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

Molecular Psychiatry volume 30, pages 251–262 (2025)Cite this article

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Abstract

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.

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Fig. 1: Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle (DASH-MC).

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Notes

  1. This includes any cisgender women, transgender men, and AFAB nonbinary individuals who ovulate (i.e., excluding those who are pre-menarche, pregnant or breastfeeding, post-menopausal, using medications such as oral contraceptives and other hormonal therapies that suppress ovulation, have undergone bilateral oophorectomy)[1].

  2. This estimate reflects the largest study of confirmed diagnoses using prospective daily ratings in a representative community sample; while initially estimated at 1.3% using DSM-IV-TR criteria, estimated rates from this data that reflect the current DSM-5 PMDD diagnostic criteria (with optional impairment) are 5.5% [3]; see [5] for review.

  3. Of note, a number of neuroimaging studies have also found stable (non-phase-specific) differences between participants with PMDD and controls, e.g. [48], [49], [50]; see [51] for a recent review on neuroimaging of PMDD broadly. While it is possible that these stable neural differences relate to vulnerability to hormone sensitivity dimensions, we focus primarily on neural changes across the cycle that may underlie dimension-specific affective and behavioral symptoms.

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Acknowledgements

The authors thank the many patients, study participants, and advocates (especially the International Association for Premenstrual Disorders) whose invaluable contributions have allowed us to develop this framework. The authors are supported by the following funding: National Institute of Mental Health R01 MH126940 (JRP, TEM), K23 MH112889 (JRP), RF1MH120843 (TEM), R01 MH122446 (TEM), T32 MH019927 (AS), R01 MH119119 (MMM); National Institute on Alcohol Abuse and Alcoholism T32 AA027488 (AGE); German Research Foundation (DFG) SCHM 3732/1-1, 470147139 (KS).

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Authors and Affiliations

  1. Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA

    Jessica R. Peters & Allison Stumper

  2. Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA

    Katja M. Schmalenberger & Tory A. Eisenlohr-Moul

  3. Department of Psychology, University of Kentucky, Lexington, KY, USA

    Ashley G. Eng & Michelle M. Martel

  4. Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Ashley G. Eng

  5. Department of Psychiatry, Rhode Island Hospital, Providence, RI, USA

    Allison Stumper

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  1. Jessica R. Peters
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  2. Katja M. Schmalenberger
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  3. Ashley G. Eng
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  4. Allison Stumper
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  6. Tory A. Eisenlohr-Moul
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Contributions

JRP and TAEM co-developed the DASH-MC theoretical framework and drafted the majority of manuscript. KMS assisted in developing and refining the framework, and KMS, AS, AEG, and MMM assisted with manuscript drafting, editing, and revisions.

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Correspondence to Jessica R. Peters.

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Peters, J.R., Schmalenberger, K.M., Eng, A.G. et al. Dimensional Affective Sensitivity to Hormones across the Menstrual Cycle (DASH-MC): A transdiagnostic framework for ovarian steroid influences on psychopathology. Mol Psychiatry 30, 251–262 (2025). https://doi.org/10.1038/s41380-024-02693-4

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