of stroke (HR, 3.15; 95% CI, 1.35-7.34), but these associations were attenuated after adjustment for CVD risk factors (HR, 1.70; 95% CI, 0.66-4.38). Migraines and persistent VMS jointly associate with greater risk for CVD and stroke, although risk is attenuated with adjustment for traditional CVD risk factors.

Should hormone replacement therapy (any route of administration) be considered in all postmenopausal women with lower urinary tract symptoms? Report from the ICI-RS 2023.

This International Consultation on Incontinence-Research Society report aims to summarize the evidence and uncertainties regarding the use of hormone replacement therapy by any route in the management of lower urinary tract symptoms (LUTS) including recurrent urinary tract infections (rUTI), with a review of special considerations for the elderly. Research question proposals to further this field have been highlighted. An overview of the existing evidence, guidelines, and consensus regarding the use of topical or systemic estrogens in the management of LUTS. There are currently evidence and recommendations to offer topical estrogens to postmenopausal women with overactive bladder symptoms as well as postmenopausal women with rUTIs. Systemic estrogens however have been shown in a meta-analysis to have a negative effect on LUTS and, therefore are not currently recommended. Although available evidence and recommendations exist for the use of topical estrogens, few women are commenced on these in primary care. There remain large gaps still within our knowledge of the use of estrogens within the management of LUTS, particularly on when it should be commenced, the length of time treatment should be continued for, and barriers to prescribing.

Changes in vaginal secretion lipidom as a result of therapy in patients with vulvovaginal atrophy

Introduction. Vulvovaginal atrophy is a chronic progressive disease that includes physiological and anatomical changes as a result of a decrease in the level of sex hormones. VVA affects approximately 50% of middle-aged and older women and has a detrimental effect on interpersonal relationships, sexual health, and overall quality of life. Dynamic quadripolar radiofrequency (DRF) is a non-invasive procedure that may be a potential treatment for vulvar diseases.Aim. To study the metabolites of vaginal swabs in postmenopausal women treated with DRF.Materials and methods. The study included 180 women divided into 3 groups: treatment with DRF; treatment with a combination of DRF and estradiol, and estradiol treatment. In all patients, vaginal swabs were taken before the start of treatment and a month after treatment, and clinical parameters were assessed at 6 time points. Lipids were extracted from the cervico-vaginal fluid by the Folch method followed by liquid chromatography-mass spectrometric analysis. A comparative analysis of the clinical data of each of the groups and lipid profiles after treatment with a zero time point and their changes and a correlation analysis of changes in lipid levels and changes in clinical parameters before treatment and after 1 month was carried out.Results. There was a statistically significant reduction in the severity of VVA symptoms one month after treatment in all groups. The most pronounced effect of the therapy was observed in groups with the use of DRF with the preservation of the effect up to 12 months. In the first and second groups, a statistically significant difference was found in the levels of 2 lipids, in the third – in 4. In the first group, a correlation was found with lipids related with pain and lubrication, in the second – with vaginal pH, in the third – with the index of vaginal health, orgasm, satisfaction and pain.Conclusions. VVA therapy by DRF and local hormonal treatment triggers an inflammatory cascade in tissues. The use of the strategy of treatment with physical methods of influence has a mechanism of influence similar to the local application of estrogen in VVA. DRF therapy leads to the normalization of the vaginal microbiota and can compete with the use of estrogen in this therapeutic effect.

A Case Report on the Successful Management of Catastrophic Antiphospholipid Syndrome: Multidisciplinary Approach

ABSTRACT Catastrophic antiphospholipid syndrome (CAPS) is a multi-organ systemic thrombotic condition precipitated due to various secondary conditions such as infection, surgery, and estrogen use. The subsequent formation of various autoantibodies and various organ involvement such as the brain, heart, and kidneys cause rapid progression of the disease. The acute features of thrombosis and the predominant involvement of kidneys and the brain make the differentiation of this condition with other thrombotic microangiopathies difficult. However, early suspicion of CAPS with prompt management is key to favorable prognosis in such patients. Multidisciplinary approach to diagnosis and medical management plays an important role in the successful outcome of CAPS patients. The three pillars of management are therapeutic plasma exchange (TPE), steroids, and anticoagulants. TPE plays a major role in eliminating incriminating antibodies, cytokines, tumor necrosis factor, and complement. We present a case of 34-year-old female with definite CAPS, managed successfully with the triple regimen comprising a total of seven TPE sessions, pulse therapy with steroids, and anticoagulants.

A randomized clinical trial of transdermal (gel) versus oral estrogen for endometrial preparation in frozen embryo transfer cycle.

The aim of this study was to compare endometrial thickness with the use of transdermal estrogen (gel) versus oral estrogen (pills) for endometrial preparation in the frozen embryo transfer cycle and serum estrogen concentrations during the preparation cycle, side effects, and chemical and clinical pregnancy rates. This was a prospective, randomized controlled trial of women undergoing endometrial preparation for cryopreserved blastocyst transfer. A total of 88 women were randomized, of which 82 completed the study protocol. Of this group, 44 received 6 mg/day of estradiol valerate orally (pills group) and 38 received 4.5 mg/day of estradiol hemihydrate transdermally (gel group). Endometrial thickness was measured using transvaginal ultrasound between the 7 and 10th day of the cycle. Serum estradiol concentrations were measured on the day of initiating the cycle, on control transvaginal ultrasounds, and on the day of embryo transfer. Side effects were documented at each study visit. p<0.05 were adopted as statistically significant. The groups were compared using Student's t-test for continuous variables and chi-square or Fisher's exact test for categorical variables. There were no significant group differences (p>0.05) in endometrial thickness, biochemical and clinical pregnancy rates, miscarriage rate, blood estradiol concentrations, duration of estradiol administration, or cycle cancellation rates. Endometrial preparation with transdermal estrogen yielded similar reproductive outcomes to oral estrogen with fewer side effects.

Preoperative promestriene for hysteroscopy: a randomized clinical trial.

Intraoperative complications of hysteroscopy, such as the creation of a false passage, cervix dilatation failure, and uterine perforation, may require suspension of the procedure. Some patients refuse a new procedure, which delays the diagnosis of a possible serious uterine pathology. For this reason, it is essential to develop strategies to increase the success rate of hysteroscopy. Some authors suggest preoperative use of topical estrogen for postmenopausal patients. This strategy is common in clinical practice, but studies demonstrating its effectiveness are scarce. The aim of this study was to evaluate the effect of cervical preparation with promestriene on the incidence of complications in postmenopausal women undergoing surgical hysteroscopy. This is a double-blind clinical trial involving 37 postmenopausal patients undergoing surgical hysteroscopy. Participants used promestriene or placebo vaginally daily for 2 weeks and then twice a week for another 2 weeks until surgery. There were 2 out of 14 (14.3%) participants with complications in the promestriene group and 4 out of 23 (17.4%) participants in the placebo group (p=0.593). The complications were difficult cervical dilation, cervical laceration, and vaginal laceration. Cervical preparation with promestriene did not reduce intraoperative complications in postmenopausal patients undergoing surgical hysteroscopy.

L-Lysine을 이용하여 가용화한 페오니플로린 난소 흡수율 및 생체 이용률 연구

Menopause refers to the period in a woman’s life when ovarian function declines, leading to a cessation of ovulation and a significant hormonal shift. Commonly associated symptoms include facial flushing, sleep disturbances, fatigue, and depression. These symptoms are typically treated with hormone therapy, although there is concern about the increased risk of endometrial cancer, cardiovascular disease, and breast cancer associated with excessive estrogen use. This has led to a growing interest in natural remedies as an alternative approach. Paeoniflorin is a pharmacologically active compound found in Paeonia lactiflora, one of the major components of this plant. Paeonia lactiflora has been traditionally used to treat women’s health issues, but there is currently insufficient research in this area compared to its historical use. Moreover, there is a lack of studies on ovarian absorption rates, prompting the present study. In this research, paeoniflorin was solubilized using L-Lysine, and its ovarian absorption rate and overall bioavailability were compared to the conventional extract. The results demonstrated a 58.5% increase in ovarian absorption when solubilized with L-Lysine. In terms of overall bioavailability, the area under the curve (AUC) value for oral administration was 3122.66 ng·hr/mL, whereas the AUC value for intravenous injection was 4191.20 ng·hr/mL. These findings suggest the potential of L-Lysinesolubilized paeoniflorin as an effective treatment for menopausal symptoms, offering a promising natural alternative to hormone therapy.

Breast cancer risk association with postmenopausal hormone therapy: Health Insurance Database in South Korea-based cohort study.

Although many physicians have been concerned that the menopausal hormones used currently in clinical practice may affect the risk of breast cancer, there are currently few informative updated studies about the associations between menopausal hormone therapy (MHT) and the risk of breast cancer. This study aims to evaluate the association between the risk of breast cancer and MHT using the National Health Insurance Database in South Korea (HISK) cohort between 2002 and 2019 retrospectively. Postmenopausal women over 40 years of age from 2003 to 2011 were selected as the subject population, and their follow-up data were collected until 2019. We analyzed the risk and mortality of breast cancer according to the type of MHT received, namely, tibolone, combined estrogen plus progestin by manufacturer (CEPM), oral estrogen, combined estrogen plus progestin by physician (CEPP), or topical estrogen. The risk of breast cancer increased in the CEPM group [hazard ratio (HR) 1.439, 95% CI 1.374-1.507, P-value < .001] in comparison with the non-MHT group. However, no significant associations were found between the use of tibolone, oral estrogen, CEPP, or topical estrogen and breast cancer risk in comparison with the non-MHT group (HR 0.968, 95% CI 0.925-1.012; HR 1.002, 95% CI 0.929-1.081; HR 0.929, 95% CI 0.75-1.15; HR 1.139, 95% CI 0.809-1.603). The mortality rate from breast cancer is lower in the MHT group in comparison with the non-MHT group, indicating that significant associations were found for tibolone, CEPM, and oral estrogen (HR 0.504, 95% CI 0.432-0.588; HR 0.429, 95% CI 0.352-0.522; HR 0.453 95% CI 0.349-0.588, P-value < .001). This study suggests that the risk of breast cancer is increased by drugs in the CEPM group but not by tibolone, oral estrogen, CEPP, or topical estrogen. The mortality rate from breast cancer is lower with MHT (tibolone, CEPM, oral estrogen) than without MHT.

A Repurposing Programme Evaluating Transdermal Oestradiol Patches for the Treatment of Prostate Cancer Within the PATCH and STAMPEDE Trials: Current Results and Adapting Trial Design

AimsAndrogen deprivation therapy (ADT), usually achieved with luteinising hormone releasing hormone analogues (LHRHa), is central to prostate cancer management. LHRHa reduce both testosterone and oestrogen and are associated with significant long-term toxicity. Previous use of oral oestrogens as ADT was curtailed because of cardiovascular toxicity. Transdermal oestrogen (tE2) patches are a potential alternative ADT, supressing testosterone without the associated oestrogen-depletion toxicities (osteoporosis, hot flushes, metabolic abnormalities) and avoiding cardiovascular toxicity, and we here describe their evaluation in men with prostate cancer. Materials and methodsThe PATCH (NCT00303784) adaptive trials programme (incorporating recruitment through the STAMPEDE [NCT00268476] platform) is evaluating the safety and efficacy of tE2 patches as ADT for men with prostate cancer. An initial randomised (LHRHa versus tE2) phase II study (n = 251) with cardiovascular toxicity as the primary outcome measure has expanded into a phase III evaluation. Those with locally advanced (M0) or metastatic (M1) prostate cancer are eligible. To reflect changes in both management and prognosis, the PATCH programme is now evaluating these cohorts separately. ResultsRecruitment is complete, with 1362 and 1128 in the M0 and M1 cohorts, respectively. Rates of androgen suppression with tE2 were equivalent to LHRHa, with improved metabolic parameters, quality of life and bone health indices (mean absolute change in lumbar spine bone mineral density of –3.0% for LHRHa and +7.9% for tE2 with an estimated difference between arms of 9.3% (95% confidence interval 5.3–13.4). Importantly, rates of cardiovascular events were not significantly different between the two arms and the time to first cardiovascular event did not differ between treatment groups (hazard ratio 1.11, 95% confidence interval 0.80–1.53; P = 0.54). Oncological outcomes are awaited. FutureEfficacy results for the M0 cohort (primary outcome measure metastases-free survival) are expected in the final quarter of 2023. For M1 patients (primary outcome measure – overall survival), analysis using restricted mean survival time is being explored. Allied translational work on longitudinal samples is underway.