The effect of genetic variation in estrogen transportation and metabolism on the severity of menopause symptoms: A study from the RIGHT 10K cohort

Objective: The severity of menopause-related symptoms varies considerably among women. The determinants of this variation are incompletely understood. The aim of this study was to assess the association between genetic variation in estrogen metabolism and transport pathways and the severity of menopause symptoms. Methods: This was a cross-sectional study of 60 peri- and postmenopausal women in the Mayo Clinic RIGHT study (which involved sequencing of genes involved in drug metabolism and transport), who had also been evaluated in the Women's Health Clinic at Mayo Clinic in Rochester, MN. All participants completed the Menopause Rating Scale (MRS) for assessment of menopause symptoms, including hot flashes. The association between severity of menopause symptoms and the variation in genes encoding 8 enzymes and transporters involved in estrogen metabolism was evaluated. Results: Lower CYP3A4 activity and higher COMT activity were associated with lower severity of somatic menopause symptoms (p = 0.04 and 0.06, respectively). These associations did not persist after adjustment for hormone therapy use. No differences in MRS scores or hot flash severity were noted among other genetic variant groups. Age at natural menopause was not affected by variations in the genes studied. Conclusion: The current study did not show an association between genetic variation in estrogen metabolism and transport pathways and the severity of menopause symptoms. Further studies with larger sample sizes may be required to understand this potentially complex association.