Testosterone therapy increases CVD risks for cisgender women, but not transgender adults
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Key takeaways:
- Cisgender women who use testosterone have higher risks for CVD than nonusers.
- Testosterone therapy was not associated with a higher CVD risk for transgender adults.
Testosterone use increases risks for cardiovascular disease, coronary artery disease and stroke among cisgender women, but not among transgender adults, according to a study published in The Journal of Clinical Endocrinology & Metabolism.
“Testosterone replacement therapy is becoming more widely accepted in women, and it is the main medical treatment for transgender males,” David S. Lopez, MS, MPH, DrPH, associate professor of epidemiology at the University of Texas Medical Branch – School of Public and Population Health, told Healio. “In addition, a recent global consensus position statement by 11 international societies endorsed hypoactive sexual desire dysfunction as the only evidence-based indication of testosterone replacement therapy for postmenopausal women. However, the association between testosterone replacement therapy and CVD in a larger sample of underserved and understudied population of cisgender women and transgender people remains poorly understood. Therefore, it was surprising to see the significant associations of this study.”
Lopez and colleagues conducted a retrospective cohort study using deidentified data from the Optum Clinformatics database from 2007 to 2021. The study population included 25,796 cisgender women (mean age, 52 years) and 1,580 transgender adults (mean age, 36 years). Adults aged 30 years and older with at least 1 year of data available in the database and no prior history of CVD were eligible. Testosterone replacement prescriptions were identified. Composite CVD was the primary outcome of the study and included incidences of chronic coronary artery disease, stroke, congestive heart failure, peripheral arterial disease (PAD) and myocardial infarction.
Of the cisgender women in the study, 6,288 had CVD. Women who used testosterone therapy had a higher risk for composite CVD (adjusted HR = 1.24; 95% CI, 1.15-1.34) compared with those who did not use testosterone. Cisgender women who used testosterone had higher risks for CAD (aHR = 1.26; 95% CI, 1.14-1.39) and stroke (aHR = 1.29; 95% CI, 1.14-1.45) than nonusers. Testosterone replacement was not associated with increased risks for congestive heart failure, PAD or MI among cisgender women. When participants were analyzed by age group, testosterone use was associated with a higher risk for composite CVD among cisgender women aged 30 to 51 years (aHR = 1.29; 95% CI, 1.15-1.45) and aged 52 years and older (aHR = 1.2; 95% CI, 1.1-1.33) compared with nonusers. Women aged 52 years and older who used testosterone had a reduced risk for PAD compared with those who did not use testosterone (aHR = 0.4; 95% CI, 0.16-0.96).
The group of transgender adults included 262 who had CVD. Transgender adults who used testosterone replacement had no difference in composite CVD risk compared with adults who did not use testosterone. There was also no difference in the risk for CVD-specific outcomes between transgender adults who used testosterone and nonusers. No associations were observed when transgender adults were stratified by age.
“Although this is a large observational study that showed a strong association between use of testosterone replacement therapy and an increased risk of CVD [for cisgender women], we can’t infer causality or provide a clinical recommendation,” Lopez said. “Yet, it lays the foundation for a potential role of the use of testosterone replacement therapy with the increasing risk of CVD in cisgender women, but it merits a further investigation with a transgender population due to the null results.”
Lopez said some limits of the study included a lack of information on serum testosterone levels at baseline, menstrual cycle information and other hormone treatments. He said information should be included in future studies to provide more insight.
For more information:
David S. Lopez, MS, MPH, DrPH, can be reached at davlopez@utmb.edu.
Perspective
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The use of testosterone in women has been a debatable topic for decades. Although in theory the benefits of testosterone to improve sexual function, bone density and frailty in women might seem obvious, the study designs have been challenging and the results inconsistent. Add to this the specific concerns about its long-term safety. We have always been concerned about the risk of virilization, erythrocytosis or cardiovascular disease, as is seen in women with polycystic ovary syndrome who have physiologic excess testosterone.
Now add to this dilemma the use of testosterone at high doses for gender-confirming care of the transgender male. The need for data on the clinical effects of transgender endocrine care is even more crucial as people are being recognized and treated earlier than ever before. As endocrinologists, we have the moral responsibility to understand the risk-benefit ratio in an objective and scientific fashion. This is particularly so since there has been a dramatic increase in the request for gender-confirming care, particularly among teens assigned female at birth. Even countries, such as Sweden, known as a pioneer in LGBTQ+ rights, has started to restrict treatment and are evaluating their protocols.
This publication by Lopez and colleagues is moving the field forward by looking at cisgender women as well as transgender men to determine CVD risk with testosterone treatment. The authors report an increased risk in cisgender women, rather than transgender men. This is surprising, since one would assume that the cisgender women were given a lower dose. The study suffers from a common problem seen in large pharmaco-epidemiologic studies, making it difficult to draw conclusions, e.g. serum testosterone levels prior to treatment or with treatment, indications for use, benefits observed, adherence to medications, route of administration, duration of treatment and misclassification of events.
We finally are becoming comfortable with prescribing testosterone to men, based on the TRAVERSE studies and several others. It is reassuring to not see a huge uptick in events with testosterone treatment in women or transgender people, however caution is clearly advised at this point. We need a better understanding of indications, dosing and monitoring of CVD comorbidities.
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