Balancing the Cardiovascular Risks of Hormone Therapy for Transgender Patients

Roughly one million adults in the United States are transgender, and that estimate may be low due to stigmas that limit accurate self-reporting of gender dysphoria,¹ or "gender incongruence," as it is classified in the ICD.²

Gender-affirming therapies, including hormone therapy for transgender patients, comprise the recommended care plans for this group of patient populations.³ These interventions have been associated with positive effects that validate their lifelong use. The psychosocial benefits of hormonal replacement therapy in transfeminine and transmasculine people are widely documented and include reductions in anxiety and depression.⁴

Given these findings, it has been concluded that stopping estrogen or testosterone therapies is "not an option" for transgender patients who wish to receive them.⁵ However, these same treatments may come with elevated risk of stroke, hypertension, and other cardiovascular events or conditions that warrant additional surveillance and care, compared to cisgender patients. Research in this area is ongoing, however, and requires further investigation.³

As evidence of these cardiovascular side effects comes to light in conjunction with the growing visibility of transgender people, cardiologists are becoming a critical part of the multidisciplinary care team for these patient populations. Moreover, advanced diagnostic tools such as ECG are essential to identifying and mitigating risks over the course of long-term hormonal treatments.

Possible Risks for Trans Women

Hormonal treatments for transgender women (women who were assigned male at birth) include oral or transdermal delivery of different formulations of estrogen, such as estradiol. In addition, hormonal treatment typically accompanies anti-androgens or gonadotropin-releasing hormone analogs to suppress unwanted masculine characteristics.³

One potential risk of this treatment is myocardial infarction. For example, a 2018 study demonstrated an elevated risk for heart attack among trans women compared to cisgender women, with a hazard ratio of 1.8. However, the risk was not increased when compared to cisgender men, which makes conclusions about the cause of the risk (whether sex assigned at birth or hormone treatments) less clear.^3,6

Other risks are connected with stronger evidence. Compared with cisgender men and women, transgender women have been found to face an increased risk for ischemic stroke after six years of hormonal treatments.^3,6 Similarly, another study identified venous thromboembolism in 5.1% of trans female patients who received estrogen for 7.7 years.^3,7 Respectively, these risks have been identified as 80% and 355% higher than cisgender men's,⁵ indicating that the outcomes may be due to the treatments rather than the sex assigned at birth. Hypertension may also be a risk to watch for, particularly after long-term use.³

One limitation of these studies is the lack of subanalyses by hormone formulations or delivery types. Many studies evaluate oral estradiol, the most commonly administered hormonal treatment for trans women.⁶ Other formulations such as oral ethinyl estradiol have previously been linked to adverse outcomes and are not typically a part of current routine gender-affirming care.⁵

Possible Risks for Trans Men

Hormonal treatments for transgender men (men who were assigned female at birth) can include various formulations of testosterone delivery via injection, skin patches, or topical gel. While these interventions require long-term use just as estrogen therapies do, their potential cardiovascular effects are understood to be much less severe—or at least less likely to result in a cardiovascular event—than those for trans women.³

Some of those effects include hypertension and dyslipidemia. For example, elevations in diastolic blood pressure have been found to be significant at 3 mmHg in one study observing 188 transgender men.^3,8 Another systematic review and meta-analysis identified marked increases in LDL and triglycerides and decreases in HDL among trans men after two years.^3,9 However, these findings do not appear to drive risk of cardiovascular disease.³

Diagnostic and Management Tools

As with any patient population, cardiologists should consider a range of ethical and clinical factors when providing care for transgender people.

Importantly, providers should contextualize the risk profile. Potential risks from hormone therapy for transgender patients coincide with other risk factors that can affect this population, including those relative to social determinants of health (such as barriers to care and potential biases across the healthcare ecosystem) and lifestyle (such as smoking or poor nutrition). Comorbidities or other conditions may be present that further exacerbate risk, including those involving mental health.¹⁰

Clinicians should also collect patients' self-identified names and pronouns, urges a scientific statement from the American Heart Association. Recognizing and affirming patients' identities helps mitigate emotional stressors that drive increased risk. However, statement authors add that clinicians should not make assumptions about a patient's sex at birth based upon this self-reported data. Understanding a patient's sex at birth is clinically important for effective decision-making,¹⁰ but this information is not a license to ignore a patient's preferred name or ways of being addressed.

Routine surveillance is encouraged. In particular, monitoring blood pressure may help stave off further risk.¹¹ Other screening measures may include laboratory workups, although there is some uncertainty about the appropriate reference ranges for transgender people.¹²

Diagnostic tools can also aid cardiologists in the surveillance of known or suspected risks, particularly for transgender women. ECG is a portable, lightweight, and fast option to identify waveform abnormalities that may indicate concerns such as venous thromboembolism, ischemic stroke, and myocardial infarction.

Creating a More Inclusive Care Environment

While the cardiovascular effects of gender-affirming hormonal therapy have only been observed in a formal research context since the late 1980s,³ much has been learned over the past three decades. However, much more study is needed in this area, as longstanding biases have often precluded or investigations or limited their usefulness.

While evidence is mounting that long-term hormone therapy comes with cardiovascular risks, stopping needed treatments is not a solution.⁵ Managing cardiovascular risk factors in transgender medicine is less an analysis of the risk-benefit ratio and more a question of how to surveil and protect patients against those concerns throughout their lifetimes.

Certain strategies—such as adjusting hormone formulation, dose, or mode—may help balance the risks. These decisions should be individualized and made in tandem with the patient and the broader care team. However, this may be more difficult with existing research, as many studies do not provide sub-analyses of formulation- or dose-specific treatments.

All cardiologists should be prepared to care for trans patient populations and should be aware of the unique concerns, risk profiles, and barriers they face when receiving vital care. Diagnostic tools such ECG will support clinicians in these workups, as will sensitivity and a commitment to creating a more inclusive, equitable care environment.

References:

---

1. Meerwijk EL, Sevelius JM. Transgender population size in the United States: a meta-regression of population-based probability samples. American Journal of Public Health. 2017;107(2):e1-e8. doi:10.2105/ajph.2016.303578.
2. M. Fernández Rodríguez, M. Menéndez Granda, Villaverde González. Gender incongruence is no longer a mental disorder. Journal of Mental Health & Clinical Psychology. 2018;2(5). https://www.mentalhealthjournal.org/articles/gender-incongruence-is-no-longer-a-mental-disorder.html. Accessed April 15, 2022.
3. Connelly PJ, Marie Freel E, Perry C, et al. Gender-affirming hormone therapy, vascular health and cardiovascular disease in transgender adults. Hypertension. 2019;74(6):1266-1274. doi:10.1161/hypertensionaha.119.13080.
4. Baker KE, Wilson LM, Sharma R, Dukhanin V, McArthur K, Robinson KA. Hormone therapy, mental health, and quality of life among transgender people: a systematic review. Journal of the Endocrine Society. 2021;5(4). doi:10.1210/jendso/bvab011.
5. Maas AHEM, Rosano G, Cifkova R, et al. Cardiovascular health after menopause transition, pregnancy disorders, and other gynaecologic conditions: A consensus document from European cardiologists, gynaecologists, and endocrinologists. European Heart Journal. 2021;42(10):967-984. doi:10.1093/eurheartj/ehaa1044.
6. Getahun D, Nash R, Flanders WD, et al. Cross-sex hormones and acute cardiovascular events in transgender persons. Annals of Internal Medicine. 2018;169(4):205. doi:10.7326/m17-2785.
7. Wierckx K, Elaut E, Declercq E, et al. Prevalence of cardiovascular disease and cancer during cross-sex hormone therapy in a large cohort of trans persons: a case–control study. European Journal of Endocrinology. 2013;169(4):471-478. doi:10.1530/eje-13-0493.
8. Van Velzen DM, Paldino A, Klaver M, et al. Cardiometabolic effects of testosterone in transmen and estrogen plus cyproterone acetate in transwomen. The Journal of Clinical Endocrinology & Metabolism. 2019;104(6):1937-1947. doi:10.1210/jc.2018-02138.
9. Maraka S, Singh Ospina N, Rodriguez-Gutierrez R, et al. Sex steroids and cardiovascular outcomes in transgender individuals: a systematic review and meta-analysis. The Journal of Clinical Endocrinology & Metabolism. 2017;102(11):3914-3923. doi:10.1210/jc.2017-01643.
10. Streed CG, Beach LB, Caceres BA, et al. Assessing and addressing cardiovascular health in people who are transgender and gender diverse: a scientific statement from the American Heart Association. Circulation. 2021;144(6). doi:10.1161/cir.000000000000100.
11. Banks K, Kyinn M, Leemaqz SY, Sarkodie E, Goldstein D, Irwig MS. Blood pressure effects of gender-affirming hormone therapy in transgender and gender-diverse adults. Hypertension. 2021;77(6):2066-2074. doi:10.1161/hypertensionaha.120.16839
12. Unger CA. Hormone therapy for transgender patients. Translational Andrology and Urology. 2016;5(6):87784-87884. https://tau.amegroups.com/article/view/11807/13169. Accessed April 15, 2022.

‌