Background: Alcohol use disorder (AUD) is a critical public health issue with sex-specific characteristics and the need for a better mechanistic understanding. Initial evidence suggests that progesterone can reduce alcohol intake, while estradiol leads to an increase. However, we lack knowledge about how progesterone relative to estradiol influences alcohol use patterns in females and males with AUD. Methods: This multicenter within-subject study analyzed data on real-life alcohol use (21,438 intensively-sampled smartphone entries), menstrual cycle, and serum progesterone/estradiol ratios (677 blood samples) gathered during a 12-month follow-up in 74 naturally cycling females and 285 males with AUD (mean age: 29.7 and 37.8 years, respectively; data collection: 2020-2022). We used multilevel modelling to identify changes in alcohol use and progesterone/estradiol ratios across the menstrual cycle in females and associations between progesterone/estradiol ratios and alcohol use in males. Results: During the late luteal phase, females showed 0.6- to 0.8-fold lower (predicted) probabilities of binge drinking and 2.8- to 5.6-fold higher mean progesterone/estradiol ratios compared to the menstrual, follicular, and ovulatory phases. Similarly, in males, an increase of 10 units in the progesterone/estradiol ratio was related to 8 and 9% lower probabilities of binge drinking and any alcohol use, respectively. Conclusions: Based on ecologically valid results, this study reveals that higher progesterone/estradiol ratios can protect against problematic alcohol use in females and males with AUD. Therefore, the progesterone/estradiol ratio is a promising treatment target. Translated into clinical practice, our results also indicate that females with AUD may benefit from menstrual cycle phase-tailored treatments.

Ulrich W. Ebner-Priemer is a consultant for Boehringer Ingelheim.

The project was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Project-ID 402170461 - TRR265 (38). C.M. is a member of the research training group 2162 'Neurodevelopment and Vulnerability of the Central Nervous System' of the DFG (GRK2162 / 270949263). The funders had no role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript.

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The project was approved by the local ethics committees of Charite - Universitaetsmedizin Berlin, Technical University Dresden, and Heidelberg University.

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