General discussion 271 depressive disorder symptoms. These biological differences could result in different associations between depression and sleep. Based on these and other studies, researchers have hypothesized that sex hormone-related depression might be a separate phenotype, characterized by strong adverse mood reactions to changes in sex hormones and allopregnanolone (Schiller et al., 2016; Schweizer-Schubert et al., 2021). However, thus far there are very few studies comparing symptomatology and phenotypes of hormone-associated depressive symptoms with major depression, so these hypotheses are thus far not supported by a large basis of empirical evidence. 3. Strengths and limitations 3.1. Observational studies on hormone use One important methodological choice in this thesis was to conduct observational studies with participants using commonly used sex hormones, instead of studying experimental sex hormone interventions that are less common in clinical practice. In previous sex hormone intervention studies, such as Ben Dor et al. (2013) and Frokjaer (2020), the effects of full endogenous hormone suppression through GnRH-analogues were studied. Others examined the effects of both hormone suppression and consecutive add-back (Schiller et al., 2022). These studies used randomized setups and placebo conditions, which meant that the authors could attribute causal effects to their sex hormone interventions. The resulting findings provided important new insights into sex hormone effects. However, the generalizability of these hormone intervention studies to real-life settings is limited, since these hormones are not commonly used in daily practice. In contrast, the approach taken in this thesis has improved the ecological validity, since all exogenous hormone forms which were studied are currently used in clinical practice. Study results can therefore be generalized to real-life hormone use settings, contributing to better-informed decisionmaking for hormone users in real life. However, this also implies that we cannot attribute direct causal effects to either OC or GAHT use, due to a lack of control groups or placebo conditions and this is an important limitation that should be taken into account.
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