Testosterone acts as a redox amplifier, not a redox protector. Mechanistic studies show that androgen signaling increases reactive oxygen species (ROS) through NADPH oxidase (NOX1 and NOX2), CYP4A-driven 20-HETE metabolism, xanthine oxidase, and mitochondrial activation (Tostes et al., 2016).
In testosterone-deficient states, a short NRF2-linked antioxidant response can appear at re-exposure, but it is brief and reflects a stress reaction to rising ROS. As androgen signaling continues, ROS generation becomes dominant, antioxidant systems weaken, and vascular, neural, and mitochondrial injury follow. Taken together, these studies show that testosterone drives oxidative throughput in a dose and duration dependent manner.
Mechanistic Synthesis
1. Testosterone chronically elevates ROS.
Androgen exposure persistently increases oxidative load through NADPH oxidase and CYP4A/20-HETE pathways, leading to endothelial dysfunction, hypertension, and lipid peroxidation (Tostes et al., 2016). This oxidative output is an intrinsic property of androgen metabolism, not a pharmacologic artifact.
2. Vascular and renal mechanisms confirm oxidative amplification.
Acute testosterone briefly relaxes vessels by modulating Ca²⁺ and K⁺ channels, but chronic exposure activates renin–angiotensin signaling and CYP4A, increasing NADPH oxidase activity and superoxide generation (Kienitz & Quinkler, 2008).
In vivo, 20-HETE blockade reversed androgen-induced ROS and hypertension, proving that DHT elevates blood pressure through the CYP4A–NOX axis (Singh et al., 2007).
These findings link androgen signaling directly to vascular oxidative stress and endothelial dysfunction.
3. Testosterone suppresses NRF2 and weakens glutathione defense.
Testosterone downregulates NRF2 nuclear accumulation and antioxidant enzyme expression while increasing NOX1-dependent ROS. NRF2 activation with bardoxolone or NOX1 inhibition restored vascular relaxation (Costa et al., 2022).
This shows that testosterone’s chronic action reduces glutathione recycling capacity and accelerates oxidative stress in vascular endothelium.
4. Transcriptional control shifts toward NRF1 and AR dominance.
DHT decreases NRF2 and increases p65-NRF1, which cooperates with the androgen receptor (AR) to enhance its transcriptional activity (Schultz et al., 2014).
This shift replaces the antioxidant function of NRF2 with an oxidative transcription program that sustains AR signaling, forming a positive feedback loop that maintains high oxidative tone.
5. Sustained oxidative signaling converges with vascular aging.
Chronic ROS exposure impairs NRF2 signaling, promotes senescence, and weakens endothelial repair, driving loss of vascular elasticity (Ungvari et al., 2019).
Long-term androgen load accelerates this process, reproducing the same molecular pattern of aging-related vascular decline.
Integration into the Model
In the stress–glutamate–ROS framework, testosterone functions as an endocrine amplifier that increases the excitatory and oxidative load across multiple systems.
- Initial phase – mild ROS activates NRF2 and upregulates temporary antioxidant genes.
- Progressive phase – chronic AR activation drives CYP4A and NOX, pushing sustained ROS and lipid peroxidation.
- Collapse phase – NRF2 suppression and NRF1 dominance shut down antioxidant transcription, leading to glutathione depletion and mitochondrial overload.
- Degenerative phase – redox imbalance spreads through vascular and neural circuits, reinforcing excitotoxic calcium signaling and chronic inflammation.
Summary
Testosterone amplifies oxidative throughput over time. The brief NRF2 response observed early is transient and progresses into prolonged oxidative signaling as androgen exposure continues. The long-term pattern shows persistent ROS generation, NRF2 suppression, and glutathione depletion. This mechanism links androgen activity to endothelial dysfunction, mitochondrial stress, and the oxidative cascade underlying aging and excitatory degeneration.