General discussion 265 brain activity in response to emotional stimuli, and showed that after 6 to 10 months of masculinizing GAHT, amygdala activity in response to emotional faces decreased compared to pre-GAHT. These two studies show that GAHT could affect emotion processing, but further studies are needed to examine the exact effects. Neurotransmitter and neurosteroid changes Studies have also found effects of sex hormones on serotonergic and GABAergic systems. In people with PMDD, who experience severe depressive symptoms in the luteal phase of the menstrual cycle, changes in serotonin receptors and transporters in the luteal phase are associated with reported adverse mood (Jovanovic et al., 2006; Sacher et al., 2023). This work supports the hypothesis that changes in the serotonergic system after OCs and GAHT could also affect mood. There are numerous studies on OCs and GAHT which find changes in the serotonergic system, although studies examined different components of the serotonergic system. Larsen et al. (2022) found reduced receptor binding for the serotoninergic 5-HT4 receptor in OC users compared to non-users. Studying the effects of GAHT on the serotonergic system, Kranz et al. (2015) found that 4 months of masculinizing GAHT resulted in increased binding potential to the serotonin reuptake transporter (SERT) in the amygdala, caudate, putamen, and median raphe nucleus, whereas 4 months of feminizing GAHT resulted in decreased SERT binding potential in the insula, anterior, and mid-cingulate cortex. The same authors also found downregulation of monamine oxidase A (MAO-A) after 4 to 9 months of masculinizing GAHT, but no changes after feminizing GAHT (Kranz et al., 2021). The neurosteroid allopregnanolone could also play a role in sex hormoneassociated mood symptoms. Allopregnanolone is synthesized from progesterone by 5-alpha reductase and it positively modulates the GABAreceptor, asserting an axiolytic and sometimes sedative effect (Diviccaro et al., 2022). In some, withdrawal from allopregnanolone during the menstrual cycle can result in mood symptoms: it is assumed that withdrawal from progesterone and allopregnanolone in the late luteal phase could contribute to the symptoms of PMDD (Hantsoo & Epperson, 2020). Although studies in humans are lacking, animal models show that allopregnanolone-based effects could also play a role in OC and GAHT users. Santoru et al. (2014) found that administration of ethinylestradiol and levonorgestrel in rodents
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