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Transgender people faced a much higher mortality rate than cisgender peers, according to a new Dutch study.

In a retrospective, observational study spanning from 1972 to 2018, a total of 10.8% (317 of 2,927) of transgender women using hormonal therapy included in the analysis died during follow-up.

This number was starkly higher than the number of cisgender men and women in the general population that died over the same period, Martin den Heijer, MD, PhD, of Amsterdam University Medical Centre in the Netherlands, and colleagues wrote in .

Specifically, transgender women died at 1.8-fold higher than expected compared with cisgender men (standardized mortality ratio 1.8, 95% CI 1.6-2.0). Even more pronounced, transgender women died at 2.8-fold higher of a rate than expected compared with cisgender women in the general population (standardized mortality ratio 2.8, 95% CI 2.5-3.1).

Some of the largest drivers of this unexpectedly high death rate were cardiovascular disease, lung cancer, HIV-related disease, and suicide. More specifically, transgender women had a 47.6-fold and 14.7-fold higher mortality rate due to HIV than general population women and men, respectively -- the highest driver of deaths in this population.

"We found that most suicides and deaths related to HIV occurred in the first decades we studied, suggesting that greater social acceptance and access to support, and improved treatments for HIV, may have played an important role in reducing deaths related to these causes among transgender people in recent years," co-author Christel de Blok, MD, also of Amsterdam University Medical Centre, explained in a press statement.

Transgender men also saw a higher-than-expected mortality rate over the past few decades. Since 1972, 2.7% (44 of 1,641) transgender men in the study who were using hormone therapy died. This was at a rate 1.8-fold higher than women in the general population (SMR 1.8, 95% CI 1.3-2.4) but on par with men in the general population during the entirety of follow-up (SMR 1.2, 95% CI 0.9-1.6).

"It was surprising that mortality risk was higher in transgender people who started gender-affirming hormone treatment in the past two decades, but this may be due to changes in clinical practice," de Blok added. "In the past, health care providers were reluctant to provide hormone treatment to people with a history of comorbidities such as cardiovascular disease. However, because of the many benefits of enabling people to access hormone therapy, nowadays this rarely results in treatment being denied."

For transgender women, the elevated mortality rate stayed high through the 5 decades of follow-up. In fact, from 2010 to 2018, transgender women had a mortality ratio that was 3.7-fold higher than cisgender men and 5.2-fold higher than cisgender women in the general population.

Similar to transgender women, transgender men saw the highest mortality rate versus women in the general population in recent years, with the authors explaining the increased risk for transgender men "was mainly because of increased mortality risk in people who started hormone treatment between 1990 and 2000."

However, at essentially no time point over the past few decades did transgender men see a higher rate of death than men in the general population. The only drivers of elevated mortality compared to the general population were non-natural causes of death and causes of death listed as "other."

For the study, the researchers reviewed data of transgender individuals using hormonal therapy who visited the gender identity clinic of Amsterdam University Medical Centre in the Netherlands from 1972 to 2018. Exclusion criteria included use of alternating testosterone and estradiol treatment, starting treatment prior to age 17, or ever having used puberty-blockers before gender-affirming hormone treatment.

The majority of transgender women included were on either cyproterone acetate (between 10 mg and 100 mg daily) or spironolactone (between 100 mg and 200 mg daily) as an antiandrogen, typically stopped after orchiectomy. Transgender men were usually treated with either testosterone gel (between 20 mg and 100 mg daily), intramuscular testosterone esters (between 125 mg and 250 mg every 2-3 weeks), or testosterone undecanoate (either oral 40 mg to 160 mg daily or intramuscular 1,000 mg every 10-14 weeks).

"The findings of our large, nationwide study highlight a substantially increased mortality risk among transgender people that has persisted for decades," said den Heijer in a statement. "Increasing social acceptance, and monitoring and treatment for cardiovascular disease, tobacco use, and HIV, will continue to be important factors that may contribute to decreasing mortality risk in transgender people."

In an , Vin Tangpricha, MD, PhD, of Emory University School of Medicine in Atlanta, cautioned that there might be a few differences in regards to the safety profiles of hormonal therapies used in the U.S. versus the Netherlands.

"Transgender people in the Netherlands as well as the rest of Europe and Asia primarily use cyproterone acetate, whereas spironolactone is commonly used in the USA and gonadotropin-releasing hormone agonists are commonly used in the UK," he pointed out. "Cyproterone acetate appears to affect serum lipid profiles, prolactin concentrations, and to stimulate meningiomas more than spironolactone does, when used with estrogens."

"Although these findings raise some safety concerns with gender-affirming hormone therapy, especially among transgender women, they could reflect regional differences in gender-affirming hormone therapy regimens," he said.

The relatively low mortality rates among transgender men were encouraging, which could be due to the fact that testosterone administration has been established already with hypogonadal men, Tangpricha noted. He suggested future studies try to pinpoint exactly which factors are underlying this unexpectedly high death rate for transgender women, whether it be hormone therapy regimens, concentrations, access to healthcare, or other biological factors at play.

"Gender-affirming hormone treatment is thought to be safe, and most causes of death in the cohort were not related to this," Tangpricha wrote. "However, as there is insufficient evidence at present to determine their long-term safety, more research is needed to fully establish whether they in any way affect mortality risk for transgender people."

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