Transgender Health: A Metabolic Wake-Up Call

Transgender healthcare has long remained a neglected area because of a mix of lack of knowledge and negative biases. In the past decade, several efforts have been made to address these issues, and more and more transgender persons are seeking healthcare. However, transgender care is not limited to hormonal therapies and gender-reaffirming surgeries. To ensure good long-term outcomes, the focus must shift towards metabolic health. Therefore, an understanding of metabolic risk factors, including sleep and mental health of transgender persons, is essential. Obesity appears to be more prevalent in transgender persons. Data from a longitudinal cohort study in the United States showed that after initiation of gender-affirming hormone treatment (GAHT), a significant increase in body mass index (BMI) was seen in transgender women but not in transgender men.1 However, a meta-analysis on the effect of testosterone therapy on transgender men reported significant increases in BMI, although the magnitude was not large.2 A systematic review on the effect of GAHT on body composition showed that transgender males gained muscle and lost fat, while transgender females lost muscle and gained fat.3 Interestingly, a study from Israel reported that transgender male adolescents were proportionately more affected by obesity as compared to transgender female adolescents, indicating that these abnormalities precede the onset of GAHT.4 Apart from a higher body fat percentage, low muscle mass was found in the transgender male adolescents, indicating a greater propensity to metabolic syndrome even before any hormonal therapy was started.4 Transgender persons are less physically active than matched cisgender controls. Furthermore, transgender persons not on GAHT are less physically active than those who are on GAHT.5 Acanthosis nigricans is a well-recognised clinical marker of hyperinsulinemia. Data from the Stanford Research Repository showed that acanthosis nigricans was seen in 4.55% of over 900 transgender male patients, which was several times higher than the overall prevalence in their database. Furthermore, acanthosis nigricans was strongly associated with obesity, metabolic syndrome and dysglycemia.6 However, the effect of GAHT on insulin resistance in transgender individuals was found to be inconclusive in a meta-analysis.3 Testosterone therapy did not cause dyslipidemia or dysglycemia in transgender men in a study.7 A meta-analysis of testosterone therapy in transgender men reported a modest rise in blood pressure and low-density lipoprotein (LDL) with a decline in high-density lipoprotein (HDL), but the studies were small and significant heterogeneity was present.2 Data from the United States points toward a significant burden of undiagnosed hypertension and dyslipidemia.8 The risk of metabolic syndrome is an important concern given the above-mentioned observations. A study from the Veterans Health Administration national database of the United States, which included persons receiving GAHT over a 13-year period, reported that transgender male veterans had the highest risk of metabolic syndrome, followed by cisgender females, cisgender males and transgender female veterans.9 The impact of GAHT on components of metabolic syndrome appears to be sex specific, with different metabolic cytokines being responsible. Fibroblast growth factor-21 (FGF-21), resistin and chemerin appear to play a role in this process. In transwomen, a decrease in triglycerides (TG) appeared to correlate well with a decrease in fat mass and an increase in FGF-21, while in transgender males, a decline in HDL: total cholesterol was correlated with a decline in adiponectin. FGF-21, resistin and chemerin were positively associated with improved hepatic insulin sensitivity in transgender males.10 A study from India found that in transgender females, serum FGF21 levels correlated positively with serum TG and serum LDL cholesterol.11 Irisin is a myokine that may be involved in energy homeostasis and metabolic syndrome. In this issue, Kamath et al. have looked at irisin levels in transgender individuals. Irisin appeared to have some association with dyslipidemia and diastolic blood pressure in transgender males and females, respectively.12 More studies are needed to elucidate the biochemical pathways involved in metabolic syndrome in transgender individuals. The presence of metabolic syndrome may also confer a high baseline cardiovascular risk in transgender person.8 Data from the 2014 to 2017 Behavioural Risk Factor Surveillance System in the United States showed that transgender persons are at a significantly high cardiovascular risk. Transgender males are at a two-fold higher risk of myocardial infarction as compared to cisgender males after adjusting for conventional risk factors, including diabetes, dyslipidemia, hypertension and smoking.13 Both transgender females and transgender males are more likely to be obese as compared to cisgender males. Transgender females have a higher odds of myocardial infarction as compared to cisgender females. This risk was, however, still less than that for cisgender males.14 The risk of diabetes, stroke and coronary artery disease was higher in transgender females as compared to cisgender females.15 A meta-analysis that looked at more than 30,000 transgender persons found that the risk of cardiovascular disease was 40% higher in transgender persons as compared with cisgender persons.16 Sleep and mental health are increasingly being studied as potential cardiovascular and metabolic risk factors.17 In this issue, Kolla and Kalra report poor sleep quality and a very high prevalence of depression and anxiety in transgender individuals under follow-up at their centre.18 Both mental health disorders and substance abuse are more common in transgender individuals than in the general population.8 Retrospective cross-sectional data from a United States-based administrative claims database have shown that insomnia, sleep apnoea and other sleep disorders may be several-fold higher in transgender youth when compared to cisgender youth.19 Similar findings have been reported in other studies.20,21 Data from the Trying to Understand Relationships, Networks and Neighbourhoods Among Transgender Women of Color Cohort Study in the United States suggest that both sleep duration and sleep quality were reduced in transgender females.22 Sleep disturbances start early in the life of transgender individuals. A study reported that transgender adolescents showed a higher prevalence of sleep disturbances, including insomnia and excessive daytime sleepiness. Caregiver reports also indicated significantly shorter sleep durations in this group, with a notably higher risk of obtaining fewer than 5 h of sleep compared with cisgender peers.23 While sleep disorders appear to be associated with transgender individuals independent of GAHT, the effect of GAHT on sleep disorders is not clear yet. A study on 12-month use of GAHT in transgender persons reported no clinically significant effects on sleep quality or insomnia. However, minor changes in self-reported latency and sleep efficiency were noted.19 The effect of GAHT on sleep architecture in transgender individuals has been studied. A study reported that sleep architecture shifts towards patterns typical of cisgender males after three months of masculinising GAHT, whereas no significant changes are observed following feminising GAHT.24 A protective effect of GAHT on sleep disorders in transgender youth has also been observed in cross-sectional data.19 With an increase in awareness and a reduction in biases, the number of transgender persons seeking medical help is slated to increase. By addressing the concerns of obesity, metabolic syndrome, sleep, and mental health, healthcare workers will be able to prevent morbidity and mortality in these individuals. Targeted interventions will be needed to address these issues. More research in these areas will be crucial to provide the necessary evidence to improve the health of transgender individuals.