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Cited by 12Sperm and Testicular FunctionHormonal and reproductive studiesReproductive Biology and Fertility

When Testosterone Fades: Leydig Cell Aging Shaped by Environmental Toxicants, Metabolic Dysfunction, and Testicular Niche Crosstalk

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Kaltsas, Aris, Dimitriadis, Fotios, Zachariou, Athanasios, Koukos, Sotirios, Chrisofos, Michael, Sofikitis, Nikolaos·2026·Cells
DOI 10.3390/cells15020158PMC PMC12839678
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Abstract

Declining Leydig cell steroidogenesis contributes to late-onset hypogonadism and to age-associated impairment of male reproductive health. Determinants of dysfunction extend beyond chronological aging. This review synthesizes recent experimental and translational evidence on cellular and molecular processes that compromise Leydig cell endocrine output and the interstitial niche that supports spermatogenesis. Evidence spanning environmental endocrine-disrupting chemicals (EDCs), obesity and metabolic dysfunction, and testicular aging is integrated with emphasis on oxidative stress, endoplasmic reticulum stress, mitochondrial dysregulation, apoptosis, disrupted autophagy and mitophagy, and senescence-associated remodeling. Across model systems, toxicant exposure and metabolic stress converge on impaired organelle quality control and altered redox signaling, with downstream loss of steroidogenic capacity and, in some settings, premature senescence within the Leydig compartment. Aging further reshapes the testicular microenvironment through inflammatory shifts and biomechanical remodeling and may erode stem and progenitor Leydig cell homeostasis, thereby constraining regenerative potential. Single-cell transcriptomic atlases advance the field by resolving Leydig cell heterogeneity, nominating subsets that appear more vulnerable to stress and aging, and mapping age-dependent rewiring of interstitial cell-to-cell communication with Sertoli cells, peritubular myoid cells, vascular cells, and immune cells. Many mechanistic insights derive from rodent in vivo studies and in vitro platforms that include immortalized Leydig cell lines, and validation in human tissue and human clinical cohorts remains uneven. Together, these findings frame mechanistically informed opportunities to preserve endogenous androgen production and fertility through exposure mitigation, metabolic optimization, fertility-preserving endocrine stimulation, and strategies that target inflammation, senescence, and regenerative capacity.

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Cited by

Sorted by citations

Authors
Kaltsas, A., Dimitriadis, F., Zachariou, A., Koukos, S., Chrisofos, M., & Sofikitis, N.
Affiliations
  • National and Kapodistrian University of Athens (GR)
  • Aristotle University of Thessaloniki (GR)
  • University of Ioannina (GR)
Corresponding author
Sofikitis, Nikolaos
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2026-01-15
Volume
15
Issue
2
Pages
158
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells15020158
PMC
PMC12839678
OpenAlex
W7124241650
Cited by
12
References
6
Citations by year
2026: 12
FWCI
11.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
Keywords
andropause, testicular steroidogenesis, endocrine disruptors, obesity, metabolic dysfunction, oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, apoptosis, autophagy, mitophagy, cellular senescence, testicular niche, Sertoli cells, peritubular myoid cells, Leydig cell regeneration, male fertility, redox signaling, inflammation
MeSH terms
Aging, Animals, Humans, Leydig Cells, Male, Testis, Testosterone, Cellular Senescence, Endocrine Disruptors

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