Hormone Replacement Therapy Users Research Articles

The impact of irritant challenge on the skin barrier and myeloid resident immune cells in post-menopausal women is modulated by hormone replacement therapy.

Sex hormone changes during menopausal transition contribute to declining skin health. However, how menopause and its treatment by hormone replacement therapy (HRT) impact the skin barrier and immune system is unclear. Therefore, we examined how menopause and HRT affect skin barrier and immune cell composition in post-menopausal women following irritant challenge. Two cohorts of post-menopausal women were recruited to the study, one untreated (HRT-; n = 10; mean age 56.5 yrs [range 48-63 yrs]) and the other receiving HRT (n = 8; mean age 54 yrs [range 48-63 yrs]). Skin irritation was induced by applying 1.25% topical Sodium Lauryl Sulfate (SLS) to occluded buttock skin for 48 hours. Clinical assessment was conducted after 24 hours, followed by biopsy of both SLS-challenged and unchallenged skin for analysis of skin barrier proteins and immune cell distribution using immunofluorescence. Clinically, there were no significant differences in skin irritant responses between those taking or not taking HRT (including increased skin redness and blood flow). In response to SLS challenge a significant increase in trans-epidermal water loss (p<0.05), filaggrin deposition and keratin-10-positive cell layers (p<0.01) was observed in individuals receiving HRT compared to the HRT- group. Following SLS challenge in individuals taking HRT, a significant (p<0.01) reduction of CD207+ cells in the epidermis was observed, accompanied by an increase of CD207+ cells in the dermis, indicative of migrating Langerhans' cells (LCs). Significantly fewer migrating LCs were observed in those not receiving HRT (p<0.01). Furthermore, the number of dermal dendritic cells (DCs), macrophages, and CD11c+CD206- and CD68+CD206- subsets were found to be significantly (p<0.05) higher in those taking HRT following SLS challenge. Individuals receiving HRT displayed enhanced skin barrier response to SLS challenge with thicker filaggrin and increased keratin-10-positive epidermal cell layers. Following challenge, HRT users exhibited elevated counts of LCs, inflammatory DCs, and macrophages in the dermis. These may render skin both, more prone to inflammation and more capable of resolving it, while also promoting skin repair.

Hormone replacement therapy in women with iatrogenic premature ovarian insufficiency after radiotherapy for cervical cancer: A retrospective cohort and survey study

ObjectivesThis study assessed the uptake of hormone replacement therapy (HRT) in cervical cancer patients with iatrogenic menopause. Survival in relation to HRT use was assessed via a retrospective chart study, and the severity of menopausal symptoms, motivations and barriers to starting HRT were examined via questionnaires. Study designIn total, 293 women under the age of 51 and treated with radiotherapy for cervical cancer between 2010 and 2020 were identified. Medical records were searched for information on HRT use. If still living, women were sent digital questionnaires addressing menopausal symptoms, quality of life (QoL) and potential barriers and motivations concerning HRT use. Univariable data were analysed using Mann-Whitney U, chi-square, and Fisher's exact test, while logistical regression was used to analyse relationships between certain variables and use of HRT and survival. ResultsOverall HRT uptake was 78.1 %, which was related to age and Charlson Comorbidity Index, but independent of the duration of radiotherapy or FIGO stage. Overall survival was higher for HRT users (χ2(1) = 4.3, p = 0.038). Questionnaires were sent to 193 patients and 100 completed it (response rate 51.8 %). Main reasons for HRT use were relief of hot flushes and improvement in QoL. For women below age 51, QoL was indeed higher for current HRT users than for non-HRT users (EQ-index 0.8 vs. 0.7, p = 0.008). ConclusionsHRT prescription rate was inversely correlated with age. Survival was not negatively affected by HRT use. It is important to stress the benefits of HRT and address women's fears regarding its use.

Could sex-specific subtypes of hand osteoarthritis exist? A retrospective study in women presenting to secondary care.

Hand osteoarthritis is more common in women, and its risk increases around the time of the menopause. We set out to describe the timing between menopause and the onset of symptomatic hand osteoarthritis (OA), and associations with the use of hormone replacement therapy (HRT) or its discontinuation, describing any identifiable subgroups of women. Retrospective healthcare-records study of sequential women referred to a specialist hand OA clinic, 2007-2015. Confirmation of hand OA diagnosis was by clinican, by accepted criteria. Demographics and clinical variables were from healthcare-records, recorded by standardised proforma. Outcomes of interest were reported age of onset of hand symptoms, reported age at final menstrual period (FMP), time from FMP to reported onset of hand symptoms and time from cessation of HRT to reported onset of hand symptoms. Exposure categories for systemic HRT use were never users, current users, previous users. Analysis of Variance compared groups; linear regression analysed associations of exposure with outcome. 82/92(89%) of eligible women were post-menopausal, mean age at FMP 49.9 years (SD5.4). In these post-menopausal women, median time from FMP to hand symptom onset was 3 years. 48/82 (59%) developed hand symptoms within the defined peri-menopausal period (FMP ± 4 years), whilst some women developed their symptoms before or after (range -25, 30 years). In women who discontinued HRT prior to symptom onset, the median time from HRT cessation to onset of hand symptoms was 6 months. Past HRT users were older at hand symptom onset than women who had not taken HRT [coeff.4.7 years (0.92, 8.39); P = 0.015]. This study adds to evidence associating the menopause/sex hormone deficiency with hand OA symptom onset in a sizeable subgroup of women (but not all). HRT use/cessation appears to influence the timing of onset of hand OA symptoms. It is not possible to interpret from this type of study whether sex hormone deficiency is causative of disease or modulates its symptoms. It is also not possible to judge whether painful hand osteoarthritis in post-menopausal women is a subtype of disease. Further investigation is indicated of sex-specific subtypes and potential for personalised medicine for post-menopausal women with hand osteoarthritis, as a clearly definable high-risk subgroup.

Antiosteoporosis medications and cardiovascular disease: a population-based nationwide nested case-control study.

Purpose: Patients with osteoporosis are at an increased risk of cardiovascular disease (CVD). Several antiosteoporosis medications have been demonstrated with the benefit of preventing osteoporosis. Our aim is to assess the CVD risks associated with antiosteoporosis medications using the National Health Insurance Research Database in Taiwan between 2000 and 2016. Methods: Among 41,102 patients of 40+ years old with newly diagnosed osteoporosis, 69.1% (N = 28,387) of patients were included in the user cohort of antiosteoporosis medicines, of whom 13, 472 developed CVD by the end of 2016, while 14,915 did not. Using the nested case-control analysis in the user cohort (88.0% women and 77.4% elderly), we applied conditional logistic regression to estimate odds ratios (ORs) of eight types of CVD for the users of denosumab, bisphosphonate, teriparatide, and hormone replacement therapy (HRT). Results: The adjusted ORs of overall CVDs were 0.13 (95% CI: 0.12-0.15) for denosumab users, 0.52 (95% CI: 0.45-0.61) for teriparatide users, and 0.80 (95% CI: 0.76-0.85) for bisphosphonate users. The HRT users were at higher odds of coronary artery and peripheral artery diseases, heart failure, pulmonary embolism, and deep vein thrombosis. Conclusion: Denosumab, teriparatide, and bisphosphonate may have more protective effects against CVD than hormone therapy. Physicians may take subsequent cardiovascular risks into account when choosing an adequate antiosteoporosis medication for patients with osteoporosis.

FRI079 Long-term Bone Consequences Of Roux-En-Y Gastric Bypass: A Cross-sectional And Case-Control Study Of Post-menopausal Women

Abstract Disclosure: G. Papadakis: None. E. Gonzalez Rodriguez: None. S. Mantziari: None. J. Pasquier: None. E. Shevroja: None. N. Vionnet: None. L. Favre: None. Bariatric surgery decreases bone mineral density (BMD) due to mechanical unloading (weight loss) and secondary hyperparathyroidism linked to nutrient deficiencies (calcium, vitamin D). Most studies on the bone impact of bariatric surgery have investigated premenopausal women after a follow up of less than 3 years. In the current study, we sought to determine the long-term bone impact of Roux-en-Y gastric bypass (RYGB) on post-menopausal women. A cross-sectional and a case-control study were performed in women for whom a Dual X-ray absorptiometry (DXA) at least 3 years after surgery was available. BMD was measured at lumbar spine (LS), total hip (TH) and femoral neck (FN). Trabecular bone score (TBS) at LS was analyzed after correction for soft tissue thickness. History of fractures was inquired and DXA images were reviewed for vertebral fractures. For patients on anti-osteoporotic drugs, the DXA scan before the onset of therapy was taken into account. One-hundred nineteen women were eligible at a mean 9.0 ± 5.6 years after RYGB. The fracture rate was 12% and 6% for major osteoporotic and vertebral fractures, respectively. As calcium/vitamin D supplements were administered to all patients, serum 25-hydroxyvitamin D levels exceeded the threshold of 75 nmol/l in 77% of participants with insufficient levels (less than 50 nmol/l) only in 3 patients. Serum PTH levels were within the normal range in 87% of participants. A multivariate regression model including BMI, age, time since RYGB, one-year weight loss and serum PTH highlighted higher BMI as the sole significant predictor for better BMD at LS and TH (p=0.001 and p=0.008, respectively). Time since RYGB was the only variable inversely associated with TBS. Plasma levels of bone turnover markers (β-crosslaps, P1NP) exhibited a strong inverse correlation with BMD at all sites. For the case-control substudy, 76 post-RYGB women were age- and BMI-matched to female participants of the OsteoLaus study, a population-based cohort in Lausanne. The patient group had significantly lower BMD at all sites: LS (p=0.03), TH (p=0.01), FN (p=0.007), as well as lower TBS (p=0.003) compared to controls. No statistical difference was observed for fractures, although more major osteoporotic fractures occurred in the post-RYGB group (8 vs 4 in the controls). Possibly contributing to the bone impairment, the post-bariatric cohort had more active smokers (21 vs 7 in the controls, p=0.006) and less hormonal replacement therapy users (2 vs 12 in the controls, p=0.009). In conclusion, post-bariatric BMI is the strongest determinant of long-term BMD levels. Despite satisfactory vitamin D/PTH levels, a history of RYGB several years ago was associated with lower BMD and altered bone structure in this postmenopausal cohort. Long-term bone health monitoring is warranted after RYGB especially in women who are smoking and achieved substantial weight loss. Presentation: Friday, June 16, 2023

Characteristics of HRT users in Japan: Evidence from the Japan Nurses' Health Study

ObjectivesLittle is known about what type of women use hormone replacement therapy (HRT) in Japan. Based on the Japan Nurses' Health Study (JNHS), a large population cohort study, we determined the characteristics of HRT users by comparing the characteristics of new HRT users and the characteristics of women who did not use HRT during a 10-year follow-up period. Study designOf the 15,019 JNHS participants, 4886 women reported an experience of menopausal transition during the 10-year follow-up period. Main outcome measurementCharacteristics of new HRT users. ResultsThe proportion of HRT users during the 10-year period was 8.5 %. Advanced age at menopause was significantly associated with a low rate of use of HRT. Past use of oral contraceptives, dysmenorrhea with disturbance in daily life and vasomotor symptoms were significantly associated with a high rate of use of HRT. The occupations of public health nurse and midwife and a history of bilateral oophorectomy were also significantly associated with a high rate of use of HRT. ConclusionsWe determined the characteristics of new HRT users among middle-aged women during a 10-year follow-up period. Women who had sufficient knowledge about endocrinological hormones and women who had less reluctance to visit doctors for gynecological problems were likely to use HRT.

Associations of life course obesity with endometrial cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2).

Adult obesity is a strong risk factor for endometrial cancer (EC); however, associations of early life obesity with EC are inconclusive. We evaluated associations of young adulthood (18-21 years) and adulthood (at enrolment) body mass index (BMI) and weight change with EC risk in the Epidemiology of Endometrial Cancer Consortium (E2C2). We pooled data from nine case-control and 11 cohort studies in E2C2. We performed multivariable logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for BMI (kg/m2) in young adulthood and adulthood, with adjustment for BMI in adulthood and young adulthood, respectively. We evaluated categorical changes in weight (5-kg increments) and BMI from young adulthood to adulthood, and stratified analyses by histology, menopausal status, race and ethnicity, hormone replacement therapy (HRT) use and diabetes. We included 14 859 cases and 40 859 controls. Obesity in adulthood (OR = 2.85, 95% CI = 2.47-3.29) and young adulthood (OR = 1.26, 95% CI = 1.06-1.50) were positively associated with EC risk. Weight gain and BMI gain were positively associated with EC; weight loss was inversely associated with EC. Young adulthood obesity was more strongly associated with EC among cases diagnosed with endometrioid histology, those who were pre/perimenopausal, non-Hispanic White and non-Hispanic Black, among never HRT users and non-diabetics. Young adulthood obesity is associated with EC risk, even after accounting for BMI in adulthood. Weight gain is also associated with EC risk, whereas weight loss is inversely associated. Achieving and maintaining a healthy weight over the life course is important for EC prevention efforts.

Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort

BackgroundThe risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT.MethodsThe analysis used baseline data from participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes.ResultsAPOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6–10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized β= −0.555, p=0.035) and left hippocampal volumes (standardized β= −0.577, p=0.028) only in APOE4 carriers.ConclusionHRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.

Association of hormone replacement therapy and the risk of knee osteoarthritis: A meta-analysis.

The relationship between hormone replacement therapy (HRT) and osteoarthritis is controversial in epidemiological studies. With the aim of better understanding the effect of HRT use, this first meta-analysis was implemented to explore the association of HRT and knee OA. A series of data is retrieved from Web of Science, PubMed, and Embase databases to observe the association of HRT and knee osteoarthritis up to December 2021. Two separated reviewers chose the research, extracted the data, and evaluated the study quality. Pooled estimates of 95% CI and HRs were acquired through a random-effects model. Finally, there existed 13 pieces of research, containing one case-control research, four cross-sectional pieces of research, as well as eight cohort pieces of research, involving 2573,164 participants. The overall results showed that the use of HRT was related to a raised risk of knee OA (HR = 1.24, 95% CI 1.07-1.45). And the pooled analysis showed a statistically significant raised risk of knee joint replacement (HR = 1.30, 95% CI 1.09-1.54) when using HRT. In addition, the outcome exhibits the raised knee OA risk for the present users of HRT (HR = 1.40, 95% CI 1.16-1.68) according to HRT status. In the past users of HRT, the augment of knee OA risk was not statistically evident (HR = 1.16, 95% CI 0.94-1.42). We observed that HRT use was related to a raised knee OA risk. Furthermore, future studies might focus on relevant mechanistic to verify our observed associations.

Exogenous hormone use and the risk of surgically treated cataract: Evidence from 91 760 female participants in the 45 and Up Study.

To investigate the association between exogenous hormone use and the risk of cataract surgery among working-aged Australian women. A total of 91 760 female participants aged 45-65 years and without prior history of cataract surgery were prospectively enrolled between January 2006 and December 2009 in New South Wales (NSW), Australia. A baseline self-reported questionnaire was used to collect information on participant demographic, socio-economic, lifestyle characteristics, medical history as well as the use of hormonal contraception and hormone replacement therapy (HRT). Cataract surgery for these participants during 2006-2019 was determined according to the Medicare Benefits Schedule database. Cox regression was used to assess the association between exogenous hormone use and incident cataract surgery during the follow-up. During a mean follow-up of 11.3 years, 10 444 participants underwent cataract surgery with a corresponding incidence of 11.4% (10 444/91 760). Compared with never users, ever and current users of HRT had a 22% and 14% increased risk of cataract surgery, respectively. A dose-response with longer HRT use resulting in a larger increase in cataract surgery risk was observed (p for trend <0.001). Among participants never used HRT, hormonal contraception had a protective effect against incident cataract surgery (hazards ratio: 0.87; 95% confidence interval: 0.80-0.94). Use of HRT significantly increased the risk of cataract surgery, and hormonal contraception use had a protective effect on cataract surgery among HRT non-users. Further studies assessing the effect of different hormone types and doses are needed.

Association between testosterone levels and bone mineral density in females aged 40–60 years from NHANES 2011–2016

Growing evidence indicates that testosterone is a conspicuous marker for assessing male bone mineral density (BMD). However, research regarding testosterone levels and BMD is sparse and controversial for females. Hence, we aimed to investigate the association between testosterone levels and BMD among adult females aged 40–60 years in the United States. In this cross-sectional study, all participants were part of the National Health and Nutrition Examination Survey (2011–2016). A weighted general linear model was used to estimate the association between testosterone levels and lumbar BMD. Age, race, income level, education level, body mass index (BMI), blood urea nitrogen (BUN) level, serum uric acid (UA) level, serum calcium (Ca) level, serum phosphorus (P) level, the use of oral contraceptive pills, the use of hormone replacement therapy (HRT), smoking status, drinking status, and the use of corticosteroids were adjusted using a weighted multiple regression model. Subgroup analyses were performed using the same regression model. We included 2198 female participants in the study, and testosterone levels were positively associated with lumbar BMD after adjusting for all the covariates (β = 1.12, 95% CI 0.31, 1.93). In subgroup analyses, the associations in the fourth quartile of testosterone levels were stronger for the participants aged 40–50 years old (quartile 4, β = 42.92, 95% CI 7.53, 78.30 vs. quartile 1) and 50 to 60-year-old (quartile 4, β = 32.41, 95% CI 0.14, 64.69 vs. quartile 1). Similar results were found in other subgroups, including subgroups for race (Non-Hispanic Black, Other), income level (income ≤ 1.3, income > 3.5), education level (college or higher), BMI > 25 kg/m2, BUN levels ≤ 20 mg/dL, UA levels ≤ 6 mg/dL, Ca levels ≤ 10.1 mg/dL, P levels ≤ 5 mg/dL, drinking status, never smoker, never taking birth control pills, and HRT user. There was no interaction among the covariates in the association between lumbar BMD and testosterone levels (P for interaction > 0.05). In US adult females aged 40–60 years, the testosterone level was a positive predictor of the lumbar BMD after adjusting for covariates.

Endometrial cancer rate in Hormone replacement therapy users with postmenopausal bleeding: Retrospective cohort study.

To establish the endometrial cancer detection rate in women using hormone replacement therapy presenting with postmenopausal bleeding. Retrospective cohort study. Setting and populationRapid access gynaecology clinic at a tertiary hospital. Women aged under 60years referred with postmenopausal bleeding. Retrospective study of referrals received between 1 January 2019 and 31 December 2020 including Hormone replacement therapy (HRT) use and histological diagnosis. Histological diagnosis of endometrial cancer, borderline ovarian tumour or endometrial intraepithelial neoplasia. Chi squared test. 1363 women were included. 214 women were using HRT when they experienced PMB and only one of these had endometrial cancer at histology (cancer detection rate 0.47%). 25 of the 1124 women who were not using HRT were diagnosed with endometrial cancer on histology (cancer detection rate 2.18%). Chi squared statistical analysis confirmed this was statistically significant (p value .0156). The endometrial cancer detection rate in women aged under 60years using HRT with PMB is very low. Referral on a two-week wait pathway for suspected cancer diagnosis induces stress and anxiety for the woman and may lead to more invasive initial investigation even though other diagnoses are far more likely. Women aged under 60years with postmenopausal bleeding that have either commenced HRT or had a change to their preparation within the last 6 months should be seen on a less urgent referral pathway if necessary given the very low probability of endometrial cancer.

Drinking Water Disinfection Byproducts, Ingested Nitrate, and Risk of Endometrial Cancer in Postmenopausal Women.

Background:Disinfection byproducts (DBPs) and N-nitroso compounds (NOC), formed endogenously after nitrate ingestion, are suspected endometrial carcinogens, but epidemiological studies are limited.Objectives:We investigated the relationship of these exposures with endometrial cancer risk in a large prospective cohort.Methods:Among postmenopausal women in the Iowa Women’s Health Study cohort, we evaluated two major classes of DBPs, total trihalomethanes (TTHM) and five haloacetic acids (HAA5), and nitrate-nitrogen () in public water supplies (PWS) in relation to incident primary endometrial cancer (1986–2014). For women using their PWS at enrollment (; ), we computed historical averages of annual concentrations; exposures were categorized into quantiles and when possible percentile. We also computed years of PWS use above one-half the U.S. maximum contaminant level (; TTHM; HAA5; ). Dietary nitrate/nitrite intakes were estimated from a food frequency questionnaire. We estimated hazard ratios (HR) and 95% confidence intervals (CI) via Cox models adjusted for age, endometrial cancer risk factors [e.g., body mass index, hormone replacement therapy (HRT)], and mutually adjusted for . We evaluated associations for low-grade () vs. high-grade () type I tumors. We assessed interactions between exposures and endometrial cancer risk factors and dietary factors influencing NOC formation.Results:Higher average concentrations of DBPs (95th percentile: TTHM , HAA5 ) were associated with endometrial cancer risk (TTHM: , 95% CI: 1.41, 3.40; HAA5: , 95% CI: 1.19, 2.83; ). Associations were similarly observed for women greater than median years of PWS use with levels , in comparison with zero years (TTHM: , 95% CI: 1.18, 2.21; HAA5: , 95% CI: 1.31, 2.62). Associations with DBPs appeared stronger for low-grade tumors (TTHM: , 95% CI: 1.17, 3.83; ) than for high-grade tumors (TTHM: , 95% CI: 0.80, 2.44; ), but differences were not statistically significant (). Associations with TTHM were stronger among ever HRT users than non-HRT users (). We observed no associations with in drinking water or diet.Discussion:We report novel associations between the highest DBP levels and endometrial cancer for our Iowa cohort that warrant future evaluation. https://doi.org/10.1289/EHP10207

Prevalence of the Use of Oral Contraceptives and Hormone Replacement Therapy in Japan: The Japan Nurses' Health Study.

BackgroundThere have been few community-based epidemiological studies in which the prevalence of exogenous hormone use, including the use of oral contraceptives (OCs) and hormone replacement therapy (HRT), has been accurately assessed in Japan.MethodsWe have been conducting repeated surveys of participants in the Japan Nurses’ Health Study (JNHS), as a nationwide prospective cohort study, since 2001. We determined the prevalence of exogenous hormone use at baseline and during a 10-year follow-up period. A total of 15,019 female nurses participated in the JNHS follow-up cohort. We determined the prevalence of OC use in 14,839 women <60 years of age at baseline and the prevalence of HRT use in 7,915 women, excluding premenopausal women, at the last time they answered a questionnaire. The duration of HRT use was estimated using the Kaplan-Meier method.ResultsSix percent of the participants used OCs. The proportion of HRT users who stopped HRT before the baseline survey, the proportion of women using HRT during the follow-up period, and the proportion of all of the participants who had used HRT were 3.2%, 10.6%, and 13.8%, respectively. The median duration of HRT use was 2 years.ConclusionsThe lifetime prevalences of exogenous hormone use during this prospective study conducted in Japanese nurses were 6.0% for OCs and 13.8% for HRT. The information obtained in this study will be useful for clarification of the association between exogenous estrogen exposure and estrogen-related diseases as future research.

Association between female reproductive factors and gout: a nationwide population-based cohort study of 1 million postmenopausal women

BackgroundPrevious studies have shown that the incidence and risk factors of gout differs according to sex. However, little research has been done on the association between reproductive factors and gout. We conducted an analysis of a large nationwide population-based cohort of postmenopausal women to determine whether there is an association between reproductive factors and the incidence of gout.MethodsA total of 1,076,378 postmenopausal women aged 40–69 years who participated in national health screenings in 2009 were included in the study. The outcome was the occurrence of incident gout, which was defined using the ICD-10 code of gout (M10) in the claim database. Cox proportional hazard models were used for the analyses and stratified analyses according to body mass index (BMI) and the presence/absence of chronic kidney disease (CKD) were performed.ResultsThe mean follow-up duration was 8.1 years, and incident cases of gout were 64,052 (incidence rate 7.31 per 1000 person-years). Later menarche, earlier menopause, and a shorter reproductive span were associated with a high risk of gout. No association between parity and gout incidence was observed. Use of oral contraceptives (OC) and hormone replacement therapy (HRT) were associated with an increased risk of gout. The association between reproductive factors and gout was not statistical significant in the high BMI group. The effects of OC and HRT usage on gout were not significant in the CKD group.ConclusionShorter exposure to endogenous estrogen was associated with a high risk of gout. Conversely, exposure to exogenous estrogen such as OC and HRT was associated with an increased risk of gout.

The effect of hormone replacement therapy on the survival of UK women: a retrospective cohort study 1984-2017.

ObjectiveTo estimate the effect of estrogen‐only and combined hormone replacement therapy (HRT) on the hazards of overall and age‐specific all‐cause mortality in healthy women aged 46–65 at first prescription.DesignMatched cohort study.SettingElectronic primary care records from The Health Improvement Network (THIN) database, UK (1984−2017).Population105 199 HRT users (cases) and 224 643 non‐users (controls) matched on age and general practice.MethodsWeibull‐Double‐Cox regression models adjusted for age at first treatment, birth cohort, type 2 diabetes, hypertension and hypertension treatment, coronary heart disease, oophorectomy, hysterectomy, body mass index, smoking and deprivation status.Main outcome measuresAll‐cause mortality.ResultsA total of 21 751 women died over an average of 13.5 years follow‐up per participant, of whom 6329 were users and 15 422 non‐users. The adjusted hazard ratio (HR) of overall all‐cause mortality in combined HRT users was 0.91 (95% CI 0.88−0.94), and in estrogen‐only users was 0.99 (0.93−1.07), compared with non‐users. Age‐specific adjusted HRs for participants aged 46–50, 51–55, 56–60 and 61–65 years at first treatment were 0.98 (0.92−1.04), 0.87 (0.82−0.92), 0.88 (0.82−0.93) and 0.92 (0.85−0.98) for combined HRT users compared with non‐users, and 1.01 (0.84−1.21), 1.03 (0.89−1.18), 0.98 (0.86−1.12) and 0.93 (0.81−1.07) for estrogen‐only users, respectively.ConclusionsCombined HRT was associated with a 9% lower risk of all‐cause mortality and estrogen‐only formulation was not associated with any significant changes.Tweetable abstractEstrogen‐only HRT is not associated with all‐cause mortality and combined HRT reduces the risks.

Clinical Impact of Hormone Replacement Therapy on Atrial Fibrillation in Postmenopausal Women: A Nationwide Cohort Study.

Individuals with atrial fibrillation (AF), especially women, have an increased risk of stroke and death. Although hormone replacement therapy (HRT) is widely used in postmenopausal women, the association between HRT use and AF risk is unclear. We aimed to investigate the association between various types of HRT and AF. This was a population-based retrospective cohort study from The Korean National Health Insurance Service-National Sample Cohort (2004–2015). Participants were aged 45–60 years and were free from cardiovascular disease and AF at baseline. Overall, 13,452 (64.03%) women had never received HRT, 5671 (26.99%) had received HRT, and 1885 (8.98%) were currently receiving HRT. In multivariable analysis, the relative hazards for AF were significantly higher among current users (p < 0.001) and lower among past users (p = 0.069). Current users—except those using estradiol-only HRT—had significantly elevated AF risk. Among past users, only estradiol plus progestin HRT users had a reduced AF risk after adjusting for covariates (p = 0.027). Ongoing HRT posed an increased risk of AF. The degree of risk varied based on the specific type of estrogen and progestins co-administration. These findings indicate that, with respect to AF risk, oral estradiol-containing HRT is superior to HRT containing oral conjugated equine estrogen or tibolone.

Estetrol (E4) is a native fetal estrogen that does not modify coagulation markers in postmenopausal women and maintains sensitivity to activated protein C (APC)

Objective: Compared to non-users, the risk of venous thromboembolism (VTE) has been reported to be increased in women using hormonal replacement therapy (HRT). This risk increase is explained, at least in part, by an acquired resistance towards activated protein C (APCr) which is induced by the estrogenic component. The APCr is assessed by measuring the amount of thrombin generated in the absence and presence of exogenous APC. Results are reported as normalized APC sensitivity ratio (nAPCsr), a scale which has been found to correlate with the VTE risk observed in COC and HRT users.

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.

1414Hormone replacement therapy, oral contraceptives and stroke risk

Abstract Background Millions of women use exogenous hormones as hormone replacement therapy (HRT) or oral contraceptives (OC). Still, time-dependent and long-term consequences of exogenous hormones on cerebrovascular health remains unclear. Methods We examined the effects of HRT and OC usage on stroke risk in 256,661 women from UK Biobank, born between 1939 and 1970. Outcomes included any type of stroke, ischemic stroke (IS), intracerebral hemorrhage (IH), and subarachnoid hemorrhage (SH). Exposures were analyzed as time-dependent variables in Cox regression models. Results are expressed as hazard ratios (HR) with 95% confidence intervals. Results During first year of exposure, HRT usage was associated with higher hazard rates of any stroke (HR = 2.12[1.66-2.70]), IS (HR = 1.93[1.04-3.56]) and SH (HR = 2.14[1.23-3.72]) compared to non-usage, which remained significant only for any stroke during remaining years of exposure. Similarly, we observed an increased hazard of any stroke during first year of OC exposure (HR = 2.29[1.34-3.92]), while the hazards were found to be comparable during remaining years of use (HR = 1.03[0.92-1.17]). Conversely, women who previously had been exposed to OC, had a lower hazard rate of any stroke later in life, (HR = 0.88[0.82-0.94]). Conclusions Our findings suggest that HRT and OC use cause immediate changes in hemostatic balance, therefore increasing the short-term stroke risk. However, long-term effects of OC use during reproductive years might improve cerebrovascular health and prevent stroke events later in life. Key messages HRT usage increase the risk of stroke, both short-term and with longer use, while the increased stroke risk might be limited to the first year of OC use.