Figure 1.

Recommendations for rodent models of GAHT. (A) Classic endocrinology studies use GDX and hormone replacement to study the role of individual hormones. Researchers should take care to best model the human condition. GAHT in trans men and transmasculine people typically involves exogenous T treatment, GAHT in trans women and transfeminine people typically involves exogenous E2 and antiandrogen treatment, sometimes combined with P4, and transgender people who have their gonads removed do so later in life after the initiation of GAHT (3,15). Therefore, better models of GAHT should use intact animals at pubertal, adult, and aged time points. In adults and aged animals, untreated, intact animals with ovaries and testes should be compared with intact animals with ovaries treated with T and intact animals with testes treated with antiandrogens, E2, and/or P4. Commonly used antiandrogens include spironolactone, cyproterone acetate, and finasteride; all 3 antiandrogens have distinct mechanisms of action and off-target effects (3). Models using all 3 should be tested in translational studies. In peripubertal animals, untreated intact mice should be compared with intact mice treated with a GnRH agonist, such as leuprolide. (B) Owing to the high levels of chronic stress faced by transgender, nonbinary, and/or gender diverse populations, researchers should strive to assess both the effect of GAHT on stress systems in the brain and periphery and the effect of various stressors on the efficacy of GAHT relative to particular experimental end points. Care should be taken to assess the effects of stressors occurring prior to, during, and after the onset of exogenous hormone treatment. (C) Relevant timelines for rodent models of GAHT. E2, estradiol; GAHT, gender-affirming hormone therapy; GDX, gonadectomy; GnRH, gonadotropin hormone-releasing hormone; P4, progesterone; T, testosterone.