Clustering of >145,000 Symptom Logs Reveals Distinct Pre, Peri, and Post Menopausal Phenotypes

Background and Objectives The transition to menopause is commonly associated with disappearance of menstrual cycle symptoms and emergence of vasomotor symptoms. Although menopausal women report a variety of mood, digestive, and pain symptoms, it remains unclear what symptoms emerge prior to menopause, if symptoms occur in predictable clusters, how these clusters change from across the premenopause-perimenopause-menopause transition, or if distinct phenotypes are present within each life stage. Methods We present analysis of self-reported symptom presentation in premenopausal to menopausal women using the MenoLife app, which includes 4,789 (n=1,115(23%) premenopausal, n=1,388(29%) perimenopausal, n=2,286(48%) menopausal) individuals and 147,501 (n=27,371(19%) premenopausal, n=57,964(39%) perimenopausal, n=61,806(42%) menopausal) symptom logs. 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 reporting, and binomial network analysis. Participants were further evaluated based on menstrual cycle regularity or type of menopause. Results Menstrual cycle-associated symptoms (e.g., cramps, breast swelling), digestive, mood, and integumentary symptoms were characteristic of premenopausal women. 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 symptoms, integumentary complaints, digestive, nervous, or sexual symptoms. 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. We consistently identified the lack of predictive power of hot flashes for other symptoms except night sweats. Conclusions: Together, premenopausal women exhibit menstrual cycle-associated symptoms and menopausal women reported vasomotor symptoms, perimenopausal women report both; and 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 research and interventions targeting mood and cognitive, digestive, and integumentary symptoms are needed across stages of female reproductive life.