Age induced nitroso-redox imbalance leads to subclinical hypogonadism in Male mice

John Alden Lee, Manish Kuchakulla, Himanshu Arora, Shathiyah Kulandavelu, Evert Gonzalez, Thomas A. Masterson, Joshua M. Hare, Ursula B. Kaiser, Ranjith Ramasamy

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Objective: The cause of age-related changes in testosterone remains unclear. We hypothesized that increased nitroso-redox imbalance with aging could affect testosterone production. Materials and Methods: We measured several markers of nitroso-redox imbalance (4-HNE, 3-NT, and NT) in serum of S-nitrosoglutathione reductase knock out (GSNOR KO) mice that have increased nitroso-redox imbalance and compared these to wild-type (WT) mice. We evaluated the impact of age-induced nitroso-redox imbalance on serum luteinizing hormone (LH) and testosterone (T) in WT young (<2 months), middle-aged (2-6 months), and aged (>12 months) mice. Finally, to elucidate the susceptibility of testes to nitroso-redox imbalance, we measured 4-HNE protein levels in the testes of WT and KO mice. Results: We identified 4-HNE as a reliable marker of nitroso-redox imbalance, as evidenced by increased protein levels in serum of GSNOR KO mice compared with WT mice. We demonstrated that 4-HNE serum protein levels increase in WT mice with age but do not accumulate in the testes. We also found that T levels were similar in all age groups. Interestingly, we found that serum LH levels in aged and middle-aged mice were increased when compared to young mice (n = 5) consistent with the phenotype of subclinical hypogonadism. Conclusions: Increased serum 4-HNE and LH levels without changes in T with age suggest that nitroso-redox imbalance is associated with subclinical hypogonadism in aged mice. Recognizing the relationship and etiology of a currently poorly understood classification of hypogonadism could be a paradigm shift in how age-related testosterone change is diagnosed and treated.

Original languageEnglish (US)
Article number190
JournalFrontiers in Endocrinology
Issue numberMAR
StatePublished - 2019


  • 4-hydroxynonenal
  • Aging
  • Compensated hypogonadism
  • Nitrosative stress
  • Nitroso-redox imbalance
  • S-nitrosoglutathione reductase
  • Subclinical hypogonadism

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism


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