Menstrual Cycle and Progesterone‐to‐Estradiol Ratio Associated With Loss of Control and Craving in Alcohol Use Disorder: A Sex‐Segregating Longitudinal Study

ABSTRACT Alcohol use disorder (AUD) causes a high burden worldwide. The menstrual cycle and the progesterone‐to‐estradiol ratio are related to alcohol consumption in females and males with AUD. However, the underlying mechanisms triggering problem drinking in everyday life remain to be determined. This longitudinal multicentre study analysed associations of menstrual cycle phases (1316 of 70 naturally cycling females with AUD) and progesterone‐to‐estradiol ratios (quantified in 567 blood samples of 256 males with AUD) with real‐world 12‐month data on loss of control over alcohol consumption and craving measured via 17296 and 10482 smartphone entries using general linear mixed models. Females with severe AUD stated less frequent loss of control in the midluteal and late luteal phases characterized by high progesterone‐to‐estradiol ratios compared to the follicular phase. In the total female sample, craving was lower during the late luteal and menstrual phases compared to the follicular phase. Similarly, males with moderate and severe AUD reported less frequent loss of control in phases of a high progesterone‐to‐estradiol ratio. The identified biobehavioural interplay suggests that increasing progesterone relative to estradiol may assist individuals with AUD in re‐establishing control over alcohol consumption and reducing craving. When employed in conjunction with customized just‐in‐time adaptive digital interventions, this approach has the potential to evolve into a novel precision medicine strategy for AUD. The findings also underscore the necessity for the development of treatments tailored to the phases of the menstrual cycle, thereby addressing the critical underrepresentation of females in AUD research.