Mortality is consistently twice as high in transgender people receiving hormone treatment compared with cisgender individuals in the general population and has not decreased over time, shows a five decades-long study from the Netherlands.
Particularly concerning is that trans women (male to female) had a mortality risk nearly double that of cis men (born and remain male) in the general Dutch population (standardized mortality ratio [SMR], 1.8), while it was nearly triple that of cis women (SMR, 2.8).
Compared with cisgender women, transgender women were more than twice as likely to die from heart disease, three times more likely to die from lung cancer, and almost nine times more likely to die from infection. HIV-related disease mortality risk was nearly 50 times higher for trans women than cis women, and the risk of suicide was almost seven times greater.
Suicide and other non-natural causes of death were more common in trans men compared with cis women.
The report, by Christel J.M. de Blok, MD, of Amsterdam University Medical Center, the Netherlands, and colleagues, was published online September 2 in The Lancet Diabetes & Endocrinology.
Is Gender-Affirming Hormone Therapy Associated With Increased Mortality?
Senior author Martin den Heijer, MD, also of Amsterdam University Medical Center, said: “The findings of our large, nationwide study highlight a substantially increased mortality risk among transgender people that has persisted for decades.”
But he pointed out that, overall, the data do not appear to suggest the premature deaths were related to gender-affirming hormone treatment.
However, he conceded that more work is needed on this aspect of care. “There is insufficient evidence at present to determine long-term safety of [gender-affirming hormone treatment]. More research is needed to fully establish whether it in any way affects mortality risk for transgender people,” said den Heijer.
Endocrinologist Will Malone, MD, of Twin Falls, Idaho, told Medscape Medical News, “The study confirms, like others before it, that individuals taking cross-sex hormones are more likely to die prematurely from a number of causes.”
“While the authors speculate that this higher mortality rate is not connected to cross-sex hormones, the study was not designed to be able to make such a claim,” he said, pointing to limited follow-up times.
In an accompanying commentary, Vin Tangpricha, MD, PhD, an endocrinologist from Emory University School of Medicine, Atlanta, Georgia, noted: “Transgender men do not appear to have as significantly increased comorbidity following receipt of gender-affirming hormone therapy when compared with transgender women.”
Tangpricha added future studies should examine which factors — hormone regimen, hormone concentrations, access to healthcare, or other biological factors — explain the higher increased risk of morbidity and mortality observed in trans women as opposed to trans men.
However, de Blok and colleagues note that, as there were relatively few deaths among transgender men in the cohort, analysis on cause of death in this group is limited.
Transgender Individuals More Likely to Die Younger
For their study, Dutch researchers retrospectively examined data from 4568 transgender people attending their clinic (2927 transgender women and 1641 transgender men) treated in 1972-2018. People were excluded if they started treatment before the age of 17 or if they had received puberty-blocking drugs.
Data on age at start of hormone treatment, type of treatment, smoking habits, medical history, and last date of follow-up were gathered from medical records. Where possible, SMRs were determined for deaths among trans men and trans women compared with rates for the adult Dutch general population.
Median age at the start of cross-sex hormone treatment was 30 years in transgender women and 23 years in transgender men. But the median follow-up time was only 11 years in transgender women and 5 years in transgender men.
A total of 317 (10.8%) trans women died, and 44 (2.7%) trans men died. The findings were higher than expected compared with the general population of cisgender women (SMR, 1.8) but not cisgender men (SMR 1.2).
Mortality risk did increase more in transgender people who started gender-affirming hormone treatment in the past two decades compared with earlier, a fact that de Blok said was surprising.
Trans men, for example, compared with cis women, had an SMR of 2.1-2.4 in 2000-2018 (compared with 1.8 overall).
“This may be due to changes in clinical practice…In the past, healthcare 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,” de Blok noted.
More Research Needed, Especially in Trans-Identifying Youth
Malone remarked that previous studies have shown associations between taking cross-sex hormones and elevated mortality, while also “not designed to detect causality,” have “generally accepted that natal males who take estrogen have estrogen-related increases in the rates of heart disease, stroke, and deep venous thrombosis.”
He added that the risks of testosterone use in natal females were less well established, “but testosterone is also felt to increase their risk of heart disease.”
He stressed the limited follow-up times in the study by de Blok and colleagues.
This “strongly suggests that the rate of elevated mortality far exceeds the doubling measured by the study, especially for natal females.”
Malone is one of several clinicians and researchers who has formed the Society for Evidence-Based Gender Medicine (SEGM), a nonprofit organization that now has at least 100 physician members. SEGM is concerned about the lack of quality evidence for the use of hormonal and surgical interventions as first-line treatment, especially for young people with gender dysphoria.
Tangpricha also highlighted that the findings do not apply to transgender people who began treatment before aged 17 years or those who had taken puberty blockers before gender-affirming hormone treatment.
There are no long-term data on transgender individuals who have received gender-affirming hormone therapies close to the time of puberty.
These data, such as those from the Trans Youth Care study, should be available in the future, he added.
The authors have reported no relevant financial relationships. Tangpricha has reported receiving funding from the National Institutes of Health and served as past president of the World Professional Association for Transgender Health. He is editor-in-chief of Endocrine Practice and has provided expert testimony for Kirkland and Ellis.