Background: The risk of developing a depressive disorder is twice as high for women as for men. This sex disparity emerges in puberty and ends at menopause, a time frame during which most women have a menstrual cycle. This suggests that the menstrual cycle and fluctuating ovarian hormones might contribute to the development of depressive disorders. In turn, ovarian hormones interact closely with one of the two major physiological stress regulators, the hypothalamus-pituitary-adrenal (HPA) -axis. Therefore, the interaction between all three entities - the menstrual cycle, depression, and stress markers – is close at hand and object of this dissertation. Methods: Firstly, the relationship between the menstrual cycle and depressive symptoms is explored by investigating if and how depressive symptoms change across the menstrual cycle in participants with and without a depressive disorder (study 1) and whether menstrual cycle irregularity, specifically irregularity in length (study 2) and anovulation (study 3), interacts with depressive symptoms. This was investigated in multiple samples (adults and adolescents) through longitudinal, smartphone-based ambulatory assessments. Secondly, possible differences in biological stress marker concentrations between menstrual cycle phases were investigated. Thereby, two meta-analyses (study 4 and 5) compared cortisol as a marker for basal HPA axis activity (study 4) and its reactivity in response to acute stressors (study 5) between cycle phases. Lastly, perceived stress was investigated as a moderator of the association between ovarian hormone fluctuations and depressive symptom changes in a sample of peripubertal females using weekly measures of stress, depressive symptoms, and hormone concentrations (study 6). Results: The results indicated that depressive symptoms fluctuate in some hormone sensitive individuals, with varying intensities and patterns (peri-menstrual or mid-cycle increase of symptoms, study 1). This cycle-related fluctuation differed between single depressive symptoms, highlighting the importance of a symptom-based approach (study 1-4). Furthermore, higher depressive symptoms were observed in irregular menstrual cycles with respect to cycle length (study 2) and anovulation (study 3). When investigating differences in biological stress markers across the menstrual cycle, meta-analytic comparisons revealed small-sized effects of higher basal cortisol concentrations (study 5) and lower cortisol reactivity (study 6) in response to stressors in the follicular phase compared to the luteal phase. Finally, subjective stress moderated the direction of the association between hormone fluctuations and depressive symptoms. Specifically, in a high-stress context, hormone surges were linked to symptom increases whereas in a low-stress context, hormone withdrawals were linked to symptom increases. Discussion: This dissertation presented a collection of interconnected studies that highlight that hormone fluctuations across the menstrual cycle are interconnected with stress and depressive symptoms. Possible biological explanations include a differential sensitivity of GABAA-receptors to allopregnanolone, but this needs further investigations. Implications for future research involve the improvement of screening tools for individuals sensitive to hormone fluctuations and the development of treatment options for premenstrual exacerbation of depression. The generalizability of the results might be limited, as only one cycle per individual was investigated for relatively small samples in the primary studies. This was compensated by highly frequent assessments throughout the cycle and meta-analyses to increase power. Further strengths of this dissertation include a variety of investigated age groups, samples from multiple countries, and a multimethodological approach across the six studies, including primary studies using biological markers and psychological assessments, meta-analyses, and guidelines for future studies. Additionally, the studies were preregistered, analyses scripts were made openly accessible, and existing guidelines were adhered to. In conclusion, it is essential to include the menstrual cycle and ovarian hormone fluctuations and their interconnection to stress in future research on depression. Identifying female-specific risk factors of depression is crucial to provide individualized and more effective treatment options and to improve the overall understanding of stress-related mental disorders.
