Clinical Context

More than a million people living in the United States identify as transgender, and gender-affirming hormone therapy (GAHT) is becoming a routine part of care in many primary care and specialty practices across America. But the long-term health implications of GAHT are largely unknown. One health domain that bears scrutiny is cardiovascular health, given the known metabolic effects of estrogen and testosterone. Although data on the direct effects of GAHT on coronary or cerebrovascular outcomes are lacking, Suppakitjanusant and colleagues previously assessed the potential effect of GAHT on weight gain. Their results were published in the July 2020 issue of the Journal of Clinical and Translational Endocrinology.^[1]

The study was conducted as a retrospective review of 227 patients at a single US center. The durations of GAHT among transgender women and transgender men were 6.59 and 3.43 years, respectively. During an average follow-up period of 7 years, the researchers found that transgender women experienced a significant increase in body mass index (BMI) after the initiation of GAHT (mean increase, 0.125 kg/m² for each quarter on continuing GAHT). There was less weight gain and a nonsignificant increase in BMI among transgender women who continued previous GAHT, and there was no effect of GAHT on the BMI of transgender men.

The current study uses a similar research model to evaluate the effects of GAHT on blood pressure among adults.

Study Synopsis and Perspective

Transgender people treated with GAHT show distinctive changes in blood pressure that begin soon after treatment initiation and do not subside during years of treatment, according to the largest and longest observational study to date to look at the issue.

"Many physicians may not be aware of the changes to blood pressure in trans patients who start hormone therapy," senior author Michael S. Irwig, MD, director of transgender medicine at Beth Israel Deaconess Medical Center in Boston, Massachusetts, told Medscape Medical News.

"The take-away message for physicians is to monitor blood pressure both before and after starting hormone therapy in transgender patients, as over a third of transgender individuals had stage 1 hypertension before starting hormone therapy and many had their blood pressure increase after starting hormone therapy."

In the study, published this week in Hypertension, Katherine Banks, MD, from The George Washington School of Medicine & Health Sciences, Washington, DC, and colleagues, followed 470 transgender adult patients for up to 5 years.^[2]

The mean systolic blood pressure levels in transgender female patients (male at birth) significantly decreased compared with baseline within a few months of them starting GAHT.

Conversely, the systolic blood pressure levels in transgender males (females at birth) who were treated with testosterone increased during the same period.

There were no significant changes in the groups in terms of diastolic blood pressure, consistent with other studies.

"Our study is the first to describe the time course of the [blood pressure] effects of GAHT and to compare the rates of elevated [blood pressure] and stage 1 and stage 2 hypertension using [blood pressure] readings from gender-diverse individuals pre- and post-GAHT," the authors note.

GAHT, which has been prescribed to transgender patients for more than 25 years, typically involves a combination of estrogen and an antiandrogen for males transitioning to female, whereas the therapy for those transitioning to male generally only involves testosterone.

The therapy has previously been linked to various cardiac effects, with evidence showing that transgender men have as much as a 5 times greater risk for heart attack vs cisgender women, the authors note.

Although the American Heart Association issued a 2020 Scientific Statement addressing the cardiovascular disease risk, evidence on the effects specifically on blood pressure in transgender patients has been inconsistent.^[3]

For the new study, Banks and colleagues enrolled 247 transgender females and 223 transgender males who were treated between 2007 and 2015 at 2 medical centers in Washington, DC. Of the individuals, who had a mean age of 27.8, about 27% were non-White and 16% were Latinx.

They had blood pressure measurements taken at baseline and at follow-up clinical visits for up to 57 months after the initiation of GAHT.

During the follow-up period, the transgender females had decreases in mean systolic blood pressure of 4.0 mm Hg within 2 to 4 months of starting hormone therapy (P < .0001), and mean declines of 6.0 mm Hg were further observed at 11 to 21 months compared with baseline.

In transgender males, mean systolic blood pressure increased by 2.6 mm Hg at 2 to 4 months (P = .02), and by 2.9 mm Hg at 11 to 21 months after starting therapy.

Furthermore, "although the average increase in systolic blood pressure was 2.6 mm Hg in transgender men within 2 to 4 months, some patients had much higher increases," Dr Irwig noted.

As many as 40% of transgender men had stage 1 hypertension after 11 to 21 months of hormone therapy.

The blood pressure changes in transgender males and females were observed across all 3 racial/ethnic groups of Whites, Blacks, and Latinx, and the changes remained consistent throughout the entire follow-up period of approximately 5 years while hormone therapy was continued.

In addition to the changes after therapy initiation, the researchers note that more than one third of individuals in both groups had stage 1 hypertension even before starting hormone therapy.

The findings are a concern in light of "clear evidence linking hypertension and higher blood pressure with cardiovascular events such as stroke and heart attacks," Dr Irwig said.

Transgender females showed as much as a 47% decrease in the prevalence of stage 2 hypertension, from 19% to 10%, within 2 to 4 months of treatment with GAHT (P = .001), and the rate declined further to 8% at 11 to 21 months, suggesting a protective effect of the treatment.

"The rate of stage 2 hypertension did drop in transgender feminine individuals, which could be protective and lower their risk for cardiovascular events," Dr Irwig said.

"This was not a surprise, as lowering testosterone and the use of spironolactone can lower blood pressure," he noted.

Of note, a sizable proportion of patients had blood pressure changes that were in fact the opposite of the patterns seen in the majority of their gender group.

Specifically, although 42% to 53% of the transgender females had systolic blood pressure readings at least 5 mm Hg lower than their baseline readings, up to 32% had increases of at least 5 mm Hg compared with their baseline readings.

Likewise, whereas 41% to 59% of transgender males had increases of at least 5 mm Hg compared with baseline, up to 35% had levels that were at least 5 mm Hg lower than baseline.

"It was a surprise that over a quarter of individuals had changes opposite to the mean changes," Dr Irwig said.

The differing blood pressure changes underscore that "more research is needed to determine which formulations of estrogen, testosterone, and antiandrogens are optimal regarding [blood pressure] and cardiovascular health, especially in older individuals," the authors note.

Various formulations for gender-affirming hormone regimens are available, including oral, transdermal, sublingual, and intramuscular preparations.

In the study, 77% to 91% of transgender males were receiving intramuscular testosterone injections, with the rest receiving transdermal formulations, and 92% of transgender female patients were started on oral estradiol, with mean doses generally increasing over time.

The study's results are consistent with evidence from other studies, with 7 of 8 involving transgender males showing mean increases in systolic blood pressure ranging from 1 to 14 mm Hg.

As reported by Medscape Medical News, other emerging research on cardiovascular risks to transgender people include a recent study showing that more than 10% of transgender males were found to have hematocrit levels that could put them at risk for blood clots.^[4,5]

And further research on transgender youth also shows concerning elevations in lipids and other cardiovascular risks.^[6]

The authors have disclosed no relevant financial relationships.

Hypertension. Published online April 19, 2021.

Clinical Implications

• In a previous retrospective study, initiating GAHT among trans feminine patients was associated with a higher BMI, but transgender women who continued GAHT did not experience weight gain. GAHT did not affect the BMI of trans masculine patients.
• In the current study, mean systolic blood pressure decreased with GAHT initiation in the trans feminine group, but it increased with GAHT in the trans masculine group.
• Outline implications for the healthcare team: The healthcare team should bear in mind that GAHT may reduce systolic blood pressure among trans feminine patients, but GAHT may raise systolic blood pressure among trans masculine patients.

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