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Behavioral and neurobiological effects of GnRH agonist treatment in mice—potential implications for puberty suppression in transgender individuals

Abstract

In the United States, ~1.4 million individuals identify as transgender. Many transgender adolescents experience gender dysphoria related to incongruence between their gender identity and sex assigned at birth. This dysphoria may worsen as puberty progresses. Puberty suppression by gonadotropin-releasing hormone agonists (GnRHa), such as leuprolide, can help alleviate gender dysphoria and provide additional time before irreversible changes in secondary sex characteristics may be initiated through feminizing or masculinizing hormone therapy congruent with the adolescent’s gender experience. However, the effects of GnRH agonists on brain function and mental health are not well understood. Here, we investigated the effects of leuprolide on reproductive function, social and affective behavior, cognition, and brain activity in a rodent model. Six-week-old male and female C57BL/6J mice were injected daily with saline or leuprolide (20 μg) for 6 weeks and tested in several behavioral assays. We found that leuprolide increases hyperlocomotion, changes social preference, and increases neuroendocrine stress responses in male mice, while the same treatment increases hyponeophagia and despair-like behavior in females. Neuronal hyperactivity was found in the dentate gyrus (DG) of leuprolide-treated females, but not males, consistent with the elevation in hyponeophagia and despair-like behavior in females. These data show for the first time that GnRH agonist treatment after puberty onset exerts sex-specific effects on social- and affective behavior, stress regulation, and neural activity. Investigating the behavioral and neurobiological effects of GnRH agonists in mice will be important to better guide the investigation of potential consequences of this treatment for youth experiencing gender dysphoria.

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Fig. 1: Leuprolide increases locomotion and changes social preference in male mice, but not female mice.
Fig. 2: Leuprolide increases hyponeophagia and despair-like behavior in females, but not in males.
Fig. 3: Leuprolide does not impact contextual fear discrimination learning in male or female mice.
Fig. 4: Leuprolide increases the corticosterone response to novelty exposure in male, but not in female mice.
Fig. 5: Leuprolide increases neural activity in the DG of female, but not male mice.

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Acknowledgements

We thank members of the laboratories for insightful comments on this project and on the manuscript.

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Correspondence to Christoph Anacker or Christine A. Denny.

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Anacker, C., Sydnor, E., Chen, B.K. et al. Behavioral and neurobiological effects of GnRH agonist treatment in mice—potential implications for puberty suppression in transgender individuals. Neuropsychopharmacol. 46, 882–890 (2021). https://doi.org/10.1038/s41386-020-00826-1

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