Is the patients’ fear of cancer the main barrier to prescribing menopausal hormone therapy?

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

Objectives: There is a large body of evidence of risk and benefits of menopausal hormone therapy (MHT). One among several safety concerns is the risk of gallstone formation and of gallbladder surgery. An increased risk of gallbladder disease might be explained by effects of oral MHT on hepatic lipid metabolism. Nonoral MHT avoids first-pass hepatic metabolism. Therefore it has been hypothesized that nonoral MHT may decrease the risk of cholelithiasis. The objective of the present study was to analyse the association between (1) use of life-time MHT (ever use) and gallbladder disease, and (2) nonoral use of MHT and gallbladder disease using data of the population-based Study of Health in Pomerania (SHIP). Methods: The study population included 994 postmenopausal women, aged 40–79 years. The subgroup of current oral and nonoral MHT users comprised 139 women. Gallbladder disease was defined as previous history of cholecystectomy or presence of current, sonographically diagnosed gallstones. Socio-demographic, medical, and reproductive characteristics were based on computer-assisted personal interviews, and selected laboratory parameters were analysed. We performed Poisson regression with Huber / White standard errors to investigate the association between ever use respective current nonoral use of MHT and gallbladder disease. Results: We found no significant association between ever use of MHT and gallbladder disease and sonographically diagnosed gallstones in fully adjusted analyses. Women who used MHT had a significantly higher risk for cholecystectomy compared to non users. There was no association between nonoral use of MHT and gallbladder disease. Conclusion: Our analyses do not lend support to the hypothesis that the use of MHT is associated with gallbladder disease. We did not identify a preferential role for nonoral MHT to reduce the pertinent risk for gallbladder disease.

The aim of this study was to evaluate recent trends and the adoption of practice recommendations for menopausal hormone therapy (MHT) use from 2001 to 2009 by formulation, dose, woman's age, and characteristics of physicians reporting MHT visits. The IMS Health (Plymouth Meeting PA) National Disease and Therapeutic Index physician survey data from 2001 to 2009 were analyzed for visits in which MHT use was reported by US office-based physicians. Estimated national volume of visits for which MHT use was reported. MHT use declined each year since 2002. Systemic MHT use fell from 16.3 million (M) visits in 2001 to 6.1 M visits in 2009. Declines were greatest for women 60 years or older (64%) but were also substantial for women younger than 50 years (59%) and women 50 to 59 years old (60%). Women 60 years or older accounted for 37% of MHT use. Lower dose product use increased modestly, from 0.7 M (2001) to 1.3 M (2009), as did vaginal MHT use, from 1.8 M (2001) to 2.4 M (2009). Declines in continuing systemic MHT use (65%) were greater than for newly initiated MHT use (51%). Compared with other physicians, obstetrician/gynecologists changed their practices less, thereby increasing their overall share of total MHT visits from 72% (2001) to 82% (2009). Total MHT use has steadily declined. Increased use of lower dose and vaginal products reflects clinical recommendations. Uptake of these products, however, has been modest, and substantial use of MHT continues in older women.

Trends in the use of menopausal hormone therapy in France, 2001-2023.

Prior research suggests a link between menopausal hormone therapy (MHT) use, memory function, and diabetes risk. The menopausal transition is a modifiable period to enhance long-term health and cognitive outcomes, although studies have been limited by short follow-up periods precluding a solid understanding of the lasting effects of MHT use on cognition. We examined the effects of midlife MHT use on subsequent diabetes incidence and late life memory performance in a large, same-aged, population-based cohort. We hypothesized that the beneficial effects of MHT use on late life cognition would be partially mediated by reduced diabetes risk. 1,792 women from the Wisconsin Longitudinal Study (WLS) were included in analysis. We employed hierarchical linear regression, Cox regression, and causal mediation models to test the associations between MHT history, diabetes incidence, and late life cognitive performance. 1,088/1,792 women (60.7%) reported a history of midlife MHT use and 220/1,792 (12.3%) reported a history of diabetes. MHT use history was associated with better late life immediate recall (but not delayed recall), as well as a reduced risk of diabetes with protracted time to onset. Causal mediation models suggest that the beneficial effect of midlife MHT use on late life immediate recall were at least partially mediated by diabetes risk. Our data support a beneficial effect of MHT use on late life immediate recall (learning) that was partially mediated by protection against diabetes risk, supporting MHT use in midlife as protective against late life cognitive decline and adverse health outcomes.

Menopausal hormone therapy (MHT) use before ovarian cancer diagnosis has been associated with improved survival but whether the association varies by type and duration of use is inconclusive; data on MHT use after treatment, particularly the effect on health-related quality of life (HRQOL), are scarce. We investigated survival in women with ovarian cancer according to MHT use before and after diagnosis, and post-treatment MHT use and its association with HRQOL in a prospective nationwide cohort in Australia. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) and propensity scores to reduce confounding by indication. Among 690 women who were peri-/postmenopausal at diagnosis, pre-diagnosis MHT use was associated with a significant 26% improvement in ovarian cancer-specific survival; with a slightly stronger association for high-grade serous carcinoma (HGSC, HR = 0.69, 95%CI 0.54-0.87). The associations did not differ by recency or duration of use. Among women with HGSC who were pre-/perimenopausal or aged ≤55 years at diagnosis (n = 259), MHT use after treatment was not associated with a difference in survival (HR = 1.04, 95%CI 0.48-2.22). Compared to non-users, women who started MHT after treatment reported poorer overall HRQOL before starting MHT and this difference was still seen 1-3 months after starting MHT. In conclusion, pre-diagnosis MHT use was associated with improved survival, particularly in HGSC. Among women ≤55 years, use of MHT following treatment was not associated with poorer survival for HGSC. Further large-scale studies are needed to understand menopause-specific HRQOL issues in ovarian cancer.

BackgroundTo examine the differences in menopausal hormone therapy (MHT) use and user profiles among women in Germany before and after the communication of the Women's Health Initiative (WHI) trial and other study results concerning the risks and benefits of MHT.MethodsCurrent MHT use was ascertained in two periodic German national health surveys conducted in 1997–1999 and 2003–2004. MHT prevalence and user profiles were assessed within each survey. The association of the survey period (2003–2004 vs. 1997–1999) with current MHT use was analyzed in weighted multivariable logistic regression (MLR) models, pooling data from both surveys.ResultsThe overall prevalence of current MHT use decreased by 40.2% from 16.9% of the sample in 1997–1999 to 10.1% in 2003–2004. The difference in prevalence between surveys varied with age decade with the smallest decreases among women 60–69 years of age (20.3% vs. 18.5%), compared to women of younger and older age groups (40–49: 10.7% vs. 3.9%; 50–59: 36.3% vs. 21.3%; 70–79: 5.7% vs. 3.2%). Variables independently associated with higher current MHT use in both health surveys included age category (curvilinear relationship with highest use among women 50–59 years) and residence in West vs. East Germany. A higher social status, lower body mass index, and more health-conscious behaviour were significantly associated with higher current MHT use in the 1997–1999 survey, but these associations were not found in the later survey. MLR analyses confirmed a significant decline in MHT use between the 1997–1999 and 2003–2004 surveys, however, the effect was modified by social status and was not significant among lowest social-status women.ConclusionCurrent MHT use considerably declined among women in Germany between the pre- and post-WHI era. A convergence of current MHT use among women of higher social status with pre-existing patterns of use among lower social-status women suggests that MHT in Germany is now less likely to be used for health promotion.

This study aimed to assess the association of menopausal status and menopausal hormone therapy (MHT) with cardiovascular risk factors (CVRF) prevalence. We analyzed data from women aged 40 to 70yo, without previous cardiovascular disease, enrolled in the prospective CARVAR 92 cohort study conducted in the Hauts-de-Seine department, France, between 2010 and 2023. CVRF were assessed through blood analysis and medical check-up results. Menopausal status and hormone therapy use were self-reported. Of the 16,879 subjects included in CARVAR 92, 7395 women were analyzed including 2607 non-menopausal and 4788 menopausal women. After adjusting for age, menopausal women were at higher risk of obesity (OR, 1.44 [95% CI, 1.21, 1.70]; p<0.001), waist obesity (OR, 1.33 [95% CI, 1.17, 1.53]; p<0.001), hypertension (OR, 1.17 [95% CI, 1.01, 1.36]; p=0.049), diabetes mellitus (OR, 1.84 [95% CI, 1.31, 2.61]; p<0.001), and dyslipidemia (OR, 1.74 [95% CI, 1.49, 2.03]; p<0.001) compared to non-menopausal women. However, menopausal women using MHT did not show significant differences in the prevalence of CVRF compared to non-menopausal women. These findings remained robust across various models. Menopausal women exhibited an increase in all modifiable CVRF compared to non-menopausal women. MHT use may have a beneficial effect on the prevalence of these risk factors. These findings highlight the importance of considering menopausal status and MHT use when assessing and managing cardiovascular risk in women.

Menopausal Hormone Therapy (MHT) use in Australia fell by 55% from 2001 to 2005, following the release of large-scale findings on its risks and benefits. Comprehensive national data, including information on overall prevalence of MHT use as well as information on duration of use in Australia have not been reported since the 2004–5 National Health Survey, when 11% of women aged 45+ years were estimated to be current MHT users. No national data are available on prevalence of use of “bioidentical” hormone therapy (BHT). The objective of this study was to determine recent prevalence of MHT and BHT use. A cross-sectional, national, age-stratified, population survey was conducted in 2013. Eligible women, aged 50–69 years, resident in Australia were randomly sampled in 5-year age groups from the Medicare enrolment database (Australia’s universal health scheme). The response rate was 22% based on return of completed questionnaires, and analyses were restricted to 4,389 women within the specified age range. The estimated population-weighted prevalence of current use of MHT was 13% (95%CI 12–14), which was broadly similar to the previously reported national figures in 2004–5, suggesting that the use of MHT in Australia has largely stabilised over the past decade. A total of 39% and 20% of current-users with an intact uterus reported use of oestrogen-progestagen MHT and oestrogen-only MHT, respectively, whereas 77% of hysterectomised current-users used oestrogen-only MHT. Almost three-quarters of current-users [population-weighted prevalence 9% (95%CI 8–10)] had used MHT for ≥5 years. In regard to BHT, estimated population-weighted prevalence of ever use was 6% (95%CI 6–7) and 2% (95%CI 2–3) for current use. The population-weighted prevalence of MHT and BHT combined, in current users in their fifties and sixties was 15% (95%CI 14–16). These data provide a recent national “snapshot” of Australian women’s use of both conventional MHT and of BHT.

The authors state that a lack of decline in breast cancer incidence within the time period of 1975-2005 in the Eindhoven cancer registry is linked to "a different history in HRT use" in European countries in terms of a lower prevalence and shorter duration of use of menopausal hormones [ 1 ]. We doubt this explanation. At least in Germany, population-based nationally representative data suggest that 80% of current users (age: 40-79 years) of menopausal hormones have been using these therapies for more than 3 years in 2003/ 2004. Among current users of menopausal hormone therapy (MHT) aged 60 years and older, 96.4% had used MHT for more than 3 years [2]. These figures appear to be broadly consistent with a population-based cross-sectional survey conducted in 1997/1998 in one area of the north east of Germany; among women aged 40 and older, 25.1% used MHT for 3-5 years, 22.0% for 61 0 years, and 6.6% for more than 1 0 years [3] . In a further regional population-based study conducted in 2000, a project evolving from one German MONICA center, long-term use of MHT exceeding 10 years, as high as 43%, was self-reported by women aged 50_74 years [4]. Surveys conducted within the framework of the European Prospective Investigation into Cancer and Nutrition 1993-1997 [5] show substantial variation in both prevalence of use (maximum of 55% for long-term use in one German center, different from the study regions mentioned above) and duration of MHT (maximum of 10 years and more in 26% of the Danish cohort) across centers. Further studies from Sweden, Norway, and the UK also suggest substantial though different magnitudes of use of long-term MHT [6-8]. Thus, we doubt that use of MHT in European populations before the publication of results from the Women's Health Initiative trials is substantially different from the pattern of use high prevalence and long-term use in the United States (US). In Germany, use of MHT appeared to have at least equalled both prevalence and duration of use compared to that of the US.

Several studies suggest that oral menopausal hormone therapy (MHT) is associated with an increased risk of gallbladder disease. It has been hypothesized that nonoral MHT may reduce the risk of cholelithiasis. The objective of the present study was to analyse the association between (1) use of life-time MHT (ever use) and gallbladder disease and (2) nonoral use of MHT and gallbladder disease. Cross-sectional study using population-based data from the Study of Health in Pomerania (SHIP). The study population included 994 postmenopausal women, aged 40-79 years. The subgroup of current oral and nonoral MHT users comprised 139 women. Sociodemographic, medical and reproductive characteristics were based on computer-assisted personal interviews, and selected laboratory parameters were analysed. Gallbladder disease was defined by either a prior history of cholecystectomy or the presence of current sonographically diagnosed gallstones. Data analyses consisted of descriptive, bivariable and multivariable procedures. We performed Poisson regression with Huber/White standard errors to investigate the association between ever use, current nonoral use of MHT and gallbladder disease. We found no significant association between ever use of MHT and gallbladder disease and sonographically diagnosed gallstones in fully adjusted analyses. Women who used MHT had a significantly higher risk for cholecystectomy compared to nonusers. There was no association between nonoral use of MHT and gallbladder disease. Our analyses do not lend support to the hypothesis that use of MHT is associated with gallbladder disease.

Cancers in Australia in 2010 attributable to and prevented by the use of menopausal hormone therapy

Cutaneous melanoma has been suspected to be influenced by female hormones. Several studies reported a positive association between menopausal hormone therapy (MHT) use and melanoma risk; however, previous findings were conflicting. We sought to explore the associations between MHT use and melanoma risk in a prospective cohort of women in France, where a particularly wide variety of MHT formulations are available. E3N is a prospective cohort of 98,995 French women aged 40-65 years in 1990. MHT use was assessed through biennial self-administered questionnaires. We used Cox proportional hazards regression models adjusted for age and skin cancer risk factors. Over 1990-2008, 444 melanoma cases were ascertained among 75,523 postmenopausal women. Ever use of MHT was associated with a higher melanoma risk (hazard ratio (HR) = 1.35, 95% confidence intervals (CI) = 1.07-1.71). The association was strongest among past users (HR = 1.55, CI = 1.17-2.07, homogeneity for past vs. recent use: p = 0.11), and users of MHT containing norpregnane derivatives (HR = 1.59, CI = 1.11-2.27), although with no heterogeneity across types of MHT (p = 0.13). Among MHT users, the association was similar across durations of use. However, a higher risk was observed when treatment onset occurred shortly after menopause (<6 months: HR = 1.55, CI = 1.16-2.07 vs. ≥2 years). Associations between MHT use and melanoma risk were similar after adjustment for UV exposure, although MHT users were more likely to report sunscreen use than nonusers. Our data do not support a strong association between MHT use and melanoma risk. Further investigation is needed to explore potential effect modification by UV exposure on this relationship.

Background and objective Genetic predisposition and menopausal hormone therapy (MHT) are established risk and preventive factors for colorectal cancer (CRC), respectively. We aimed to evaluate the joint associations of a polygenic risk score (PRS) and MHT on CRC risk for informing CRC prevention. Methods We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent from 38 studies. MHT use was assessed as the use of any MHT, estrogen-only (E-only) or combined estrogen-progestogen (E+P) therapy at reference time. A PRS based on 141 genetic variants previously identified by genome-wide association studies of CRC was modelled as categorical variable in quartiles and also as per-standard deviation difference between PRS and minimum of PRS [(PRS-min(PRS))/SD(PRS)] (PRS.minsd). Multiplicative interaction between PRS and MHT was evaluated using standard logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). Results The use of any MHT as well as E+P and E-only were associated with reduced CRC risk (Odds ratio [OR] 0.70, 0.71, 0.65, respectively). PRS was associated with increased CRC risk, whether as continuous variable (PRS.minsd) (OR 1.53) or in quartiles (OR 1.49, 1.92, 2.87, respectively). We identified statistically significant negative multiplicative interaction (OR: 0.92; 95%CI: 0.87, 0.98) as well as negative additive interaction (RERI: -0.13; 95%CI: -0.15, -0.10) between PRS.minsd and any MHT use. Results were limited to additive interactions with PRS.minsd for E-only use (RERI: -0.14; 95%CI: -0.18, -0.11) and E+P use (RERI: -0.12; 95%CI: -0.16, -0.08). The magnitude of negative additive interactions increased with higher quartiles of PRS for all MHT variables and was consistently significant for the highest quartile compared to the lowest quartile of PRS for any MHT use (RERI: -0.78; 95%CI: -1.03, -0.52), E-only use (RERI: -0.78; 95%CI: -1.18, -0.39), and also E+P use (RERI: -0.53; 95%CI: -0.96, -0.10). Negative multiplicative interaction was also observed for higher PRS quartiles of all MHT variables but significant only for the highest quartile with E-only use (OR: 0.73; 95%CI: 0.55, 0.97). These negative interactions on both multiplicative and additive scales indicate that MHT has a relatively more protective effect on CRC risk for those women with larger PRS scores. For example, compared to women in the lowest PRS quartile with no MHT use, the risk of CRC for women in higher quartiles of PRS was more strongly reduced with MHT use (ORPRS.Q3+noMHT: 1.93 vs ORPRS.Q3+MHT: 1.38, OR MHT/noMHT in PRS.Q3: 0.71; ORPRS.Q4+noMHT: 2.81 vs ORPRS.Q4+MHT: 1.77, OR MHT/noMHT in PRS.Q4: 0.63). Conclusions The protective effect of MHT use on the risk of CRC is stronger in women with higher genetic risk. Risk prediction models incorporating PRS may need to account for potential effect modification by non-genetic risk factors. Citation Format: Yu Tian, Yi Lin, Andre E. Kim, Stephanie A. Bien, Polly A. Newcomb, Graham Casey, Elizabeth A. Platz, Loic Le Marchand, Peter T. Campbell, Hermann Brenner, Michael Hoffmeister, Feng Guo, Xuechen Chen, Marc J. Gunter, Niki Dimou, Stephen B. Gruber, Andrew T. Chan, Amit D. Joshi, Sonja I. Berndt, Emily White, Victor Moreno, Ross L. Prentice, Ulrike Peters, William Gauderman, Li Hsu, Jenny Chang-Claude. Association of polygenic risk score and menopausal hormone therapy for colorectal cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 818.

INTRODUCTIONMenopausal hormone therapy (MHT), along with the apolipoprotein E (APOE) ε4 allele, has been suggested as a possible risk factor for Alzheimer's disease (AD). However, the relationship between MHT and cerebrospinal fluid (CSF) biomarkers is unknown: we investigated this association, and whether APOE ε4 carrier status moderates it.METHODSIn an observational study of 136 cognitively unimpaired female participants (Mage = 66.0; standard deviation = 6.3), we examined whether MHT use alone or in interaction with APOE ε4 carrier status was associated with CSF levels of phosphorylated tau (p‐tau), amyloid beta (Aβ)40, Aβ42, p‐tau/Aβ42, and Aβ42/40 ratios.RESULTSSignificant interactions were found between APOE ε4 and MHT use for CSF biomarkers. APOE ε4 carriers who were MHT users showed worse levels of CSF p‐tau/Aβ42 and Aβ42/40 ratios than all other users and non‐users.DISCUSSIONThe presence of both APOE ε4 and MHT may be associated with elevated amyloid deposition and AD pathology in this sample of participants who demonstrated high familial AD risk.HighlightsSignificant interactions were found between apolipoprotein E (APOE) ε4 and menopausal hormone therapy (MHT) use for cerebrospinal fluid (CSF) phosphorylated tau (p‐tau)/amyloid beta (Aβ)42 and Aβ42/40 ratios.APOE ε4 carriers who were MHT users showed worse levels of CSF biomarkers than non‐users and non‐carriers, both users and non‐users.Younger age at MHT initiation was associated with worse levels of the p‐tau/Aβ42 and Aβ42/40 ratios in carriers only.The presence of both APOE ε4 carriage and MHT use may be associated with elevated amyloid deposition and AD pathology.Further studies with larger sample sizes are necessary to confirm the differences observed in the current study.