Cardiovascular and metabolic risk factors are increased among transgender youths compared with youths who are not transgender. Elevations in lipid levels and body mass index (BMI) also occur in adult transgender patients, new research shows.

"This is the first study of its size in the United States of which we are aware that looks at the odds of youth with a diagnosis of gender dysphoria having medical diagnoses that relate to overall metabolic and cardiovascular health," first author Anna Valentine, MD, said in a press statement.

Although previous studies have shown that among transgender adults, BMI is higher and there is an increased risk for cardiovascular events, such as stroke or heart attack, compared with nontransgender people, research on adolescent transgender patients has been lacking.

With a recent survey showing that nearly 2% of adolescents identify as transgender, interest in health outcomes among younger patients is high.

To investigate, Valentine, of Children's Hospital Colorado, Aurora, Colorado, and colleagues evaluated data from the PEDSnet pediatric database on 4177 youths who had received a diagnosis of gender dysphoria. The participants had been enrolled at six sites from 2009 to 2019. The researchers compared these patients in a ratio of 1:4 with 16,664 control persons who had not been diagnosed with gender dysphoria. They reported their findings as a poster at the recent virtual ENDO 2021: The Endocrine Society Annual Meeting.

For the propensity score analysis, participants were matched according to year of birth, age at last visit, site, race, ethnicity, insurance status, and duration in the database.

In both the transgender and control groups, about 66% were female at birth, 73% were White, and 9% Hispanic.

For both groups, the average age was 16.2 years at the last visit. The average duration in the database was 7 years.

Study Didn't Distinguish Between Those Receiving and Those Not Receiving Gender-Affirming Hormones

In the retrospective study, among those who identified as transgender, the rates of diagnoses of dyslipidemia (odds ratio [OR], 1.6; P < .0001) and metabolic syndrome (OR, 1.9; P = .0086) were significantly higher compared with those without gender dysphoria.

Among the transgender male patients (born female) but not transgender female patients (born male), rates of diagnoses of overweight/obesity (OR, 1.7; P < .0001) and polycystic ovary syndrome were higher (OR, 1.9, P = .0006) compared with controls.

Gender-affirming hormone therapy, such as with testosterone or estradiol, is among the suspected culprits for the cardiovascular effects. However, importantly, this study did not differentiate between patients who had received estradiol or testosterone for gender affirmation and those who had not, Valentine said.

"We don’t know [whether gender-affirming hormone therapy is a cause], as we have not looked at this yet," she told Medscape Medical News. "We are looking at that in our next analyses and will be including that in our future publication.

"We'll also be looking at the relationship between having overweight/obesity and the other diagnoses that influence cardiovascular health (high blood pressure, liver dysfunction, and abnormal cholesterol), as that could certainly be playing a role as well," she said.

For many transgender patients, gender-affirming hormone therapy is lifelong. One question that needs to be evaluated concerns whether the dose of such therapy has a role on cardiovascular effects and if so, whether adjustments could be made without compromising the therapeutic effect, Valentine noted.

"This is an important question, and future research is needed to evaluate whether doses [of gender-affirming hormones] are related to cardiometabolic outcomes," she said.

Potential confounders in the study include the fact that rates of overweight and obesity are higher among youths with gender dysphoria. This can in itself can increase the risk for other disorders, Valentine noted.

Furthermore, rates of mental health comorbidities are higher among youths with gender dysphoria. One consequence of this may be that they engage in less physical activity, she said.

Hormone Therapy, Healthcare Disparities, or Both Could Explain Risk

In commenting on the study, Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery, the Mount Sinai Health System, New York City, said that although similar cardiovascular effects are known to occur in transgender adults as well, they may or may not be hormone related. Other factors can increase the risk.

"With transgender adults, any differences in lipids or cardiac risk factors relative to cisgender people might be attributable either to hormone therapy or to healthcare disparities," he told Medscape Medical News.

"The data are mixed. It may be that most differences relate to lack of access to care and to mistreatment by society," he said. "Even studies that focus on hormones see a worsened situation for trans women vs trans men."

Other recent research that shows potential cardiovascular effects among adult transgender men includes a study of more than 1000 transgender men (born female) who received testosterone. That study, which was also presented at the ENDO meeting and was reported by Medscape Medical News, found an increased risk for high hematocrit levels, which could lead to a thrombotic event.

However, a study published this month in Pediatrics, which was also reported by Medscape, that included 611 transgender youths who had taken gender-affirming hormone therapy for more than a year found no increased risk for thrombosis, even in the presence of thrombosis risk factors, including obesity, tobacco use, and family history of thrombosis. However, the senior author of that study pointed out that the duration of follow-up in that study was relatively short, which may have been why they did not find an increased risk for thrombosis.

Safer noted that transgender youths and adults alike face a host of cultural factors that could play a role in increased cardiovascular risks.

"For adults, the major candidate explanations for worse BMI and cardiac risk factors are societal mistreatment, and for trans women specifically, progestins.

"For youth, the major candidate explanations are societal mistreatment and lack of access to athletics," he said.

The authors and Safer have disclosed no relevant financial relationships.

ENDO 2021: The Endocrine Society Annual Meeting: Abstract P44-2. Presented March 20, 2021.

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