The Impact of Hormone Therapy on Cardiometabolic Risk Factors in Trans Persons: Implications and Future Perspectives.

Excessive fat accumulation in the abdominal region is associated with the development of obesity-related chronic diseases such as type 2 diabetes and cardiovascular disease (1). Sexual dimorphism in body fat distribution, adipose tissue biology, and substrate metabolism in skeletal muscle and the liver explain a significant portion of sex differences in cardiometabolic health (2). In addition to sex hormone-independent factors [ie, lifestyle-related factors and (epi)genetic mechanisms] (3), sex hormone-dependent mechanisms seem to affect metabolic complications and cardiometabolic disease risk in a sex-specific manner (2).

Adult trans men (birth assigned females) are prescribed testosterone, and adult trans women (birth assigned males) generally are prescribed a combination of estrogen and an antiandrogen to induce the desired physical (ie, changes in body composition, facial/body hair, breast size, voice, reproductive/sexual function) and psychological effects (4,5). Given the importance of sex hormones in metabolic regulation, changes in body fat deposition and cardiometabolic risk factors may occur in trans persons.

I have read with great interest the article by Klaver et al (6), in which the authors report the results of an original study that builds upon previous findings of changes in body composition and cardiometabolic risk factors following hormone therapy in trans persons. More specifically, the team of investigators set out to investigate the impact of hormone therapy on the amount of visceral fat (VAT), total body fat (TBF) and the VAT/TBF ratio over approximately 1 year in 179 trans women and 162 trans men with gender dysphoria and examined the associations between changes in body fat mass/distribution and cardiometabolic risk factors.

Klaver et al (6) found that hormone therapy increased estradiol and decreased testosterone levels in trans women. This was accompanied by an increase in TBF, while the amount of VAT did not change, resulting in a decrease in the VAT/TBF ratio of 17% (95% CI: 15%-19%) in trans women. These changes were paralleled by reduced lean body mass, total cholesterol, high- and low-density lipoprotein cholesterol, and triglyceride concentrations, while homeostatic model assessment of insulin resistance (HOMA-IR) increased (6). In agreement with these findings, recent data suggest that the long-term administration of cyproterone acetate, which was used in the present study by Klaver et al (6), in combination with estradiol reduces insulin sensitivity (7). Furthermore, Klaver et al (6) found that in trans men hormone therapy increased testosterone concentrations and induced a modest increase in estradiol, likely due to aromatization of testosterone to estradiol. TBF was decreased, while the amount of VAT did not change, thereby increasing the VAT/TBF ratio by 14% (95% CI: 10-17] in trans men. Furthermore, the authors found increased lean body mass, low-density lipoprotein cholesterol, and triglyceride levels; unchanged total cholesterol; and decreased high-density lipoprotein cholesterol concentrations and HOMA-IR following hormone therapy in trans men. Notably, in both groups, the changes in body fat distribution (VAT/TBF) were similar between different BMI categories and were not associated with changes in the lipid profile or HOMA-IR. These data suggest that (early) cardiometabolic effects of hormone therapy might not be mediated through changes in VAT or VAT/TBF ratio but could be the results of rapid direct metabolic effects of sex hormones on different target organs (2), especially given the relatively short study duration.

A particular strength of the study by Klaver et al (6) is the longitudinal assessment of (the relationship between) changes in VAT/TBF mass and several cardiometabolic risk factors in a large population of trans men and trans women. However, this study has some limitations. First, important confounding factors that may have affected body composition, body fat distribution, and cardiometabolic risk factors, including changes in physical activity, diet, medication, smoking status, sleep and stress, were not assessed. Although acknowledged by the authors, the lack of an age- and body mass index–matched control group (no hormone therapy) can be considered as an important limitation of this study, especially since persons with overweight and obesity were advised to maintain a healthy lifestyle to lose body weight because of requirements when applying for genital surgery. This may have impacted study outcomes and could have contributed to the large interindividual variation in VAT changes during hormone therapy. Second, insulin sensitivity was assessed using HOMA-IR. Although it may not have been feasible to determine (tissue-specific) insulin sensitivity using the hyperinsulinemic-euglycemic clamp (gold standard) given the large study population, an oral glucose tolerance test would have provided more detailed insight into the impact of hormone therapy on different aspects of (postprandial) glucose metabolism (ie, beta-cell function and insulin sensitivity). Likewise, the application of magnetic resonance imaging methodology instead of dual-energy X-ray absorptiometry would have resulted in more accurate quantification of different fat depots, including VAT. Third, the investigators did not examine the time course of changes in the outcome parameters after initiation of hormone therapy. In contrast, a very recent large longitudinal study performed body weight measurements at baseline and at multiple follow-up clinical visits up to 57 months after the initiation of gender-affirming hormone therapy in a racially and ethnically diverse population consisting of 247 trans women and 223 trans men (8). This study demonstrated that hormone therapy was associated with an increase in mean body weight within 2 to 4 months in trans men and after 22 months in trans women. Of note, changes in body fat distribution or cardiometabolic risk markers were unfortunately not examined (8). Thus, it cannot be excluded that the impact of changes in body composition and fat distribution on cardiometabolic risk factors becomes more important after more prolonged hormone therapy.

Collectively, the novel findings by Klaver et al (6) contribute to our current knowledge on alterations in body composition and cardiometabolic risk factors following hormone therapy in trans men and trans women. These data further support routine monitoring of body composition and cardiometabolic risk factors before and after the initiation of hormone therapy in trans persons. Importantly, however, the present findings require confirmation in future studies that are performed in a more controlled study setting, in which important confounders are taken into account. Moreover, these studies should use more sophisticated methodology to quantify changes in body fat distribution as well as the metabolic phenotype and preferably have a longer study duration. In addition, insight into the biological underpinnings of changes in body composition and cardiometabolic risk factors in trans persons is warranted, with attention to the effects of different antiandrogens as well as route of hormone administration. More specifically, more research should be directed toward a better understanding of the effects of hormone therapy on adipose tissue biology (lipid storage and mobilization, fat cell size, and inflammation), skeletal muscle, and liver metabolism in trans men and trans women. Finally, the efficacy of (multidisciplinary) lifestyle interventions to dampen any detrimental health outcomes of hormone therapy in trans persons should be investigated. Together, this knowledge will contribute to optimizing the clinical management of trans persons during hormone therapy.