Abstract
The literature suggests a bidirectional relationship between testosterone (T) and iron, but mechanisms underlying this relationship remain unclear. We investigated effects of iron on advanced glycation end products (AGEs) in obesity-related androgen deficiency. In total, 111 men were recruited, and iron biomarkers and N(ɛ)-(carboxymethyl)lysine (CML) were measured. In an animal study, rats were fed a 50% high-fat diet (HFD) with (0.25, 1, and 2 g ferric iron/kg diet) or without ferric citrate for 12 weeks. Obese rats supplemented with >1 g iron/kg diet had decreased testicular total T compared to HFD alone. Immunohistochemical staining showed that >1 g of ferric iron increased iron and AGE retention in testicular interstitial tissues, which is associated with increased expression of the receptor for AGEs (RAGE), tumor necrosis factor-α, and nitric oxide. Compared with normal weight, overweight/obese men had lower T levels and higher rates of hypogonadism (19% vs. 11.3%) and iron overload (29.8% vs.15.9%). A correlation analysis showed serum total T was positively correlated with transferrin saturation (r = 0.242, p = 0.007) and cathepsin D (r = 0.330, p = 0.001), but negatively correlated with red blood cell aggregation (r = −0.419, p<0.0001) and CML (r = −0.209, p < 0.05). In conclusion, AGEs may partially explain the underlying relationship between dysregulated iron and T deficiency.
Highlights
Numerous studies have documented that androgen deficiencies and dysregulation of iron homeostasis are common features observed in obese men [1,2,3]
A trend toward decreased serum total T was apparent in the 1- and 2-g ferric iron groups compared to the high-fat diet (HFD) alone group, only the 1-g ferric iron group reached statistical significant difference (p < 0.01), while the 2-g iron group did not due to high group variation (Figure 1D)
Both 1 and 2 g of ferric iron caused a significant reduction in testicular total T levels compared to the HFD-only group (Figure 1E)
Summary
Numerous studies have documented that androgen deficiencies and dysregulation of iron homeostasis are common features observed in obese men [1,2,3]. There is a bidirectional relationship between iron metabolism and androgen synthesis, and obesity may affect this relationship. It has been known for more than half a century that T, the male sex hormone, is involved in erythropoiesis [8]. Recent clinical studies showed that T administration increase iron absorption and red blood cells (RBCs) synthesis through the suppression of the master iron regulator hepcidin hormone [11,12,13]. Gauiter et al [19] studied
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