Transgender women — patients who identify as female but were assigned male sex at birth — who would like to develop secondary female sex characteristics often elect to receive hormonal replacement therapy (HRT). By increasing estrogen levels and decreasing testosterone levels, transgender women may achieve breast growth, facial and body hair reduction, body fat redistribution, and muscle mass reduction.

Recently, researchers have started to investigate the risks associated with HRT. The most serious risk for transgender women receiving HRT is an increased risk for thromboembolic events.1-4 This article summarizes recent studies on this risk, reviews the thrombotic issues associated with HRT for transgender women, and reports current recommendations for managing thrombotic risk.

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Reported rates of venous thromboembolism (VTE) in transgender women receiving estrogen therapy vary across studies. After conducting a systematic literature review and meta-analysis, Khan and colleagues estimated that the incidence of VTE in this patient population is 2.3 per 1000 person years (95% confidence interval [CI]: 0.8-6.9). This rate falls within the range of VTE incidence in cisgender women (patients who identify as female and were assigned female sex at birth) receiving HRT, which increases with age from 0.72 per 1000 women per year in women over 50 years of age to 3.84 per 1000 women per year in women over 80. Conversely, Getahun and colleagues found increased 2- and 8-year risk differences in transgender women after starting estrogen therapy of 8.8 and 32.1 per 1000 persons, respectively, relative to cisgender men and 6.9 and 37.0 per 1000 persons, respectively, relative to cisgender women.

The 12 studies assessed by Khan and colleagues reported incidence rates ranging from 0.66 to 12.5 per 1000 person years.5,6 These differences can be attributed to numerous factors, including heterogeneity in study populations, differences in estrogen therapy regimens and modes of administration, type of androgen blocker used, and predisposing thrombotic risk factors.

Some forms of estrogen are especially thrombogenic; these include diethylstilbestrol and ethinyl estradiol, both of which are no longer used. Gooren and colleagues found that transgender women receiving ethinyl estradiol had a VTE incidence of 6% to 8%.7 In contrast, the researchers reported no increase in VTE among transgender women receiving other forms of estrogen. The predominant form of estrogen currently used in the United States for HRT in transgender women is 17 beta-estradiol (referred to as estradiol), which is typically administered orally or transdermally.8

The delivery method of estrogen is an important consideration for VTE risk. Orally administered estrogens appear to increase VTE risk. Wierckx and colleagues found that 5% of transgender women taking either transdermal or oral estradiol in combination with cyproterone acetate (the most potent progestin known, which helps develop breast tissue but is not approved for use in the United States) developed venous thrombosis or pulmonary embolism, and 5 of these events happened within the first year of therapy.9

However, Arnold and colleagues found a low incidence (0.15%) of VTE in transgender women receiving unopposed oral estradiol — in other words, an estrogen therapy regimen lacking a combination progestin. This result suggests that combination progestins and antiandrogens may contribute to increased VTE risk in transgender women.