Chapter 9 262 It is also possible that tissue-specific effects of GAHT in the brains of transgender persons might differ from their cisgender counterparts. As explained in Chapter 6, rodent studies provide evidence for the organizational effects of sex hormones, meaning sex hormone exposure during development can affect the brain's sensitivity to the effects of sex hormones later in life (Barth et al., 2015). This could would mean that someone who starts masculinizing GAHT but who has been exposed to high levels of estrogen and progesterone during development and adolescence, could have a different sex hormone sensitivity to testosterone compared to a cisgender man. Vice versa, the brain of someone who starts feminizing GAHT but was exposed to high levels of testosterone during development and adolescence could have a different sensitivity to estradiol and progesterone compared to the brain of a cisgender woman. This could imply that the neurobiological effects of GAHT in transgender people who start GAHT might not be generalizable to the effects of the same hormones in cisgender people. 2.2. Sex hormones and depression There is a number of explanations for the possible effects of sex hormones on mood and depression. This section will focus on three of these mechanisms: stress and the HPA axis, emotional processing, and neurotransmitters and neurosteroids. These mechanisms are then summarized in Figure 9.2. Stress and HPA axis dynamics The hypothalamic-pituitary-adrenal (HPA) axis is an important endocrine system regulating the diurnal and responsive production of cortisol, and disrupted cortisol dynamics (e.g., lower cortisol responses to stress, lower cortisol awakening response, higher evening-time cortisol) are associated with poorer mental and physical health (Adam et al., 2017). There is a bidirectional relationship between the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis: endogenous testosterone and estradiol can moderate HPA axis activity, and vice versa, increased HPA axis activity can inhibit testosterone and estradiol release (Toufexis et al., 2014). In OC users, studies find higher circulating cortisol levels, higher glucocorticoid signaling (Hertel et al., 2017), and lower cortisol responses
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