Primary authors: Asa Radix, MD, MPH and Madeline B. Deutsch, MD, MPH
Sex is an independent predictor of cardiovascular health outcomes. The role played by sex hormones in this difference between the sexes is unclear. A 2010 Cochrane analysis found no interaction between menopausal hormone therapy and all-cause mortality, cardiovascular-related mortality, non-fatal myocardial infarction or angina, or the need for bypass surgery or coronary angioplasty. This same analysis found a slight increase in risk of stroke (RR 1.26, 95% CI 1.11-1.43, number needed to harm = 164); however a 2015 Cochrane update found no increased risk of stroke among the subgroup of women who began hormone therapy less than 10 years after menopause, which is more likely representative of transgender women. Few studies have investigated cardiovascular disease risk and burden among transgender people on hormone therapy, adjusting for risk factors such as tobacco use. Larger studies have been retrospective and did not adjust for numerous coexisting risk factors. Prospective studies have been smaller and over shorter terms. Any analysis of the possible negative effects of hormone therapy on cardiovascular disease and stroke should take into consideration the significant benefits of hormone therapy on quality of life and psychosocial functioning.[3-5]
Evidence from several studies suggests that cardiovascular risk is unchanged among transgender men using testosterone compared with non-transgender women.[6-8] Evidence in transgender women is less clear. Some studies have found increased morbidity and mortality from myocardial infarction and stroke compared with non-transgender men, however these studies did not adjust for a number of risk factors including tobacco use, obesity, and diabetes.[6-8] Evidence from several studies suggests that cardiovascular risk is unchanged among transgender men using testosterone compared with non-transgender women.[6-8] Evidence in transgender women is less clear. Some studies have found increased morbidity and mortality from myocardial infarction and stroke compared with non-transgender men, however these studies did not adjust for a number of risk factors including tobacco use, obesity, and diabetes.[6-8] The largest study published to date is a report on mortality in a retrospective cohort of more than 1000 Dutch transgender women and men which did not control for a number of risk factors, including tobacco use. All-cause as well as cardiovascular- and cerebrovascular-specific mortality among transgender men did not differ from the general Dutch population. Among transgender women, all-cause mortality was 51% higher (95% CI 47 to 55) than in the general Dutch population, with the overwhelming majority of the difference due to HIV, drug overdose and suicide; a 64% increased risk (95% CI 43 to 87) in cardiovascular mortality was seen, however no significant difference was seen for cerebrovascular mortality.
Several factors may contribute to an elevation of cardiovascular disease in transgender women, such as higher rates of tobacco use, obesity, diabetes and lipid disorders, and reduced physical activity. Older studies demonstrating increased morbidity and mortality among transgender women included users of high doses (>100mcg/day) of ethinyl estradiol, a known thrombogenic synthetic estrogen used in oral contraceptives at typical doses of only 20-30mcg/day. A meta-analysis of lipids and blood pressure in transgender people using hormone therapy found a mean increase in triglycerides of 23mg/dl (95% CI 5 to 42) among transgender women, and a mean increase in triglycerides of 31mg/dl (95% CI 7 to 55) and systolic blood pressure of 1.7mmHg (95% CI 0.2 to 3.3), and mean decrease in HDL of 6mg/dl (95% CI 0.7 to 11) among transgender men; all other lipid and blood pressure parameters showed no statistically significant change. Such statistically significant changes have small effect sizes and are of questionable clinical significance, especially in the context of primary prevention.
Direct study of the effects of hormones on lipids and blood pressure in transgender people has been limited. A retrospective study of lipids in 169 Austrian transgender people found trends of poorer lipid profiles in both transgender women and men at 5 years however these changes were mild at most, and seemed to be mitigated to some degree by the use of transdermal estradiol. A prospective 6 month study of a young and healthy cohort of 31 transgender women and 17 transgender men in the U.S. found modest overall improvement in lipids in transgender women and only a slight reduction in HDL in transgender men; while statically significant, the effect sizes were small and of questionable clinical significance.[12-14]
Current American Heart Association - American College of Cardiology guidelines for prevention and lipid management involve the use of sex-specific calculators to determine risk and guide interventions. Determination for the use of aspirin also uses these calculators when conducting a risk-benefit assessment for gastrointestinal bleeding. Currently there is no guidance on whether to use risk calculators based on natal sex or affirmed gender. It may be reasonable to use natal sex-based calculators in transgender people who have transitioned later in life, given their long-term exposure to the natal hormonal milieu. However with an increasing percentage of transgender people beginning hormone therapy in adolescence and young adulthood, affirmed gender-based calculators may be more appropriate in these cases. Ultimately a primary goal is to calculate a realistic risk-benefit ratio between the benefits of statin therapy or aspirin and the risks of these treatments. Depending on the age at which hormones are begun and total length of exposure, providers may choose to use the risk calculator for the natal sex, affirmed gender, or an average of the two (Grading: X C M). Another goal of calculating risk is to provide adequate information during the informed consent process to allow transgender people of any age, and with or without existing cardiovascular or cerebrovascular disease, to make informed decisions about the long term implications of gender affirming hormones.
For transgender women with cardiovascular risk factors or established CVD, using the transdermal route of estrogen may be preferred due to lower rates of venous thromboembolism, and lack of associated changes in lipid profile or markers of coagulation (Grading: NT O M).[15,16] Additional modifiable interventions to reduce risk include smoking cessation, weight loss, management of diabetes, and encouraging physical activity. It is theoretically possible that the psychosocial benefits of hormone therapy may have an independent and protective effect through reduction of stress, improved body image resulting in healthier lifestyle choices, reduced tobacco use, and increased physical activity.
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