The Interplay between Finasteride-Induced Androgen Imbalance, Endoplasmic Reticulum Stress, Oxidative Stress, and Liver Disorders in Paternal and Filial Generation

Abstract

Finasteride (Fin) causes androgen imbalance by inhibiting the conversion of testosterone (T) to its more active metabolite, dihydrotestosterone (DHT). Androgen receptors (AR) are present (e.g., in hepatocytes), which have well-developed endoplasmic reticulum (ERet). Cellular protein quality control is carried out by ERet in two paths: (i) unfolded protein response (UPR) and/or (ii) endoplasmic reticulum associated degradation (ERAD). ERet under continuous stress can generate changes in the UPR and can direct the cell on the pathway of life or death. It has been demonstrated that genes involved in ERet stress are among the genes controlled by androgens in some tissues. Oxidative stress is also one of the factors affecting the functions of ERet and androgens are one of the regulators of antioxidant enzyme activity. In this paper, we discuss/analyze a possible relationship between androgen imbalance in paternal generation with ERet stress and liver disorders in both paternal and filial generation. In our rat model, hyperglycemia and subsequent higher accumulation of hepatic glycogen were observed in all filial generation obtained from females fertilized by Fin-treated males (F1:Fin). Importantly, genes encoding enzymes involved in glucose and glycogen metabolism have been previously recognized among UPR targets.

Finasteride delays atherosclerosis progression in mice and is associated with a reduction in plasma cholesterol in men

“…Sex hormones have a profound impact on gene expression in tissues including the liver, where they regulate inflammation and lipid metabolism (recently reviewed in ( 94 , 95 )). Finasteride treatment resulted in a shift in circulating sex hormones and hepatic sex hormones toward estrogen excess, as reported in the past ( 18 , 50 , 61 , 72 ). Our LC-MS data revealed an increase in hepatic estradiol in mice fed finasteride, which could be responsible, at least in part, for the reduction in hepatic lipid levels and antiinflammatory effects in our experimental model ( Fig.…”

“…As previously mentioned, finasteride results in androgen imbalance through changes in steroid metabolism ( 50 ). Hence, we quantified the levels of the main sex hormones serving as upstream and downstream metabolites of SRD5A2 and AKR1D1 in plasma and the liver samples.…”

The Role of Reactive Oxygen Species, Inflammation, and Endoplasmic Reticulum Stress Response in the Finasteride Protective Effect against Benign Prostate Hyperplasia

“…Previous investigations indicate that finasteride lowers intracellular reactive oxygen species (ROS) levels by upregulating antioxidant genes [ 7 ]. Further, it is known that androgens regulate antioxidant enzyme activity, and resulting oxidative stress influences endoplasmic reticulum (ER) function [ 8 ]. Androgen receptors are present in various cells with a well-developed ER.…”