117 Summary and General Discussion This is what I tested in the subsequent testosterone administration study (chapter 4). The results from this testosterone administration study indicated that testosterone versus placebo administration resulted in a more reactive fear level pattern during exposure (i.e., steeper increase followed by a steeper decrease in fear levels). As shown in chapter 4, this effect was partly depended on endogenous baseline testosterone levels. This suggests that testosterone administration can enhance important mechanisms of exposure. In-session fear reactivity may be a relevant indicator of whether the individual is engaged in the exposure and faces the threat maximally, as this would lead to initial increase in fear, which should reduce over time. This is what we observed during exposure and what was amplified after testosterone administration over the whole group and in individuals with high baseline in particular (see below). However, unlike the endogenous reactivity study in chapter 3, the pharmacological testosterone-activation in chapter 4 was only linked to in-session fear and did not induce significant reduction in symptom severity post-exposure. Of course, it is hard to compare those two studies for several reasons: The endogenous testosterone reactivity study (chapter 3) had a larger sample size, mixed sex, and differed in terms of the number and timing of the speeches. We cannot exclude that the samples of chapter 3 and 4 differed in terms of baseline testosterone, avoidance tendencies and individual differences in HPG-axis responsiveness (for example, due to individual differences in sensitivity of the androgen receptor (AR) (Geniole & Carré, 2018; Hogervorst et al., 2005). Unlike in chapter 3, it was not possible to assess endogenous testosterone reactivity in preparation to the exposure in the study described in chapter 4, since the exposure preparation took place after testosterone/placebo administration. Apart from the contextual differences between the endogenous and exogenous testosterone challenges, there are two additional factors that may explain these differential effects for social anxiety symptoms. First, we cannot exclude the possibility that even single-dose administration of testosterone may affect the HPG-axis feedback loop (inhibition of hypothalamus and pituitary by testosterone, see also chapter 2, page 28). Such effect has been demonstrated after repeated testosterone administration. For instance, Khodamoradi et al., (2021) describe in a review that repeated testosterone administration reduced endogenous testosterone production in testosterone replacement therapy for hypogonadal men. However, this review included different methods of testosterone administration that all required repeated doses, which brings me to the second factor: It remains the question whether the administration of a single dose testosterone is optimal to achieve effects that can be obtained by challenging the endogenous system, or whether one needs multiple session enhancement to achieve similar effects. I will address this point further in my suggestions for future research. 6
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