Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common clinical problems in urology. While the precise molecular etiology remains unclear, sex steroids have been implicated in the development and maintenance of BPH. Sufficient data exists linking androgens and androgen receptor pathways to BPH and use of androgen reducing compounds, such as 5α-reductase inhibitors which block the conversion of testosterone into dihydrotestosterone, are a component of the standard of care for men with LUTS attributed to an enlarged prostate. However, BPH is a multifactorial disease and not all men respond well to currently available treatments, suggesting factors other than androgens are involved. Testosterone, the primary circulating androgen in men, can also be metabolized via CYP19/aromatase into the potent estrogen, estradiol-17β. The prostate is an estrogen target tissue and estrogens directly and indirectly affect growth and differentiation of prostate.Estrogens in men
Estradiol-17β (E2) is considered the most potent estrogen in men and is important for a variety of physiologic processes including bone maturation and mineralization, peak bone mass, and skin and lipid metabolism [114]. In men, the majority of circulating E2 is formed from aromatization of T, mainly in fat and muscle, while up to 20% is secreted by Leydig cells of the testes [114]. However, serum levels of E2do not necessarily reflect tissue levels of E2 [114]. In this regard, prostate in situ E2 production may influence local estrogen regulated processes. Such local production of E2 has been implicated in prostatic hyperplasia and loss of aromatase expression causes decreased estrogen-induced prostate proliferation [62, 115]. However, an important question remains: which estrogens or estrogen interactions affect prostate pathologies?
The prostate is commonly thought of as an androgen target tissue, but it is also an important target of estrogens. Although E2 is the primary estrogen evaluated in prostate research, a number of other potential estrogenic sources may play significant positive or negative roles in the prostate, as outlined in Figure 2. These estrogens can be divided into multiple categories including those that are found systemically (in serum) or those produced in situ in the prostate. Local steroids with estrogen receptor agonist activity include E2, 5α-androstane-3β, 17β-diol (3βAdiol), and 7α-hydroxy-DHEA (7HD). The effects of these sex steroids are not fully appreciated but are likely to influence prostate hyperplasia. Their mechanism of action, including promotion or suppression of proliferation and differentiation is dependent upon their specificity and activation of estrogen receptors (ERs).
Estrogens within the circulation can be endogenous or exogenous (Figure 2). Commonly found endogenously derived estrogens include estrone (E1), E2 and estriol (E3). E1 is a weak estrogen formed mainly from peripheral aromatization of adrenal androstenedione, and as such is considered to have minimal influence on estrogenic pathways within the prostate. However, E2 (as discussed above) has been shown to be a potent estrogen and a powerful inducer of prostatic proliferation. In men, serum concentrations of E3, the predominant estrogen of pregnancy, are minimal, and the potential role of E3 in male physiology and in the prostate is not well understood. Recently another endogenous estrogen, 27-hydroxy-cholesterol (27HC), an oxysterol, was found to bind ERs and regulate ER mediated transcription [116]. Although the affinity of 27HC for estrogen receptors is lower compared to E2, the concentrations of 27HC in serum and tissues are significantly higher [116–120]. This suggests that 27HC may be an important regulator of ER activity in estrogen target organs such as the prostate. Circulating exogenous estrogens may also affect estrogen action in men. Serum levels of xenoestrogens are dependent upon dietary and other environmental exposures and as such, levels may vary among different populations. Such estrogens include phytoestrogens, therapeutic selective estrogen receptor modulators (SERMs), and endocrine disruptors (e.g. BPA, insecticides, etc.) (Figure 2).
Phytoestrogens are commonly associated with various diets (e.g. Western vs. Eastern diets) and are generally assumed to have a positive effect on the prostate. Phytoestrogens include polyphenols, flavonoids, and isoflavanoids, reviewed by [121]. An example of a polyphenol is resveratrol, which is commonly found in grape skins and red wine. Flavonoids are subgrouped into flavanones, flavones, flavonols, and catechins and are found in many foods including fruits, parsley, celery, kale, broccoli, chocolate, and green tea. Isoflavanoids are categorized into isoflavones, isoflavans, and coumestans and are found in foods like legumes, clover, and spinach.