Declining Leydig cell steroidogenesis is shaped by environmental endocrine-disrupting chemicals, metabolic dysfunction, and testicular aging, which converge on impaired organelle quality control, oxidative stress, and senescence-associated remodeling to compromise androgen production and male reproductive health.
Key Findings
Results
Environmental endocrine-disrupting chemicals (EDCs) and metabolic stress converge on impaired organelle quality control and altered redox signaling in Leydig cells.
Toxicant exposure and metabolic stress both lead to downstream loss of steroidogenic capacity
In some settings, these stressors promote premature senescence within the Leydig compartment
Key cellular mechanisms include oxidative stress, endoplasmic reticulum stress, mitochondrial dysregulation, apoptosis, disrupted autophagy and mitophagy, and senescence-associated remodeling
Results
Aging reshapes the testicular microenvironment through inflammatory shifts and biomechanical remodeling that may erode stem and progenitor Leydig cell homeostasis.
Age-associated changes constrain regenerative potential of the Leydig compartment
Inflammatory shifts and biomechanical remodeling are identified as key age-dependent processes
These changes affect the interstitial niche that supports spermatogenesis
Results
Single-cell transcriptomic atlases resolve Leydig cell heterogeneity and identify subsets that appear more vulnerable to stress and aging.
Single-cell transcriptomic atlases nominate specific Leydig cell subsets as more vulnerable to stress and aging
These atlases map age-dependent rewiring of interstitial cell-to-cell communication
Communication networks affected include interactions with Sertoli cells, peritubular myoid cells, vascular cells, and immune cells
Background
Declining Leydig cell steroidogenesis contributes to late-onset hypogonadism and age-associated impairment of male reproductive health beyond chronological aging alone.
Determinants of dysfunction extend beyond chronological aging
Both environmental EDCs and obesity/metabolic dysfunction are identified as contributors
The review integrates evidence across multiple model systems and translational contexts
Discussion
Most mechanistic insights derive from rodent in vivo studies and in vitro platforms, and validation in human tissue and clinical cohorts remains uneven.
In vitro platforms include immortalized Leydig cell lines
The authors note that translation to human tissue and human clinical cohorts is uneven
This represents a key limitation of the current evidence base
Conclusions
The review frames mechanistically informed opportunities to preserve endogenous androgen production and fertility.
Identified strategies include exposure mitigation and metabolic optimization
Fertility-preserving endocrine stimulation is proposed as an approach
Additional strategies target inflammation, senescence, and regenerative capacity of Leydig cells
Kaltsas A, Dimitriadis F, Zachariou A, Koukos S, Chrisofos M, Sofikitis N. (2026). When Testosterone Fades: Leydig Cell Aging Shaped by Environmental Toxicants, Metabolic Dysfunction, and Testicular Niche Crosstalk.. Cells. https://doi.org/10.3390/cells15020158