Leydig Cell Steroidogenesis and Oxidative Stress Mechanisms

Leydig cells, located in the interstitial compartment of the testis, are the principal site of androgen biosynthesis. Steroidogenesis in these cells begins with cholesterol uptake and transport into mitochondria, a step mediated by the steroidogenic acute regulatory protein (StAR), followed by a series of enzyme-catalysed conversions to produce testosterone. During this process, reactive oxygen species (ROS) are generated as by-products of mitochondrial activity and enzymatic reactions. Under physiological conditions, Leydig cells maintain redox balance through endogenous antioxidant systems, including superoxide dismutase and glutathione peroxidase. However, when ROS production exceeds antioxidant defences, oxidative stress ensues, leading to impaired mitochondrial function, downregulation of StAR and P450scc, lipid peroxidation and activation of stress-responsive kinases. Chronic oxidative stress and associated inflammatory signalling—particularly via p38 MAPK and NF-κB pathways—further suppress steroidogenic enzyme expression, culminating in reduced testosterone output and compromised male reproductive health. Understanding the interplay between redox regulation and steroidogenic machinery is crucial for devising interventions to preserve endocrine function in ageing and disease.

Research from Nature Portfolio

Recent investigations into age-related testicular dysfunction have revealed that increased ROS and pro-inflammatory cytokines activate p38 MAPK→COX2 and NF-κB→COX2 signalling cascades in Leydig cells, directly inhibiting StAR and P450scc expression. Experimental blockade of p38 MAPK or NF-κB in isolated Leydig cell preparations restored steroidogenic enzyme levels and testosterone synthesis, highlighting stress-kinase inhibition as a promising strategy to ameliorate age-associated hypogonadism and to safeguard androgen production against chronic oxidative insults.

Leydig Cell Steroidogenesis and Oxidative Stress Mechanisms publication trend

The graph below shows the total number of articles in leydig cell steroidogenesis and oxidative stress mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Steroidogenesis: Series of enzymatic reactions converting cholesterol into steroid hormones.

Leydig cell: Testicular interstitial cell responsible for androgen synthesis.

Reactive Oxygen Species (ROS): Highly reactive molecules derived from oxygen metabolism.

Oxidative stress: Pathological state arising from excess ROS over antioxidant defences.

Steroidogenic acute regulatory protein (StAR): Mitochondrial protein facilitating cholesterol import.

p38 MAPK signalling pathway: Stress-activated kinase cascade regulating inflammation and apoptosis.

NF-κB signalling pathway: Transcription factor network controlling immune and inflammatory gene expression.

References

1. A Review on the Impact of Oxidative Stress and Medicinal Plants on Leydig Cells. Antioxidants (2023).
2. Prevention of Male Late-Onset Hypogonadism by Natural Polyphenolic Antioxidants. Nutrients (2024).
3. The roles of p38 MAPK → COX2 and NF-κB → COX2 signal pathways in age-related testosterone reduction. Scientific Reports (2019).
4. Anthocyanins Prevent AAPH-Induced Steroidogenesis Disorder in Leydig Cells by Counteracting Oxidative Stress and StAR Abnormal Expression in a Structure-Dependent Manner. Antioxidants (2023).