Steroid Hormones Oxidative Stress and Prostate

Prostate development, maturation, and normal function depends on the activity of the androgens testosterone and its derivative dihydrotestosterone (DHT). DHT, synthesized from testosterone in the prostate by 5a-reductase, has a more potent effect due to its higher affinity to the androgen receptor (AR) [81]. The AR in turn binds to androgen receptor elements (ARE) present in the promoter regions of many genes involved in cellular proliferation [82]. Traditionally, the initial stages of prostate cancer are controlled by androgen deprivation therapy; however, aberrant AR activity in prostate tumors finally leads to the development of a highly malignant state of disease unresponsive to androgen control [83] .

Many studies have dwelt on the increased oxidative damage in cells due to ROS as a result of abnormal and increased androgen stimulation of androgen-sensitive prostate cancer cells [84, 85]. Though studies have not pointed out a potential mechanism for the increased levels of ROS after androgen stimulation, as discussed above, changes in the balance of prooxidant and antioxidant molecules in a cell may play an important role. Intracellular redox balance is largely the result of cyclic reduction and oxidation of Glutathione both in the cytoplasm and mitochondria of a cell [86], Glutathione, synthesized in the cytosol and imported into the mitochondria, plays an important role in the protection of mitochondria from the deleterious effects of ROS generated as a result of electron transport [87]. Even though testosterone is the predominant hormone responsible for the regulation of prostate gland growth and functioning, recent discovery of estrogen receptors in the prostate has brought estrogen role in prostate cancer progression to prominence [88, 89]. Estradiol can be synthesized from testosterone in the prostate epithelial cells or taken up from general circulation. Certain isoflavonoids can also have weak estrogenic effects [90] and have been observed to cause significant infiltration of neutrophils and lymphocytes in the prostatic lobes of rats fed with dietary isoflavonoids. Chronic administration of DHT and estradiol to rats induces the expression of proinflammatory cytokines within the prostate [91]. These inflammatory infiltrates have been identified to be a major source of ROS production and the incidental oxidative injury to the prostate epithelium has been suggested to be the cause for the formation of proliferative inflammatory atrophy (PIA) [92], These lesions generally form the basis for enhanced epithelial cell proliferation, regeneration, and give rise to prostatic intraepithelial neoplasia (PIN), and progressively to prostate cancer. It is generally believed that estrogen alone is not enough to cause malignancy, but abnormal estrogen receptor a (ERa) signaling in conjunction with elevated levels of testosterone have been shown to induce prostate hyperplasia and prostate cancer in mice [93, 94],

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