Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle (DASH-MC): A Transdiagnostic Framework for Ovarian Steroid Influences on Psychopathology

Fluctuations in progesterone (P4) and estradiol (E2) across the menstrual cycle can exert direct effects on biological systems implicated in neuropsychiatric disorders and represent a key biological source of variability in affective, cognitive, and behavioral disorders. Although these cyclical symptoms are most readily identified when they occur exclusively in relation to the cycle, as in DSM-5 premenstrual dysphoric disorder, changes of similar magnitude occur in a larger proportion of patients with ongoing psychiatric disorders. Studies investigating cyclical regulation of brain and behavior often produce inconsistent or conflicting results, which may be attributed to a lack of focus on specific hormonal events and individual differences in related sensitivities. We propose a transdiagnostic Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle (DASH-MC) framework, postulating that altered neural responses to several key hormonal events provoke specific temporal patterns of affective and behavioral change across the menstrual cycle. We review prospective and experimental evidence providing initial support for these dimensions. These patterns include 1) midluteal-onset negative affect caused by a sensitivity to E2 or P4 surges (mediated by neuroactive metabolites such as allopregnanolone), typified by irritability and hyperarousal; 2) perimenstrual-onset negative affect caused by a sensitivity to low or falling E2, typified by low mood and cognitive dysfunction; and 3) preovulatory-onset positive affect dysregulation caused by a sensitivity to E2 surges, typified by harmful substance use and other risky reward-seeking. This multidimensional, transdiagnostic framework for hormone sensitivity can inform a more precise generation of research on ovarian steroid regulation of psychopathology, including further mechanistic research, comparisons across reproductive transitions, diagnostic refinement, and precision psychiatry treatment development. Additionally, given the high rates of hormone sensitivity across affective disorders, the DASH-MC may guide the generation of broader insights into the complex neurobiological vulnerabilities driving female-biased affective risk, as well as the general mechanisms of affective state change in psychiatric disorders.