Presentation Authors: John Lee*, Manish Kuchakulla, Himanshu Arora, Shathiyah Kulandavelu, Evert Gonzalez, Thomas Masterson, Joshua Hare, Ranjith Ramasamy, Miami, FL
Introduction: The cause for age-related changes in testosterone remains unclear. We hypothesized that increased nitroso-redox imbalance with aging could affect testosterone production.
Methods: Using western blotting we assessed several markers of nitroso-redox imbalance (4-HNE, NT, 3-NT, and S-NO) 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 mice at pre-pubertal ( < 2months), middle-aged (2-6 months), and aged (>12 months) mice. Finally, we evaluated whether ascorbate, an antioxidant, can be used to reverse age-induced nitroso-redox imbalance.
Results: We identified 4-HNE as a reliable marker of nitroso-redox imbalance as evidenced by increased expression in serum of GSNOR KO mice compared with WT mice. We demonstrated that 4-HNE expression in serum increases in WT mice with aging (Figure 1). We also identified that testosterone levels were similar in middle-aged and aged mice and as expected, were increased compared to pre-pubertal mice. Interestingly, we found that serum LH levels in aged (n=8) and middle-aged (n=5) mice were increased when compared to pre-pubertal mice (n=5) consistent with the phenotype of subclinical hypogonadism (Figure 2). GSNOR KO mice treated with ascorbate for 5 weeks had reduced the expression of 4-HNE and increased serum T levels compared to untreated mice.
Conclusions: Increasing 4-HNE expression with age suggests that nitroso-redox imbalance is a possible mechanism for subclinical hypogonadism. Recognizing the relationship and etiology on a currently poorly understood classification of hypogonadism could be a paradigm shift in how age-related testosterone change is diagnosed and treated.