General discussion 261 2. Mechanisms connecting sex hormones with depression and sleep 2.1. Exogenous compared to endogenous sex hormones One limitation to take into account in this thesis is that the effects of exogenous sex hormones, including OCs and GAHT, cannot directly be generalized to the effects of endogenous sex hormones. This is due to three important variables: potency and selectivity of exogenous sex hormones, timeframe in which sex hormones are administered, and possible differences in sensitivity of brain tissue to endogenous and exogenous hormones. In the studies on OCs, there are examples of differences in potency and selectivity of exogenous sex hormones compared to endogenous sex hormones. As mentioned in Chapter 1, forms of estradiol in OCs (commonly ethinylestradiol) are more potent than bioidentical estradiol (Jeyakumar et al., 2011), and the progestins in OCs can also affect glucocorticoid and androgen receptors (Kuhl, 2005), and possibly cortisol dynamics, as shown in Chapter 4. In the studies on GAHT, the timeframe of hormone fluctuations cannot directly be generalized to endogenous hormone status. As shown in Figure 9.2 in Chapter 1, the endogenous hormone levels of naturally cycling females follow a slow and predictable fluctuation over about 28 days, whereas endogenous hormone levels of males follow a 24-hour rhythm (Rose et al., 1972). In contrast, hormone levels in GAHT users strongly depend on the form of GAHT that is used. In masculinizing hormone users, daily administration of testosterone gel is likely to result in more stable dayto-day hormone levels, mirroring fluctuations in cisgender males, whereas testosterone injections can result in testosterone fluctuations over multiple weeks (Madsen et al., 2022). In feminizing hormone users, androgens are most likely constantly suppressed, and levels of estradiol likely fluctuate daily, in the case of oral estradiol use, or over the course of 2 to 3 days, in the case of estradiol patch use (Scott et al., 1991). In the studies in this thesis, we did not conduct stratified analyses for different administration routes of GAHT, but this could be a relevant point for future studies.
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