Imbalance in the estrogen/androgen ratio may affect prostate fibrosis through the TGF-β/Smad signaling pathway

The present study aimed to investigate the effects of an imbalance in the estrogen/androgen ratio on prostate fibrosis.

Different concentrations of dihydrotestosterone (DHT) or estradiol (E₂) dissolved in corn oil were injected subcutaneously into the nape of the castrated Sprague-Dawley (SD) rats over 28 consecutive days. Masson's trichrome staining and immunohistochemical staining were performed to detect the content of collagen fibers and the expression of collagen I, fibronectin, and elastin in the rat prostate of each group, respectively. DHT + E₂ at different concentrations was administered to human normal prostate stromal immortalized cells (WPMY-1 cells) for 1 week. The expression of collagen I, fibronectin, elastin, transforming growth factor-β₁ (TGF-β₁), Smad3, and Smad7 was detected by Western blotting (WB). Then, WPMY-1 cells treated with 10 nM DHT + 5 pM E₂ were incubated with the TGF-β/Smad pathway inhibitor SD208 for 1 week, after which collagen I, fibronectin, and elastin expression was detected by WB.

Compared with the uncastrated control and corn oil injection groups, the collagen fiber content and collagen I and fibronectin expression were increased and elastin expression was decreased in the castrated rat prostate with corn oil injection group (p < 0.01). Compared to castrated corn oil injection group, collagen fiber content, collagen I, and fibronectin expression were significantly decreased, and elastin expression was significantly increased in the castrated rat prostate 0.15 mg/kg DHT treatment group (p < 0.01). Following treatment with 0.15 mg/kg DHT, the content of collagen fibers, and the expression of collagen I and fibronectin were increased, and the expression of elastin was decreased in the rat prostate with increasing concentrations of E₂ treatment group compared to the 0.15 mg/kg DHT group (p < 0.05, p < 0.01). Following treatment with 0.05 mg/kg E₂, the collagen fiber content and the expression of collagen I and fibronectin were decreased, and the expression of elastin was increased in the rat prostate with increasing DHT concentration treatment group compared to the 0.05 mg/kg E₂ group (p < 0.05, p < 0.01). Compared with the Control group, the expression of collagen I, fibronectin, TGF-β₁ and Smad3 was decreased, and the expression of elastin and Smad7 was increased in WPMY-1 cells after treatment with 10 nM DHT (p < 0.01). Following treatment with 10 nM DHT, the expression of collagen I, fibronectin, TGF-β₁, and Smad3 was increased, and the expression of elastin and Smad7 was decreased in WPMY-1 cells with increasing E₂ concentration treatment compared to the 10 nM DHT group (p < 0.05, p < 0.01). Following treatment with 5 pM E₂, the expression of collagen I, fibronectin, TGF-β₁, and Smad3 was decreased, and elastin and Smad7 expression was increased with increasing DHT concentration compared to the 5 pM E₂ group (p < 0.05, p < 0.01). Compared to the 10 nM DHT + 5 pM E₂ group, the expressions of collagen I and fibronectin were decreased; the expression of elastin was increased in WPMY-1 cells after the supplement of TGF-β/Smad pathway inhibitor SD208 group (p < 0.05, p < 0.01).

An imbalance in the estrogen/androgen ratio may affect prostate fibrosis. E₂ may activate the degree of prostate fibrosis. In contrast to the effect of E₂, DHT may inhibit the degree of prostate fibrosis, which might involve the TGF-β/Smad signaling pathway.