Transgender women are at increased risk for venous thromboembolism (VTE) and ischemic stroke, particularly if they initiate some form of estrogen therapy, the largest study to date of transgender people in the United States indicates.

And this risk with estrogen treatment for transition seems to present very differently from the risks of thromboembolism observed with hormone replacement therapy (HRT) for menopause, the authors observe.

To date, postmenopausal women on HRT have been the reference population for trying to quantify the risks of female hormones for transgender women simply because data were lacking in the transgender population.

"Acute cardiovascular events have been singled out as high priority research in transgender health because the association between sex hormones and cardiovascular health in general is biologically [plausible]," senior author Michael Goodman, MD, MPH, Emory University School of Public Health, Atlanta, Georgia, told Medscape Medical News.

He added that there have been anecdotal reports of acute cardiovascular events in transgender patients.

Now, "our results...indicate that transfeminine participants had higher rates of VTE and, to a lesser extent, ischemic stroke relative to the corresponding rates among cisgender men and women," say Goodman and his co-authors, led by Darios Getahun, MD, PhD, of the Department of Research & Evaluation, Kaiser Permanente, Pasadena, California.

The study was published online July 10 in the Annals of Internal Medicine.

"These results may indicate the need for long-term vigilance in identifying vascular side effects of cross-sex estrogen," the researchers stress.

Transgender Status Carefully Validated

Getahun and colleagues extracted data from electronic medical records (EMRs) from Kaiser Permanente sites in Georgia, northern California, and southern California, which were used to identify 2842 transfemales (assigned male at birth but transitioning to female) and 2118 transmales (assigned female at birth).

The participants were followed from their index date — namely the first evidence of their transgender status — from 2006 through to 2014. The average follow-up was 3.5 to 4 years.

These two groups were then matched to 48,686 men and 48,775 women who were cisgender (individuals whose gender identity corresponds to their sex assigned at birth).

"We used both male and female cisgender reference groups because hormone serum concentrations among transgender persons may range from normal physiologic male to normal physiologic female levels, depending on receipt and doses of hormone therapy as well as individual characteristics," the authors explained.

Participants who had initiated some form of hormone therapy were identified through EMR linkages to prescription data.

The transwomen "had an increase in post-index date incidence of VTE compared with either reference cohort, and the difference seemed more pronounced with increased follow-up," the investigators reported.

For example, transwomen had a 1.9-fold higher risk of VTE over the full follow-up interval compared with cisgender men and about a 2-fold higher risk relative to cisgender women.

For ischemic stroke, the risk for transwomen was about 1.2-fold higher than for cisgender men and 1.9-fold higher than for cisgender women.

There were not enough cardiovascular events among transgender men to reliably arrive at any conclusions about this group, the researchers note.

HRT for Menopause Is No Guide for Cross-Sex Hormone Treatment

The really striking differences in acute cardiovascular risk were seen, however, in the smaller cohort of transwomen who had initiated some form of estrogen therapy.

The most common formulation of estrogen taken by transwomen was estradiol, at an average maximum daily dose of 4.1 mg.

In this cohort of 853 transwomen, the adjusted hazard ratio (HR) for VTE was between 1.5- and 3.2-fold higher, depending on length of follow-up, compared with cisgender men and between 1.7- and 2.5-fold higher compared with cisgender women.

For ischemic stroke, the risk was again substantially higher for transwomen who had taken estrogen, who had an almost 10-fold higher risk of ischemic stroke after 6 years or more of follow-up compared with cisgender men and an over 4-fold higher risk compared with cisgender women.

The rates and patterns of VTE and ischemic stroke observed in transwomen on estrogen therapy are therefore clearly different from reported risks for postmenopausal women taking HRT, the investigators note.

For example, in one clinical trial of HRT therapy in postmenopausal women, VTE rates increased relatively rapidly after the intervention began and seemed to decline and then plateau by 5 years of follow-up.

But here among transgender women, the VTE rates increased only after 2 years of follow-up and continued to rise for another 5 to 6 years.

Likewise, the ischemic stroke rates in the estrogen-initiation and two reference cohorts did not differ during the first 6 years of follow-up "but clearly diverged afterward."

So one of the main take home messages from the study is that researchers cannot, as yet, provide any kind of clinical guidance for physicians treating transgender people based on data from women taking HRT for postmenopausal reasons, Goodman stressed.

"Up until now, these inferences were made because people didn't have any relevant data," he emphasized.

Transgender People Are a Different Population, More Data Needed

"[Transfeminine people] are simply a different population, so in my view, these inferences are not warranted," Goodman explained.

But he also emphasized that by no means should their findings on increased thromboembolic risk in transwomen be viewed as a reason not to give transgender patients hormones.

"One needs to understand the risk [of acute cardiovascular events] but also in the context of potential benefits," he stressed.

"And the most important next step we need to take is to understand the types of regimens that may increase VTE risk and the types of regimens that may not. We really need data on transgender people to answer questions that are relevant to them," he concluded.

Goodman has reported no relevant financial relationships.

Ann Intern Med. Published online July 10, 2018. Abstract

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