Influence of sex hormone use on sleep architecture in a transgender cohort 181 However, this study by Kunzel and colleagues found no other changes in sleep architecture, which is in line with our current findings. It is important to note that, although transmasculine participants were using testosterone, it is not clear whether the androgenic effects of testosterone are also causing the changes in sleep. Testosterone can affect androgenic pathways, as testosterone or via conversion into dihydrotestosterone (DHT), or it be aromatized locally into estradiol and affect estrogen receptors (Konkle & McCarthy, 2011). Previous work showed that in female rats, treatment with testosterone affected sleep, but treatment with DHT, which cannot be aromatized into estradiol, did not (Cusmano et al., 2014). Therefore, it is also possible that in our participants, the reported effects are not exclusively caused by the androgenic effects of testosterone, but that the administered testosterone was instead converted into estradiol, and that changes in estrogen activity affected sleep architecture. There is robust evidence that sleep-regulating areas of the brain are sensitive to sex hormones (Dorsey et al., 2021). Estradiol has been shown to affect the ventrolateral preoptic nucleus (VLPO): this area showed decreased firing rates after estradiol therapy in mice, although changes in sex hormones in male rats had no effect (Deurveilher et al., 2008; Hadjimarkou et al., 2008) and administration of estradiol into the VLPO resulted in increased physical activity in mice (Ribeiro et al., 2009). Furthermore, estradiol could affect the expression of orexin receptors, a sleep-stabilizing steroid. Orexin receptor expression changes with the estrous cycle in female rats as well as after removal and add-back of estradiol in female rats (Silveyra et al., 2007), as well as after gonadectomy or add-back of androgens in male rats (Silveyra et al., 2009). Estradiol could also affect the serotoninergic activity in the dorsal raphe nucleus: exposure to estradiol and progestins has been found to alter expression of serotonin receptors (Bethea et al., 2002). Changes in firing rates in the VLPO and serotonin system could also affect the duration of REM sleep (Lu et al., 2002; Monti & Jantos, 2008) and non-REM sleep (Popa et al., 2006). Furthermore, sex hormones are known to affect the suprachiasmatic nucleus (SCN) (Bailey & Silver, 2014) and the dynamics of diurnal cortisol via the hypothalamuspituitary-adrenal (HPA) axis (Juster et al., 2016). For a full review of neural mechanisms between sex hormones and sleep, see (Dorsey et al., 2021).
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