ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 6.13 | DOI: 10.1530/ey.18.6.13

Neuropsychopharmacology. 2021 Apr;46(5):882–890.doi: 10.1038/s41386-020-00826-1. PMID: 32919399.

This mouse study addresses the question of the psychological effects of treatment with the GnRH analogue (GnRHa) leuprolide. Six-week-old, i.e. early-pubertal, male and female mice were injected daily with leuprolide (20 μg) or saline for 6 weeks. The mice were subjected to a number of behavioral tests, and hormonal stress response was assessed. The effects on reproductive function, social and affective behaviour, cognition, and brain activity were studied.

A main focus has previously been the effects of GnRHa on bone mineral density in adolescents receiving GnRHa in the context of gender dysphoria. Neuropsychiatric and neurobiological effects, other than halting puberty and possibly alleviating the stress of gender dysphoria and allowing for thorough psychological assessment, have been increasingly discussed, as GnRH receptors are particularly abundant in the hippocampus and the limbic system.

These data show for the first time that GnRH agonist treatment after puberty onset has sex-specific effects on social and affective behavior, stress regulation, and neural activity in mice. More specifically, increased hyperlocomotion, changes in social preference, and increased neuroendocrine stress responses were seen in male mice, while increased hyponeophagia and despair-like behaviour (reactions responsive to antidepressant treatment) were noted in females. In addition, corticosterone response was increased in male but not female mice on exposure to a new situation.

The authors discuss the possibility that increased signs of depression in adolescents with gender dysphoria who are treated with GnRHa may not be readily detectable due to a decrease in depressive symptoms related to the physical changes of the treatment. Although mice and humans differ particularly with regards to hormonal effects in the brain, this study raises further questions about the eventual neuropsychological off-target effects of GnRH agonists as used in adolescents with gender dysphoria.

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