The Role of Estradiol in Oxidative Stress in Health and Cystathionine ß‐Synthase Deficiency: A Mechanistic Model

Oxidative stress occurs when there is an imbalance between oxidants and antioxidants, leading to the accumulation of reactive oxygen species (ROS). Excessive ROS can damage lipids, proteins, and DNA, contributing to cellular dysfunction and disease. Interestingly, premenopausal females tend to have lower levels of oxidative stress and higher concentrations of certain antioxidants, such as glutathione (GSH), compared to males and postmenopausal females. These differences point to the important role of sex hormones in regulating oxidative stress and its effects on the body. Yet, clinical and experimental studies report conflicting effects of estradiol, particularly across the menstrual cycle in premenopausal females and in estradiol supplementation in postmenopausal females. Here, we present a mechanistic mathematical model of hydrogen peroxide (H2O2), a key ROS, that explicitly incorporates estradiol and progesterone regulation of key enzymes. Using this model, we elucidate the mechanisms underlying females' lower oxidative stress and provide an explanation for the seemingly contradictory clinical observations at both steady state and during the menstrual cycle. We further apply the model to examine sex differences in cystathionine β-synthase deficiency, explaining the attenuation of sex differences in key metabolites in the pathway. By connecting clinical observations with mathematical modeling, this work provides insights into the underlying mechanisms and paves the way for sex- and menopausal status-specific approaches in medicine and drug development.