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Thursday, January 5, 2017

Benign Prostate Hyperplasia: Role of the Estrogen Pathway

Benign Prostate Hyperplasia: Role of the Estrogen Pathway

Estrogens regulate their effects at the level of the target cells through interaction with estrogen receptors (ER). Both ER-α and ER-β, similarly to the AR, are transcription factors24. ER-β is similar to ER-α in DNA-binding and ligand domains, but differs for the N-terminal transactivation domain. The role of estrogen in the pathogenesis of BPH is based on the observation that treatment of dogs with estrogen (in addition to androgens) leads to the development of BPH and LUTS BPH-related (Coffey & Walsh, 1990).

In men, while serum androgen levels decrease during aging, the levels of 17ß-estradiol (E2) remain constant increasing the ratio E2/T. This altered relationship is clearly associated with the development of the disease BPH/LUTS (Roberts et al., 2004). Some authors have shown a correlation between serum estrogen levels and the prostate volume (Hammarsten et al., 2009). Finally, E2 levels in the stromal cells of BPH patients increase during aging, and this seems to be associated with a high expression of aromatase, the enzyme that converts androgens into estrogens (Ho et al., 2008). However, previously, other authors had not shown the same results (Negri-Cesi et al., 1998).

The role of ER-α and ER-β in the pathogenesis of BPH is not yet fully understood. It is thought that the two receptor subtypes may perform different functions depending on the interaction with different ligands, changes in the balance between classical and non-classical signaling, and interactions with different co-repressors and co-activators. In general, activation of ER-α in the prostate is associated with hyperplasia and inflammation (Nicholson & Ricke, 2011). In addition, the epithelial-to-mesenchymal transition is an important mechanism in the etiology of BPH and ER-α plays a crucial role in this mechanism (Shao et al., 2014); while ER-β are located in the epithelial cells (Macoska, 2011), ER-α are primarily found in stromal cells. ER-β is associated with antiproliferative activity, indeed, ER-β knockout mice develop hyperplasia of the stromal cells during aging. Moreover, in rats, neonatal exposure to diethylstilbestrol cause prostatic hyperplasia and dysplasia, which probably results from an up-regulation of ER-α and down-regulation of ER-β. Finally, it has been reported that the activation of ER-β causes apoptosis in BPH with an androgen-independent mechanism (McPherson et al., 2010). The epithelium-stroma interactions mediated by growth factors are well-known, while the role of estrogen in these interactions is not yet clear. However, it is known that the ER-α, expressed in stromal cells, induces the secretion of growth factors that act in a paracrine manner stimulating the proliferation of epithelial cells (Shao et al., 2014); ER-α also seems to cause a proliferative effect on stromal cells.


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