Abstract
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<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<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-<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.
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