Impact of Hormone Therapy on Ocular Disease Risk in Postmenopausal Women: Evidence from the Korean National Health Insurance Service Database

Menopausal hormone therapy and risk of seropositive rheumatoid arthritis: A nationwide cohort study in Korea

10506 Background: Use of menopausal hormone therapy (MHT) is contraindicated for women with a personal history of breast cancer. This topic is of importance among women with a pathogenic or likely pathogenic variant (mutation) in BRCA1 or BRCA2 given their tendency to develop early onset disease as well as the recommendation to undergo oophorectomy prior to natural menopause. Methods: We conducted a prospective analysis of MHT use following breast cancer in BRCA carriers and the risk of death. The study included BRCA carriers with a diagnosis of breast cancer, no history of another cancer, no prior MHT use, and who were enrolled in a longitudinal study. Women who initiated MHT after their diagnosis were matched to women who did not use MHT on year of birth, age of diagnosis, and treatments received – resulting in 183 matched pairs. We followed women from the date of first MHT use in the exposed and the matched date in the unexposed. Cox proportional hazards was used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for the risk of death associated with MHT use. Results: Among the 183 MHT users, 53 (29%) used a local MHT and 130 (71%) used a systemic MHT. After 6.0 years of follow-up (range 0.01-22.7); there were 9 (4.9%) deaths in the MHT group vs. 22 deaths (12%) in the no MHT group ( P = 0.01). The corresponding number of breast cancer deaths were 6 (3.3%) vs. 16 (8.7%) ( P = 0.03). The HR for all-cause mortality was 0.31 (95%CI 0.14-0.69; P = 0.004) and for breast cancer-specific mortality was 0.27 (95%CI 0.10-0.70; P = 0.007). The corresponding risk estimates for all-cause death by invasiveness were 0.25 (95%CI 0.11-0.61; P = 0.002) and 0.54 (95%CI 0.07-4.02; P = 0.54) for invasive disease and DCIS, respectively. All-cause mortality with use of systemic MHT was 0.27 (95%CI 0.11-0.67; P = 0.005) and was 0.19 (95%CI 0.03-1.45; P = 0.11) for local MHT. Compared to never HRT use, the HR for E-alone was 0.35 (0.12-1.02; P = 0.05) and was 0.58 (95%CI 0.08-4.29; P = 0.59) for E+P. Subgroup analyses by formulation, gene mutation and tumour pathology are on-going. Conclusions: Although based on small strata, the preliminary findings are suggestive of no increased risk of death with MHT use after BRCA -breast cancer and may offer an opportunity to improve quality of life in this unique population. Replication in larger datasets are needed.

The effects of menopausal hormone therapy for the risk of systemic lupus erythematosus: A nationwide cohort study in Korea.

ObjectiveTo analyze the relationship between pelvic organ prolapse (POP) and menopausal hormone therapy (MHT).MethodsThis retrospective cohort study used Korean National Health checkup and insurance data from 2002 to 2019. Women who used MHT for more than 6 months between 2002 and 2011 were included in the MHT group; postmenopausal women with no MHT use comprised the non-MHT group.ResultsIn the non-MHT group, there were 1,001,350 women, while the MHT group had 353,206 women. Tibolone (adjusted hazard ratio [aHR], 0.87; 99% confidence interval [CI], 0.818-0.926) and combined estrogen plus progestin by the manufacturer (CEPM) (aHR, 0.821; 99% CI, 0.758-0.89) were associated with reduced POP risk. The other oral MHT groups and the transdermal estrogen group showed no significant difference in POP risk compared with the non-MHT group (other oral MHT: aHR, 1.045; 99% CI, 0.941-1.161) (transdermal estrogen: aHR, 1.252; 99% CI, 0.731-2.145). Lower body mass index (BMI) (<18.5) was associated with reduced POP risk (aHR, 0.822; 99% CI, 0.698-0.968), while a BMI between 23 and 29.9 was associated with increased risk (BMI 23-24.9: aHR, 1.143; 99% CI, 1.088-1.2) (BMI 25-29.9: aHR, 1.173; 99% CI, 1.12-1.228). All parities had a higher POP risk than parity 1 (parity 0 or no response: aHR, 1.785; 99% CI, 1.589-2.005; parity 2: aHR, 1.434; 99% CI, 1.292-1.592; parity ≥3: aHR, 1.916; 99% CI, 1.712-2.144).ConclusionTibolone and CEPM use were associated with reduced POP risk in postmenopausal women. Other MHT types showed no significant association with POP.

To evaluate the association between various regimens and combinations of menopausal hormone therapy (MHT) and the risk of cardiovascular disease (CVD) in clinical practice. This was a population-based cohort study. This population-based cohort study used data from the Health Insurance Review and Assessment Service. The data of women who reported entering menopause at ≥40 years of age with no history of CVD in the national health examination between 2011 and 2014 were extracted. A total of 134 298 pairs were included in the MHT and non-MHT groups after 1:1 propensity score matching. The participants were followed until December, 31, 2020. During a median follow-up of 7.9 (IQR 6.9-8.9) years, the incidences of CVD were 146 per 100 000 person/year and 179 per 100 000 person/year for the non-MHT and MHT groups, respectively. After adjusting for covariates, MHT use was associated with an increased CVD risk (hazard ratio [HR], 1.22 [1.14-1.31]) compared with the non-MHT group; the risk was based on an increased risk of stroke and coronary artery revascularization. Tibolone (HR, 1.38, [1.27-1.50]) was associated with increased CVD, but estrogen alone or combined estrogen/progestogen was not. There was no difference in CVD risk, regardless of the type of estrogen agent used. For combined estrogen/progestogen therapy, dydrogesterone was associated with reduced CVD risk. There was an increased risk of CVD in MHT users. By regimen, tibolone use was associated with increased risk of CVD, whereas estrogen either alone or in combination with progestogen was not. There was no difference according to the type of estrogen. The type of progestogen seems to modify the results, since dydrogesterone was associated with reduced CVD risk.

Menopausal hormone therapy decreases the likelihood of diabetes development in peri‑menopausal individuals with prediabetes

Background: The Women’s Health Initiative (WHI) provided divergent results regarding the effects of menopausal hormone therapy (MHT) on breast cancer risk, with women in the conjugated equine estrogen plus medroxyprogesterone (CEE+MPA) arm at elevated risk, and women in the CEE alone arm at reduced risk. Although direct progestin-mediated effects may largely explain the elevated risk, we hypothesize that in addition, these MHT treatments may differentially influence patterns of estrogen metabolism, with CEE alone preferentially inducing metabolism along the 2-hydroxylation pathway, a pattern previously linked to reduced breast cancer risk. Study methods/population: Women in a case-control study of estrogen metabolites (EM) and ovarian and endometrial cancer from the WHI Observational Study were identified for this analysis. Unlike the WHI trial, no medication restrictions were applied. At enrollment, serum, anthropometric measures, and self-administered questionnaires which ascertained reproductive history, lifestyle factors and health behaviors including MHT use, were obtained. 615 women reported current use of estrogen plus progestin formulations (E+P), of whom 343 used CEE+MPA; 266 used estrogens alone (E alone), with 148 using CEE. Fifteen EM were measured by liquid chromatography/mass spectrometry and analyses were conducted separately for each EM. EM differences between E alone and E+P users were assessed using inverse probability weighted linear regression. Primary analyses included women using any MHT formulation; secondary analyses were restricted to CEE users. Results: Compared to users of E+P, concentrations of all EM were higher in E alone users, and significantly so for unconjugated estrone, estradiol, 2-methoxyestrone, 4-methoxyestrone and unconjugated estriol. Relative to total EM, concentrations of 2- and 4-pathway EM did not differ by MHT group (for E alone and E+P users, 2-pathway EM were ~14% of the total EM; 4-pathway EM were &amp;lt;2% of the total), but E+P users had a significantly higher proportion of 16-pathway EM compared to E alone users (32% vs. 30%, p=0.025). Similar patterns were observed in analyses comparing users of CEE alone to CEE+MPA, albeit not significant. Conclusion: Our data suggest that women using E alone may preferentially metabolize estrogens along the 2- and 4-hydroxylation pathways, whereas in E+P users, more extensive metabolism occurs along the 16-pathway. However, we did not observe these effects in the smaller groups of women using CEE alone or CEE+MPA, the MHT formulations administered in the treatment arms of the WHI trial. Our findings in E alone users are consistent with epidemiologic investigations demonstrating reduced breast cancer risk in postmenopausal women with more extensive 2-pathway estrogen metabolism, and may provide a clue to the breast cancer risk reduction observed in these women. Citation Format: Roni T. Falk, Garnet L. Anderson, Vanessa M. Barnabei, Louise A. Brinton, Jane A. Cauley, Chu Chen, Rowan T. Chlebowski, Sally B. Coburn, JoAnn E. Manson, Ruth M. Pfeiffer, Kerryn W. Reding, Thomas E. Rohan, Gloria E. Sarto, Nicolas Wentzensen, Britton Trabert. Estrogen metabolism in menopausal hormone users: Does it differ between estrogen plus progestin and estrogen alone users in the Women’s Health Initiative Observational Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4237. doi:10.1158/1538-7445.AM2017-4237

To determine whether menopausal hormone therapy (MHT) increases the risk of gallstones and gallbladder cancer. A retrospective cohort study. Data from the Korea National Health Insurance Corporation was obtained between January 1, 2002, and December 31, 2019. Participants were divided into MHT and non-MHT groups; the MHT group was analyzed in detail by dividing participants into tibolone, combined estrogen plus progestin by the manufacturer (CEPM) or physician (CEPP), oral estrogen alone, and topical estrogen subgroups. The incidence of gallstones and gallbladder cancer was compared between the two groups. This study enrolled 1,004,034 and 381,711 patients in the non-MHT and the MHT groups, respectively. The incidence of gallstones was 2.6% in the non-MHT group and 3.4%, 2.6%, 3.4%, 3.2%, and 4.4% in the tibolone, CEPM, oral estrogen alone, CEPP, and topical estrogen groups, respectively. Cox proportional hazard analysis revealed that all hormones increased the risk of gallstones ([tibolone] hazard ratio [HR]: 1.347, 95% confidence interval [CI]: 1.309-1.387, [CEPM] HR: 1.146, 95% CI: 1.1-1.19, [oral estrogen alone] HR: 1.241, 95% CI: 1.18-1.305, [CEPP] HR: 1.164, 95% CI: 1.01-1.341, [topical estrogen] HR: 1.602, 95% CI: 1.295-1.983). However, the risk of gallbladder cancer did not change with any hormone therapy. All types of MHT including tibolone, increased the risk of gallstones. This risk was the highest with topical estrogen, which may be a result of selection bias due to concerns regarding the adverse effects of CEE and MPA.

PurposeThe t(14;18) translocation might represent an intermediate step in the pathogenesis of follicular lymphoma (FL), one of the most common subtypes of non-Hodgkin lymphoma. Circulating t(14;18)-positive cells can also be detected in 30–60 % of healthy individuals at low frequencies. Some studies found a negative association between reproductive factors or use of menopausal hormone therapy (MHT) with FL. The objective of this study was to evaluate whether there is an association between number of frequencies, oral contraceptive (OC) use, menopausal status and MHT, and t(14;18) prevalence and frequency in a representative population analysis based on an epidemiologic study in the northeastern part of Germany.MethodsThe analysis is based on results of buffy coat samples from 1,981 women of the Study of Health in Pomerania (SHIP-0) and data obtained in standardized face-to-face interviews. For prevalence, odds ratios (OR) and 95 % confidence intervals (CI) were calculated using unconditional logistic regression. Frequency data were analyzed using negative binomial regression. The multivariable models included age, number of pregnancies, menopausal status (premenopausal, natural, medical/surgical menopause), OC use and MHT as a measure for exogenous hormone exposure use.ResultsWe found no association between reproductive history and combined exogenous hormone use on the prevalence of circulating t(14;18)-positive cells. Modeling MHT and OC use separately in a sensitivity analysis, the MHT parameter yielded statistical significance [OR 1.37 (95 % CI 1.04;1.81)]. t(14;18) frequency was associated with use of OC [incidence rate ratio (IRR) for ever use 3.18 (95 % CI 1.54;6.54)], current use [IRR 3.86 (1.56;9.54)], >10 years use [IRR 3.93 (1.67;9.23)] and MHT [restricted to postmenopausal women; IRR 2.63 (95 % CI 1.01;6.85)] in bivariate age-adjusted analyses. In the multivariable model, medical/surgical menopause [IRR 2.46 (1.11;5.44)] and the category ever use of OC and MHT were statistically significant [IRR 2.41 (1.09;5.33)].ConclusionsExogenous hormone use might be a risk factor for t(14;18) frequency rather than for t(14;18) prevalence. Further research on healthy individuals carrying a t(14;18) translocation and possible risk factors for malignant lymphoma is necessary to determine the additional molecular or immunological events that have to occur to develop FL.Electronic supplementary materialThe online version of this article (doi:10.1007/s10552-015-0525-4) contains supplementary material, which is available to authorized users.

Aim - to evaluate the impact of menopausal hormone therapy (MHT) on the levels of systemic inflammation markers (interleukin-6 and C-reactive protein) and the quality of life in postmenopausal women. Materials and methods. A comparative analysis of 80 postmenopausal women was conducted: 40 women receiving combined MHT (estrogen + progestin) and 40 women without MHT. The serum levels of interleukin-6 (IL-6) and C-reactive protein (CRP), quality of life using the MENQOL scale, and the prevalence of genitourinary syndrome of menopause (GSM) were assessed. Results. The MHT group had significantly lower levels of IL-6 (3.2±1.8 vs 5.1±2.4 pg/ml) and CRP (1.8±1.2 vs 3.4±1.8 mg/l) compared to the non-MHT group. The prevalence of GSM was lower in the MHT group (15.0% vs 35.0%). Quality of life was significantly better in the MHT group across all MENQOL domains. A strong correlation was found between the levels of inflammatory markers and the severity of GSM symptoms (r=0.64-0.79). Conclusions. Menopausal hormone therapy has a pronounced anti-inflammatory effect, which is confirmed by a significant reduction in the levels of key biomarkers of systemic inflammation — IL-6 and CRP. The use of MHT is associated with a decrease in the prevalence of genitourinary syndrome of menopause and a significant improvement in the quality of life of postmenopausal women in all key aspects (vasomotor, urogenital, psychosocial, and physical). There is a strong positive correlation between the levels of systemic inflammation markers (IL-6, CRP) and the severity of urogenital symptoms, which confirms the role of chronic inflammation in the pathogenesis of GSM. The study was carried out in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Committee on bioethics and deontology of these institutions. The informed consent of the children's parents was obtained for the research. No conflict of interests was declared by the authors.

The effect of menopausal hormone therapy on thyroid cancer survivors from the National Health Insurance Database in South Korea cohort.

This study evaluated the effect of menopausal hormone therapy (MHT) on serum concentration of copper in postmenopausal women depending on passive or active exposure to tobacco smoke or lack thereof. The study included healthy postmenopausal women aged 42–69 years, who used (n = 76) or did not use (n = 76) MHT. Salivary cotinine and serum copper concentrations were determined in all the study subjects. Salivary cotinine exceeded 14 ng/ml in 14 women from the MHT group (18.5%) and in 16 controls (21.1%). Up to 41 (27%) study subjects had serum copper above the upper normal limit (1.17 mg/l). No correlation was found between salivary cotinine and serum copper in women with cotinine concentrations <14 ng/ml, and these two parameters correlated weakly in subjects with cotinine >14 ng/ml. Salivary concentration of cotinine increased with serum copper level in the MHT group, but not in the controls; smokers using MHT presented with significantly higher serum copper than nonsmokers. These findings imply that MHT does not affect serum concentration of copper in women who are not exposed to tobacco smoke. However, MHT seems to contribute to unfavorable increase in serum copper in passive and active smokers.

Most studies have reported that the risk of coronary heart disease decreases when menopausal hormone therapy (MHT) is initiated before the age of 60 years or within 10 years of menopause. However, the findings regarding stroke risk remain conflicting. This study investigated the association between the risk of ischemic stroke and MHT, categorized by the type of MHT. This population-based, retrospective cohort study was based on the Korean National Health Insurance Service-National Sample Cohort (2004-2015). Participants were aged 45-60 years with no cardiovascular disease or preexisting stroke, classified as never, past, and current users of MHT. Among the study participants, 16915 (88.77%) women had never undergone MHT, 1437 (7.54%) had previously undergone MHT, and 703 (3.69%) were currently using MHT. During the study period, with a mean follow-up of 11.23±2.13 years, the risk of ischemic events was significantly higher among current users [hazard ratio (HR): 2.98, 95% confidence interval (CI): 1.95-4.57, p<0.001], particularly in those using estrogen-only MHT (HR: 3.49, 95% CI: 1.12-10.90, p=0.032) and tibolone (HR: 3.52, 95% CI: 2.05-6.03, p<0.001), compared to never users. Meanwhile, no significant difference in the risk of ischemic events was observed between past users and never users, even after analyses accounting for estrogen type and progestin co-administration. Women currently receiving MHT without underlying cardiovascular disease exhibited an increased risk of ischemic stroke, particularly those treated with E-only MHT or tibolone. However, this increased risk returned to baseline after discontinuing MHT, indicating that past use of MHT was not associated with an increased risk of ischemic stroke.

Background: Prior observational studies have identified an elevated breast cancer risk associated with current MHT use for ER+ (Estrogen Receptor positive), and for ER+ / PR+ (Estrogen and Progesterone Receptor positive) breast cancers than for ER- and ER-/PR- subtypes respectively. We have previously reported, from a large case-control study for all cancer types (the NSW CLEAR study) that current MHT use was associated with a doubling of the odds of breast cancer. Here, we describe further analyses investigating the MHT-breast cancer association for the breast cancer tumor receptor subtypes defined by ER expression, by ER and PR expression and by the joint expression of ER, PR, and HER-2 (Human Epidermal growth factor Receptor-2). Methods: Analyses were carried out for a subset of registry-verified CLEAR breast cancer cases with hormone receptor status data (n=410) and CLEAR (cancer-free) controls recruited over the same period (n=324). We used a multinomial logistic regression model to estimate Odds Ratios (ORs) adjusted for other breast cancer risk factors and 95% Confidence Intervals (CI) for current and past MHT use in subgroups defined by tumor receptor subtypes. Never users comprised the reference group. Findings: In a multinomial model, current MHT use was associated with an elevated risk of ER+ breast cancer (aOR= 2.04, 95%CI: 1.28 -3.24). When breast cancers were categorised by ER and PR status, current use was associated with an elevated risk of developing ER+PR+ breast cancer (aOR= 2.29, 1.41-3.72). Current MHT use was associated with the surrogate luminal A breast cancer characterized by ER+/PR+/HER2- phenotype (aOR= 2.30, 1.42-3.73). None of the other subtypes of breast cancer (ER+/PR+/HER2+, ER-/PR-/HER2+, and ER-/PR-/HER2-) were significantly associated with current MHT use. A significant difference in the odds of developing breast cancer for current MHT users was detected between the surrogate luminal A and luminal B (ER+/PR+/HER2+) subtypes only (aOR= 0.28, 0.09-0.88, p=0.029). None of the other groups were significantly differently associated with MHT use, although this may be due to lack of power. Past MHT use was not associated with an increased risk of breast cancer for any breast cancer subtype. Conclusion: The findings from this contemporary Australian study are consistent with findings from other studies that current, but not past, use of MHT is associated with increased risk of breast cancer, with higher risks reported for ER+, ER+ and PR+ and ER+/PR+/HER2- (surrogate luminal A) subtypes. Our findings are consistent with the hypothesis that breast cancers induced by MHT may occur through receptor-mediated mechanisms. Citation Format: Usha G. Salagame, Emily Banks, Dianne O’Connell, Sam Egger, Karen Canfell. Menopausal hormone therapy (MHT) use and breast cancer risk by receptor subtypes: results from the New South Wales Cancer Lifestyle and EvAluation of Risk (CLEAR) study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2285. doi:10.1158/1538-7445.AM2017-2285

We investigated the association of prediagnostic use of menopausal hormone therapy (MHT) with breast cancer survival among women with type 2 diabetes (T2D). The study cohort was identified from a Finnish nationwide diabetes database, and consisted of women with T2D, who were diagnosed with breast cancer between 2000 and 2011 (n = 3189). The patients were classified according to their previous MHT use: systemic MHT, local MHT, and no history of any MHT. The cumulative mortality from breast cancer, cardiovascular diseases, and other causes in three MHT groups was described by the Aalen-Johansen estimator. The cause-specific mortality rates were analyzed by Cox models, and adjusted hazard ratios (HRs) were estimated for the use of MHT. The breast cancer mortality appeared to be lower among systemic MHT users (HR 0.49, 95% Cl 0.36–0.67) compared with non-users of MHT. The mortality from cardiovascular diseases and from other causes of death was found to be lower among systemic MHT users, (HR 0.49, 95% Cl 0.32–0.74), and (HR 0.51, 95% Cl 0.35–0.76), respectively. In conclusion, prediagnostic systemic MHT use is associated with reduced breast cancer, cardiovascular, and other causes of mortality in women with T2D.