Effects of Hormone Therapy on survival, cancer, cardiovascular and dementia risks in 7 million menopausal women over age 65: a retrospective observational study

Background The long-term influence of menopausal hormone therapy remains unanswered due to the termination of randomized clinical trials and discordant findings from observational studies. Methods From 2007-2019 enrollment records of 100% Medicare beneficiaries, we identified 7 million female enrollees aged 65 or more. We identified type, route and strength of estrogen based on their prescription drug utilization records. Using vital status record and encounter records, we defined the first onset of thirteen patient outcomes; all-cause mortality; 5 cancers (breast, lung, endometrial, colorectal, ovarian cancers); 6 CV conditions (ischemic heart diseases, heart failure, venous thromboembolism, stroke, atrial fibrillation, acute myocardial infarction); and dementia. Then, we implemented an extended Cox regression analysis to examine the effects of type, route, and strength of estrogens on each of 13 study outcomes. Findings Estrogen monotherapy (ET) exhibited a significant, 20% (aHR=0.80; 95% CI 0.78-0.82), relative risk reduction of mortality. The reduction was greater with estradiol (aHR=0.78; 95% CI 0.75-0.80) than conjugated estrogen (aHR=0.86; 95% CI 0.85-0.88), and with vaginal (aHR=0.69; 95% CI 0.65-0.74) than oral (aHR=0.89; 95% CI 0.87-0.90) and transdermal (aHR=0.78; 95% CI 0.75-0.81) preparations. ET also exhibited significant risk reductions for all study cancers, breast (aHR=0.82; 95% CI 0.80-0.84), lung (aHR=0.87; 95% CI 0.84-0.90), endometrial (aHR=0.65; 95% CI 0.62-0.69), colorectal (aHR=0.86; 95% CI 0.82-0.90) and ovarian (aHR=0.83; 95% CI 0.79-0.88). ET slightly increased risks of ischemic heart diseases (aHR=1.03; 95% CI 1.01-1.04). However, such risk was not observed with low dose ET (aHR=0.98; 95% CI 0.97-0.99). Both combination therapy (aHR=1.11; 95% CI 1.08-1.14) and progestogen monotherapy (aHR=1.09; 95% CI 1.05-1.13) exhibited a significantly increased risk of breast cancer. Oral HT exhibited a moderately increased risk of dementia. Conclusions Among female Medicare beneficiaries aged ≥65, the effect of menopausal hormone therapy varies by type, route, and strength but overall estrogen seemed beneficial. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was supported by the intramural Research Program of the National Library of Medicine, National Institutes of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was declared not human subject research by the Office of Human Research Protection at the National Institutes of Health and by the Centers for Medicare & Medicaid Services' Privacy Board. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript