Clustering of > 145,000 symptom logs reveals distinct pre, peri, and menopausal phenotypes

The transition to menopause is associated with disappearance of menstrual cycle symptoms and emergence of vasomotor symptoms. Although menopausal women report a variety of additional symptoms, it remains unclear which emerge prior to menopause, which occur in predictable clusters, how clusters change across the menopausal transition, or if distinct phenotypes are present within each life stage. We present an analysis of symptoms in premenopausal to menopausal women using the MenoLife app, which includes 4789 individuals (23% premenopausal, 29% perimenopausal, 48% menopausal) and 147,501 symptom logs (19% premenopausal, 39% perimenopausal, 42% menopausal). Clusters generated from logs of 45 different symptoms were assessed for similarities across methods: hierarchical clustering analysis (HCA), K-Means clustering of principal components of symptom reports, and binomial network analysis. Participants were further evaluated based on menstrual cycle regularity or natural versus medically induced menopause. Menstrual cycle-associated symptoms (e.g., cramps, breast swelling), digestive, mood, and integumentary symptoms were characteristic of premenopause. Vasomotor symptoms, pain, mood, and cognitive symptoms were characteristic of menopause. Perimenopausal women exhibited both menstrual cycle-associated and vasomotor symptoms. Subpopulations across life stages presented with additional correlated mood and cognitive, integumentary, digestive, nervous, or sexual complaints. Symptoms also differed among women depending on the reported regularity of their menstrual cycles or the way in which they entered menopause. Notably, we identified a set of symptoms that were very common across life stages: fatigue, headache, anxiety, and brain fog. Finally, we identified a lack of predictive power of hot flashes for any symptom except night sweats. Together, premenopausal women exhibit menstrual cycle-associated symptoms and menopausal women reported vasomotor symptoms, while perimenopausal women report both. All report high rates of fatigue, headache, anxiety, and brain fog. Limiting focus of menopausal treatment to vasomotor symptoms, or to premenstrual syndrome in premenopausal women, neglects a large proportion of overall symptom burden. Future interventions targeting mood and cognition, digestion, and the integumentary system are needed across stages of female reproductive life.