Overview
Male and female cells maintain distinct redox baselines. Estradiol promotes NRF2 activation and sustains a low oxidative setpoint. Testosterone often raises metabolic throughput and increases ROS when antioxidant systems do not keep pace. This difference extends beyond reproduction to energy metabolism, vascular health, and vulnerability to oxidative disease. Within our stress, glutamate, and ROS model, the female NRF2 advantage provides greater protection against excitotoxic and mitochondrial stress. The male profile favors higher energy output but with an increased oxidative cost.
Estrogenic NRF2 activation
Estradiol signaling through ERα and ERβ stabilizes NRF2 and promotes its movement into the nucleus. This enhances transcription of antioxidant genes such as HO-1, NQO1, SOD2, and GPX4. The result is improved mitochondrial function and reduced lipid peroxidation. In myocardial cells, 17β-estradiol increased NRF2 translocation and upregulated antioxidant enzymes, lowering ROS during hypoxia and reoxygenation (Yu et al., 2012). In vascular endothelium, estradiol increases SOD2 through an ER and Sp1 interaction that protects mitochondria and restores vasorelaxation under oxidative stress (Liu et al., 2014). Estrogen deficiency also induces endothelial ferroptosis by suppressing the NRF2 and GPX4 pathway. Estrogen replacement restores NRF2 signaling and prevents lipid peroxidation (Lv et al., 2023). These findings show that estrogen maintains a continuous feedback loop between NRF2 activity and mitochondrial redox stability.
Androgen driven oxidation
Testosterone and DHT support anabolic growth and metabolic drive but often elevate oxidative pressure when NRF2 activity is insufficient. In high-fat-fed male mice, testosterone reduced NRF2 expression and antioxidant capacity, causing vascular dysfunction. Castration or AR blockade restored NRF2 signaling and normalized ROS levels (Costa et al., 2022). In human endothelial cultures, testosterone and DHT increased eNOS and SOD activity but reduced catalase. The overall outcome was higher ROS and an oxidized setpoint that normalized after AR inhibition (Koukoulis et al., 2022). These results suggest that androgen signaling is not always pro-oxidant, but its metabolic stimulation can overwhelm antioxidant systems when NRF2 activation does not scale accordingly.
Comparative redox physiology
Female cells typically express more NRF2 targets and generate less ROS across tissues. Endothelial and cardiac models show that female cells maintain stronger SOD and GPX4 activity, while male cells exhibit greater NADPH oxidase activity and higher superoxide levels. These sex-linked traits appear early in development and persist through adulthood. They create an intrinsic buffer against oxidative stress until estrogen levels decline. The loss of this protection after menopause matches the rise in cardiovascular and neurodegenerative diseases driven by oxidative stress.
Implications for disease in our model
In our framework, sex differences in NRF2 tone alter how cells handle stress-induced glutamatergic and calcium load. Cells under androgen tone begin with a higher oxidative baseline. When stress activates the HPA axis and increases glutamate release, these cells reach mitochondrial failure sooner. This produces lipid peroxidation, ferroptosis, and neuron loss. Estrogenic systems, through sustained NRF2 activation, delay this threshold by maintaining antioxidant defenses and calcium buffering capacity. This mechanism may contribute to the greater frequency of ALS and other oxidative or excitotoxic diseases in males.
Therapeutically, the goal is to reduce this gap. Compounds that enhance NRF2 activity, including dietary activators or drugs that stabilize the protein, can shift the male redox profile toward the female protective state. Reinforcing GPX4, HO-1, and SOD2 expression is especially important. Strategies that limit NADPH oxidase and improve mitochondrial antioxidant efficiency can also counteract testosterone’s oxidative drive. In women, particularly after menopause, selective ER agonists or NRF2 activators can compensate for the loss of estrogenic redox control.