Effects of Leuprolide on Juvenile Behavior and Gonadal Development in Sprague Dawley Rats - Implications for Gender-affirming Healthcare in Transgender and Gender-diverse Youth
Thomas Niepsuj, B.S.1, Walid Farhat, M.D.1, Anthony Auger, PhD.2, Gabriela de Faria Oliveira, B.S.1, Leykza Carreras Simons, B.S.1, Joan Jorgensen, PhD., DVM.3, Rithika Nurani, N/A1, Aimee Johnson, N/A1, Arushi Gupta, N/A1, Eden Lev, N/A1.
1University of Wisconsin, Madison, WI, USA, 2University of Wisconsin - Department of Psychology, Madison, WI, USA, 3University of Wisconsin - School of Vetinary Medicine, Madison, WI, USA.
BACKGROUND: Transgender and gender-diverse youth have higher rates of depression, anxiety, and suicidality. However, studies have shown that gender-affirming healthcare can improve their mental health outcomes. One form of gender-affirming healthcare is the use of GnRH agonists, like leuprolide, to halt the development of secondary sex characteristics. As these treatments become more common, it is important to investigate the biological impact of leuprolide on adolescent brain, periphery, and social development. In this study, we aimed to investigate the effects of leuprolide on social and anxiety-like behavior in relation to gonadal and hormonal development of juvenile Sprague Dawley rats.
Methods: Forty-eight Sprague Dawley rats (24 females and 24 males) were injected daily with either saline (control) or leuprolide (20 μg/kg) from postnatal day 27 (prepubertal) until postnatal day 39 (post pubertal onset). The rats were assessed for rough-and-tumble play behavior, which involves chasing, boxing, pouncing, and pinning, in their home cage between postnatal days 27 and 37. On postnatal days 38 and 39, the rats were placed in an elevated plus maze and tested for anxiety-like behavior. Following behavioral testing, rats were euthanized, serum and organs were collected, and tissues were flash frozen for further analysis.
Results: We found significant effects of both sex and treatment on rough-and-tumble play behavior. As expected, male control rats exhibited higher rates of pinning and pouncing than female control rats (p-value = .0074). However, male rats treated with leuprolide were behaviorally most similar to female controls and showed reduced rough-and-tumble play behavior (p-value = .0093) as well as reduced testosterone levels (p-value = .0034) when compared to male controls. Additionally, leuprolide treatment had no effect on rough-and-tumble play behavior or estrogen levels in female rats. Interestingly, both male and female rats treated with leuprolide exhibited reduced anxiety-like behavior compared to control groups (p-value = .0175). All rodents treated with leuprolide also exhibited reduced gonadal mass when compared to sex matched controls (testes p-value = .0002, ovaries p-value = .0312). Furthermore, reduced testicular size correlated with reduced testosterone levels (p-value = .0049) and lower frequency of rough-and-tumble play (p-value = .0454).
Conclusions: Our study provides valuable insights into the effects of leuprolide on juvenile development. The findings suggest that leuprolide treatment has the potential to not only halt the development of secondary sex characteristics but also reduce sex differences in juvenile rough-and-tumble play behavior and alleviate anxiety-like symptoms. These findings support the potential benefits of gender-affirming healthcare for transgender and gender-diverse youth, considering the high prevalence of depression, anxiety, and suicidality in this population. However, further research is necessary to fully understand the effects of gender-affirming healthcare on overall juvenile development, encompassing both peripheral and central aspects, in transgender and gender-diverse youth. Such research will contribute to optimizing the care and well-being of transgender and gender-diverse youth.
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