Monitoring liver enzymes unnecessary during gender-affirming HT
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The incidence of abnormal liver enzymes among transgender men and women prescribed gender-affirming hormone therapy is low, with no cases of symptomatic liver injury observed after 1 year of treatment, data show.
The Endocrine Society clinical practice guideline for the treatment of people with gender incongruence lists severe liver dysfunction as a medical risk associated with testosterone therapy, Theresa Stangl, MD, a researcher with Spaarne Gasthuis in Haarlem, the Netherlands, and colleagues wrote in the study background. In the most recent guideline for drug-induced liver injury, the European Association for the Study of the Liver mentions an association between use of anabolic androgenic steroids, oral contraceptives and anti-androgens with drug-induced liver injury or liver tumors, they wrote.
“In this study, we found that the incidence of abnormal liver enzymes is very low in this healthy transgender population using hormone therapy,” Stangl, formerly with the division of endocrinology at Amsterdam University Medical Centre, told Healio. “This main finding implicates that monitoring liver enzymes during hormone treatment is not necessary.”
In a prospective study, Stangl and colleagues analyzed data from 1,044 transgender men (mean age, 26 years) and 889 transgender women (mean age, 33 years), who initiated HT between 2010 and 2020. Transgender women received cyproterone acetate (25-100 mg daily) combined with oral estradiol valerate (2-4 mg daily), estradiol patches (100 g per 24 hours twice weekly) or transdermal 17-beta-estradiol gel (1.5 mg twice daily). Transgender men used testosterone gel (50 mg daily), testosterone esters injections (250 mg per 2-3 weeks), testosterone enanthate injections (250 mg per 2-3 weeks) or testosterone undecanoate injections (1,000 mg per 12 weeks).
Researchers assessed alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) before HT and again at 3 and 12 months, using reference intervals for the birth-assigned sex. Liver injury was defined as either an elevation of two times the upper limit of normal for ALP, three times the upper limit of normal for ALT or three times the upper limit of normal for AST.
The incidence of liver injury within 12 months after start of HT, without attribution to alcohol abuse, medical history or comedication was 0.1% and 0%, respectively, for transgender women, and 0.6% and 0.4%, respectively, for transgender men (using female and male reference intervals).
In a subset of 381 individuals (194 transgender women and 187 transgender men), liver enzyme measurements were also available after 36 months of HT. Of those, only one transgender man had unexplained liver injury according to female, but not male, reference intervals.
“In this study, only people who used our standard protocol of hormone treatment were included,” Stangl said. “However, today more gender-variant people who experience all kinds of identity issues may wish to receive different treatments. These treatments may result in different effects on liver enzymes and should be studied in further research.”
For more information:
Theresa Stangl, MD, can be reached at t.stangl@amsterdamumc.nl.
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Stangl and colleagues studied the trajectories of liver enzymes — AST, ALT, ALP and GGT — after 3, 12 and, for a smaller but still sizeable subcohort, 36 months, among people aged at least 16 years prescribed gender-affirming HT. The incidence of liver injury at 12 months — well within the timeframe one would expect to see drug-induced liver injury — was extremely low. These data support the cited smaller studies and reviews, as well as other publications (Velho I, et al. Andrology. 2017; doi:10.1111/andr.12382; Cheung AS, et al. J Clin Endocrinol Metab. 2021; doi:10.1210/clinem/dgaa546) with the conclusions that the incidence of liver injury after gender-affirming HT initiation is very low, any significant changes in liver enzymes are not likely clinically significant, and routine monitoring of liver enzymes during gender-affirming HT follow-up is not necessary.
The 2017 Endocrine Society’s clinical practice guideline lists severe liver dysfunction, defined as transaminases greater than three times the upper limit of normal, as a “moderate risk” of testosterone therapy, the mainstay of masculinizing gender-affirming HT. However, it also acknowledges in the text that “because oral 17-alkylate testosterone is not recommended, serious hepatic toxicity is not anticipated with parenteral or transdermal testosterone use.” For feminizing gender-affirming HT, typically comprised of estrogen plus antiandrogen, liver dysfunction is mentioned as a potential outcome that can be minimized by avoiding supraphysiologic doses and serum levels of estrogen. Nonetheless, routine monitoring of liver function is not recommended in those guidelines. Additionally, routine monitoring of liver function with masculinizing gender-affirming HT in the 2009 guideline was removed for the 2017 version.
Another important issue this study and a recent commentary (Irwig MS. J Clin Endocrinol Metab. 2021; doi:10.1210/clinem/dgaa671) raise is the need for future research to establish laboratory reference ranges for transgender people rather than relying on binary male and female reference ranges that may lead to statistically, but potentially not clinically, significant changes. Additionally, future studies of longer duration and more diversity of age, gender identity, race, ethnicity, geographic location, HT regimens, concurrent non-HT medications, and medical comorbidities can help us identify any predictors of liver dysfunction after HT initiation that may impact routine monitoring or screening recommendations for hepatic pathology in the future.
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