Transgender Males show increased monocyte GLUT1 and ROS expression

Background: Currently, up to 2% of people identify as transgender and gender affirming hormone therapy (GAHT) is on the rise. However, cardiovascular risk profile is enhanced in transgender compared to cis-gender individuals - especially for transgender men on testosterone therapy. Classical monocytes are important for genesis and progression of atherosclerosis and in healing of myocardial infarction and monocyte metabolism and activity relies on expression of glucose transporter (GLUT) 1 and 4. However, the impact of testosterone on GLUT expression on monocytes and the association with reactive oxygen species (ROS) generation has not been investigated.

Methods: In this mono-center pilot study, transgender men that were planned for mastectomy (collaboration with Dr. Naja Pluto, Plastic Surgery Medienhafen, Düsseldorf) were included. GLUT1 and GLUT4 as well as ROS expression on monocytes separated into classical (CD14+) and non-classical (CD16+) monocytes were measured by flow cytometry. Moreover, the whole leukocyte distribution was quantified. Testosterone levels were measured by ELISA. In addition, in-vitro incubation of untreated female blood with testosterone in increasing concentrations (0/2.5/10/20 ng/mL) was conducted to identify direct short-term effects of testosterone.

Results: We included 61 transgender men (39 without GAHT, 22 with GAHT). The mean age of individuals was 29.95 ± 8.36, 29.5% were smokers, 13.11% were obese. Testosterone as GAHT led to increase of GLUT1 expression on all monocytes as well as separated in classical and non-classical subtypes (monocytes: 249.9 ± 55.9 vs. 305.7 ± 68.94 [geometric mean] – p=0.0036; classical: 208.7 ± 52.59 vs. 252.6 ± 62.12 – p=0.0087; non-classical: 1059 ± 490.8 vs. 1467 ± 226.3 – p=0.0020). Interestingly, GLUT1 expression only showed direct correlation with testosterone levels in low concentration with no correlation at all at high doses. GLUT4 did not show an increase by testosterone therapy. However, at very high testosterone levels there was a positive correlation with GLUT4 expression and testosterone. In line with the increased GLUT expression, ROS was increased as well on classical and on non-classical monocytes in the GAHT group (classical: 501.9 ± 139.5 vs. 615 ± 186.9 – p=0.0161; non-classical: 2900 ± 1131 vs. 3762 ± 1349 – p=0.0115). Distribution of leukocytes was equal. In-vitro incubation revealed different effects by short term testosterone treatment with reduction of GLUT1 with increasing concentrations (all monocytes: 285.1 ± 33.58 - 233.4 ± 55.47 - 213.9 ± 35.12 - 208.2 ± 34.26 – p=0.009). In line, ROS was reduced (all monocytes: 844.8 ± 347.7 - 562.1 ± 15.7 - 502.1 ± 87.36 - 484.8 ± 70.91– p=0.0126). 

Conclusion: In this study, we could reveal that testosterone as gender affirming therapy leads to increased ROS formation and GLUT1 expression on classical and non-classical monocytes. Interestingly, short-term incubation reduced both indicating differences by duration of testosterone treatment. These findings might explain one possible mechanism for the increased cardiovascular risk profile in transgender men with long-term GAHT. Future research is needed for further comprehension in this field of transgender patients.