Cross-Sex Hormone Therapy: What Are the Long-Term Risk Factors?

Cardiovascular disease concept
Cardiovascular disease concept
Primary prevention of cardiovascular disease through risk factor modification, including tobacco cessation, maintenance of a body mass index, and management of abnormal lipid levels, diabetes, and hypertension, is of great importance for the health of transgender individuals.

Major medical organizations, including the American Medical Association, the American Psychiatric Association, and the American Psychological Association, recognize hormone therapy (HT) as a medically necessary treatment option for transgender people.1 Although numerous studies have examined the effects of long-term HT in cisgender (nontransgender) adults, less is known about the long-term use of cross-sex HT (CSHT) in transgender adults.2 A leading concern that has emerged from studies of prolonged HT use in cisgender men and women is the potential for adverse cardiovascular events. To determine whether similar concerns exist with long-term use of CSHT in transgender men and women, researchers from Brigham and Women’s Hospital and Johns Hopkins Hospital reviewed findings from 13 studies identified during an extensive literature search.

The studies included 3 of CSHT in transgender women only, 3 of CSHT in transgender men only, and 7 of CHST in transgender men and women.2 In 9 of the 10 studies that included transgender men, participants were receiving testosterone, which was administered as an oral capsule, injection, gel, patch, or cream; in 1 study, participants received the aromatase inhibitor anastrozole. In the 10 studies involving transgender women, participants were using systemic estrogen, alone or combined with a progestogen, an androgen blocker, or both.2

Doses and durations of CSHT varied between the studies. The authors found that CSHT appeared to exacerbate certain risk factors for cardiovascular disease (CVD) in transgender adults. However, transgender men using CSHT had the same CVD risk as cisgender men or cisgender women who were not using HT. In addition, CSHT was not associated with an increased risk for CVD morbidity or mortality.2 Data suggested transgender women using exogenous estrogen had a greater risk for thromboembolic events than cisgender women in the general population, but their risk was similar to that observed in cisgender women taking exogenous estrogen.2 Transgender women taking CSHT also appeared to have a greater risk for CVD mortality than cisgender women in the general population.

The authors pointed out that transgender people may have a higher prevalence of modifiable CVD risk factors, such as smoking, and may have a higher baseline risk for CVD than cisgender people.2 Endocrinology Advisor interviewed lead author Carl Streed Jr, MD, about the review’s findings and their implications for clinicians and transgender patients.

Endocrinology Advisor: What are the implications of your research for transgender women using CSHT?

Dr Streed: Transgender individuals may seek any number of interventions to affirm their gender identity; CSHT is one such intervention. CSHT for transgender women has potential thromboembolic risks, but [thromboembolic events] are rarely seen with lower-dose transdermal and oral bioidentical estrogen formulations, and these are preferred to high-dose oral ethinyl estradiol formulations.

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Endocrinology Advisor: What are the implications for transgender men using CSHT?

Dr Streed: In transgender men, we found that CSHT, particularly with testosterone, is associated with worsening cardiovascular risk factors, such as increased blood pressure, insulin resistance, and lipid derangements, but not with increases in cardiovascular morbidity or mortality.

Endocrinology Advisor: Did you identify any patient-related factors that significantly increased the risk for adverse cardiovascular events in patients using CSHT?

Dr Streed: There is insufficient evidence to suggest any specific transgender population is at particularly high risk for adverse cardiovascular events from CSHT. That said, the same risk factors for cardiovascular events in the cisgender population are present in the transgender population. As such, primary prevention of CVD through risk factor modification, including tobacco cessation, maintenance of a body mass index of 25 kg/m2 or less, and management of abnormal lipid levels, diabetes, and hypertension, is of great importance for the health of transgender individuals.

Endocrinology Advisor: How can clinicians improve care for their transgender patients?

Dr Streed: Because transgender individuals may seek out a number of interventions to affirm their gender identity, it is critical for clinicians to be aware of the multidisciplinary needs of their transgender patients. Urology, gynecology, endocrinology, and primary care are just some of the disciplines that must collaborate and be in open dialogue to provide the best care for transgender patients. In addition, specialists in fields such as dermatology, plastic surgery, otolaryngology, and voice coaching must be prepared to be involved in the complete care of transgender patients.

Endocrinology Advisor: How should future studies be conducted to improve understanding of the risks of hormone therapy in transgender men and women?

Dr Streed: Future research ideally should involve large prospective cohort studies that include cisgender men and women, transgender men and women who are receiving CSHT, and transgender men and women who are not receiving CSHT. Such studies should be powered to evaluate differences among various CSHT regimens. They should also have sufficient follow-up to allow adequate assessment of cardiovascular outcomes such as myocardial infarction and stroke, which often require more than a decade for adequate power to be generated. Adequate duration of follow-up is especially important when you consider that transgender men tend to begin CSHT at a younger age than transgender women.

Endocrinology Advisor: Does your institution have any future studies planned? 

Dr Streed: Other researchers and I are preparing retrospective and prospective studies to explore the long-term effects of CSHT on cardiovascular health in transgender men and women. 

Endocrinology Advisor: What should clinicians take away from your study?

Dr Streed: Cross-sex hormone therapy is associated with improved psychological functioning of transgender persons. As such, reducing cardiovascular risk factors, including hypertension, diabetes, and tobacco use, remains critical for preventing CVD in transgender populations.


Conclusions of the literature review are limited by the lack of randomized controlled trials and disparities between the included studies in terms of treatment doses and durations, age range of participants, and cohort size.


  1. Lambda Legal. Professional organization statements supporting transgender people in health care. Updated May 25, 2016. Accessed August 24, 2017.
  2. Streed Jr CG, Harfouch O, Marvel F, et al. Cardiovascular disease among transgender adults receiving hormone therapy: a narrative review. Ann Intern Med. 2017;167:256-267.