Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle (DASH-MC): A transdiagnostic framework for ovarian steroid influences on psychopathology

• Published in: Molecular psychiatry 2025, Vol.30 (1), p.251-262
• Main Authors: Peters, Jessica R., Schmalenberger, Katja M., Eng, Ashley G., Stumper, Allison, Martel, Michelle M., Eisenlohr-Moul, Tory A.
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; 631/378; 631/477; 692/699/476; Affect - physiology; Affective disorders; Behavioral Sciences; Biological Psychology; Brain - metabolism; Brain - physiopathology; Emotional behavior; Emotions; Estradiol - metabolism; Female; Hormones; Humans; Medicine; Medicine & Public Health; Menstrual cycle; Menstrual Cycle - physiology; Menstrual Cycle - psychology; Menstruation; Mental disorders; Neurosciences; Ovaries; Ovary - metabolism; Pharmacotherapy; Pregnanolone; Premenstrual Dysphoric Disorder - metabolism; Premenstrual Dysphoric Disorder - physiopathology; Progesterone; Progesterone - metabolism; Psychiatry; Psychopathology; Psychopathology - methods; Review Article; Steroids; Substance use
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-024-02693-4

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 may be most readily identified when they occur exclusively in relation to the menstrual cycle, as in DSM-5 premenstrual dysphoric disorder, symptom changes of similar magnitude occur in a larger proportion of people with ongoing psychiatric disorders. Studies investigating cyclical regulation of brain and behavior often produce inconsistent 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 atypical 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, which include (1) luteal-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 more precise research on ovarian steroid regulation of psychopathology, including further mechanistic research, diagnostic refinement, and precision psychiatry treatment development. Additionally, given the high rates of hormone sensitivity across affective disorders, the DASH-MC may guide broader insights into the complex neurobiological vulnerabilities driving female-biased affective risk, as well as potential triggers and mechanisms of affective state change in psychiatric disorders.