Investigação da expressão do receptor de estrógeno ER e de componentes relacionados à via metabólica de esteroides estrogênicos no complexo prostático de ratos Wistar durante o envelhecimento

Abstract

Although the prostate is androgen-dependent, it is also influenced by estrogens, which act via the estrogen receptors ER and ER, the last one being highly expressed in the glandular epithelium. It has been shown that 3-diol, a DHT metabolite, is the alternative ER ligand, regulating the cell proliferation, apoptosis and differentiation in the prostate. There is a body of evidences that ER is decreased in malignant prostate, suggesting that it plays an important role in protecting this tissue. Despite the relationship between reductions in ER and abnormal growth of the gland, few are known about the age-dependent variation of this receptor. Therefore, we aimed to investigate ER expression, as well as others components of the metabolic pathway of estrogenic steroids, such as aromatase and CYP7B1, as well as estradiol and DHT levels in the prostatic lobes of aging Wistar rats (3 to 24 months). We also investigated whether the treatment of senile rats with 3-diol would be able to reverse the aging prostate changes. Histopathological alterations, including hyperplasia, intraluminal concretions, nuclear atypia and prostate intraepithelial neoplasias (PIN), were observed in the prostates of aging rats. In the ventral prostate, areas of cribriform proliferation and epithelial atrophy were also observed, whereas in the lateral prostate, there was frequent prostatitis. Immunohistochemistry revealed that the expression of ER was reduced in restricted areas related to atrophy, cellular atypia and PIN in senile animals. Corroborating the involvement of the receptor with anti-proliferative activity, the punctual reduction in ER paralleled the increase in cell proliferation especially in areas of PIN and nuclear atypies. These changes occurred in a hormonal milieu characterized by a constant concentration of estradiol but decreased plasmatic and tissue DHT. These data point out that the focal ER reduction may be associated with the premalignant and malignant conditions in the prostate. Aromatase was detected in the glandular epithelium, in which some sparse basal cells were found intensely stained for the enzyme (basal cell/Aro+). In senile animals, there were an increased in the basal cell/Aro+density, especially in cribriform proliferation areas, PIN and prostatitis corroborating that the estrogens may lead to adverse effects on the aging prostate, similar to those induced by estrogenization. In these areas there was also moderate reduction in the CYP7B1 expression, reinforcing a possible hormonal imbalance, since the DHT availability for conversion to 3-diol is reduced. The treatment of senile rats with 3-diol promoted substantial improvement in the cytoarchitecture of the prostate complex, as well as promoted increase in ER expression, decrease in cell proliferation and increase in apoptosis without changing the intra-prostatic DHT levels, thus corroborating the anti-proliferative, pro-apoptotic and pro-differentiation role of ER/3-diol in the prostate. These data point out that exposure of senile animals to 3-diol may be an alternative in the prevention of prostate diseases. Considering the set of results, it may be concluded that estrogens, 3-diol and their receptors have significant importance for the development and progression of prostate diseases. The results also reinforce the importance of careful study in the prostate tissue to better understand the changes related to prostate diseases.