Th17 cell-linked mechanisms mediate vascular dysfunction induced by testosterone in a mouse model of gender-affirming hormone therapy

Abstract

Clinical data point to adverse cardiovascular events elicited by testosterone replacement therapy. Testosterone is the main hormone used in gender-affirming hormone therapy (GAHT) by transmasculine people. However, the cardiovascular impact of testosterone in experimental models of GAHT remains unknown. Sex hormones modulate T cells activation, and immune mechanisms contribute to cardiovascular risk. The present study evaluated whether testosterone negatively impacts female cardiovascular function by enhancing Th17 cells-linked effector mechanisms. Female (8 weeks-old) C57BL/6J mice received testosterone (48 mg.Kg-1.week-1) for 8 weeks. Male mice were used for phenotypical comparisons. The hormone-treatment in female mice increased circulating testosterone to levels observed in male mice. Testosterone increased lean body mass and body mass index, and decreased perigonadal fat mass, mimicking clinical findings. After 8 weeks, testosterone decreased endothelium-dependent vasodilation and increased circulating Th17 cells. After 24 weeks, testosterone increased blood pressure in female mice. Ovariectomy did not intensify phenotypical or cardiovascular effects by testosterone. Female mice lacking T and B cells [Rag1 knockout (-/-)], as well as female mice lacking IL-17 receptor (IL-17Ra-/-), did not exhibit vascular dysfunction induced by testosterone. Testosterone impaired endothelium-dependent vasodilation in female mice lacking γδ T cells, similarly to the observed in wild type female mice. Adoptive transfer of CD4+ T cells restored testosterone-induced vascular dysfunction in Rag1-/- female mice. Together, these data suggest that CD4+ T cells, most likely Th17 cells, are central to vascular dysfunction induced by testosterone in female mice, indicating that changes in immune cells balance are important in the GAHT in transmasculine people.

Insights Into the Cardiomodulatory Effects of Sex Hormones: Implications in Transgender Care

“…The hypertension was attributed to immune cell imbalance. 38 Interestingly, the same study demonstrated that age-matched, untreated male mice did not show any difference in mean arterial pressure compared with control females at either the 8- or 24-week time points. 38 These data suggest that despite having the same plasma level of androgens as male mice, the vasopressor response to androgens is exacerbated in testosterone-treated female mice.…”

“…Body composition measured by dual-energy x-ray absorptiometry after 2 months of treatment showed a significant increase in lean mass and decrease in fat mass in testosterone-treated females compared with untreated control females, an outcome that is quite different from low-dose dihydrotestosterone in the PCOS model discussed above. Similarly, Santos et al 38 showed that female mice injected twice weekly with a dose of testosterone cypionate that resulted in male-comparable serum levels had significantly smaller perigonadal fat and higher gastrocnemius muscle mass, higher body mass index along with skeletal muscle hypertrophy within 2 months after starting treatments.…”

“…In the majority of those GAHT models, androgen hormonal therapy starts at ≈6 to 10 weeks of age (after the onset of puberty in female rodents) to model adolescent and early adulthood transitions and continues for varying amounts of time that ranged from 6 to 24 weeks (Table 3). 37–45…”

“…In the majority of those GAHT models, androgen hormonal therapy starts at ≈6 to 10 weeks of age (after the onset of puberty in female rodents) to model adolescent and early adulthood transitions and continues for varying amounts of time that ranged from 6 to 24 weeks (Table 3). [37][38][39][40][41][42][43][44][45] Body Composition and Lipids in Testosterone-Treated Female Rats Lichtenecker et al 37 investigated the effect of testosterone cypionate on female Wistar rats starting at 2 months of age using a dose that caused a ≈30-fold increase in the serum testosterone levels (to male-comparable levels) with no change in estradiol levels. Body composition measured by dual-energy x-ray absorptiometry after 2 months of treatment showed a significant increase in lean mass and decrease in fat mass in testosterone-treated females compared with untreated control females, an outcome that is quite different from lowdose dihydrotestosterone in the PCOS model discussed above.…”

Testosterone Restores Body Composition, Bone Mass, and Bone Strength Following Early Puberty Suppression in a Mouse Model Mimicking the Clinical Strategy in Trans Boys

“…In recent years, a plethora of rodent models have been developed to study the impact of gender-affirming therapy on a variety of outcomes. (24)(25)(26)(27)(28) The vast majority of these studies, however, mimicked the clinical approach in transgender adults. As such, those models were restricted to GAH administration and did not involve puberty suppression to avoid or halt appearance incongruent development in transgender youth.…”