Estrogens in men
) 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 E2
do not necessarily reflect tissue levels of E2
]. In this regard, prostate in situ
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
]. 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 . 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 (). Commonly found endogenously derived estrogens include estrone (E1
and estriol (E3
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
]. 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.) ().
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. Phytoestrogens have been suggested have a role in the prevention of estrogen associated diseases such as prostate cancer [122
]. The role of phytoestrogens in BPH remains unclear, but they may act as inhibitors of proliferation.
Therapeutic SERMs, including Raloxifene, Toremifene and diethylstilbesterol (DES), have been used for prevention of prostate cancer progression and amelioration of side effects of androgen ablation therapy, as well as, other medical conditions [123
]. In general, SERMs are compounds which modulate the activity of ERs and may have agonist or antagonist effects in different cells types, depending on the activation or inactivation of different ERs or the differential stabilization of the conformation of ERs by individual SERMs. The anti-estrogen Toremifene has been shown to prevent prostate cancer progression and has been reported to have few side effects [124
]. The utility of anti-estrogenic SERMs in BPH remains to be evaluated; however, given the importance of estrogens in the manifestation and maintenance of BPH and toleration of antiestrogens in men, therapeutic SERMs may be ideal preventatives and therapies for BPH.
The effects of various estrogens on the prostate are complex, as estrogens have both indirect and direct effects. In 1941, Huggins and Hodges demonstrated that injection of estrogens caused marked reduction of elevated acid phosphatase and improvement of prostate cancer bony metastases, similar to treatment with bilateral orchiectomy [126
]. High doses of exogenous estrogens cause chemical castration due to suppression of pituitary gonadotropin secretion, leading to decreased testicular androgen secretion, lower plasma androgens and prostatic epithelial atrophy [127
]. Exogenous estrogen administration also causes release of prolactin from the anterior pituitary, which is a mitogen that induces prostatic dysplasia in rats that is preventable by simultaneous administration of the dopamine agonist bromocriptine [128
]. Exogenous estrogens, unopposed by androgens also act directly on the prostate to induce squamous metaplasia of the epithelium, by inducing proliferation of basal epithelial cells, which then differentiate into cells with a squamous cell phenotype [30
]. DES, a potent synthetic exogenous estrogen, used to be administered to men with advanced prostate cancer and to pregnant women for potential prevention of miscarriage and premature birth [131
]. Among men with prostate cancer the effect of DES is primarily to decrease circulating T by feedback inhibition of the hypothalamus-pituitary-gonadal axis, ultimately inhibiting neoplastic growth of the prostate. The direct effects of DES on the prostate and signaling pathways are largely unknown. The administration of DES to pregnant women exposed their fetuses, in utero
, to this potent estrogen. Female fetuses exposed to DES have a higher risk of vaginal clear cell adenocarcinoma, and multiple teratogenic effects on the reproductive tract [131
]. Male fetuses exposed to DES have a variety of urogenital malformations, including testicular hypoplasia, cryptorchidism and epididymal cysts [131
]. DES exposure in utero
has been modeled in rodents and shown to have profound effects on the prostate including increased prostate size and dysplasia later in adulthood [132
]. Accumulating data is now becoming available for “DES sons” [135
], but further studies are needed. Estrogenic exposure may have positive and/or negative effects on an organism but the exposure is dependent upon the type of estrogens/SERMs, time of life of the exposure, and stage of disease.
Another group of xenoestrogens found in the circulation are endocrine disruptors. Insecticides, in general, and in particular metabolites of dichlorodiphenyltrichloroethane (DDT), act as weak estrogens or as anti-androgens and have potentially adverse effects on male reproduction [136
]. In addition, endocrine disruptors such as Bisphenol-A (BPA) have demonstrated adverse effects on the lower urogenital tract [133
]. BPA, which acts as a weak estrogen, is nearly ubiquitous in the environment and is commonly found in plastics and food containers. As such, BPA is found in high concentrations (2–3 ng/ml) in the serum of nearly all Americans [140
]. Developmental BPA, DES, or E2
exposure in rodents causes increased prostate susceptibility to adult-onset of dysplasia and hormonal carcinogenesis [137
]. The role of BPA and other environmental estrogens in BPH has not been fully determined but the effects of endocrine disruptors are likely to be observed in estrogen target tissues such as the prostate.
Perhaps the least understood area of ER regulation in biological processes is ER dimerization [145
]. As mentioned above, ligand bound ERs (α and β) form dimers. These dimers are either homodimers (ER-α/α, ER-β/β) or heterodimers (ER-α/β). Depending upon the ER dimerization state, whether ER-α/α, ER-β/β, or ER-α/β, it is expected that profound differences in gene expression and cell biological outcomes will be observed [145
]. Although incompletely understood in the prostate, ER-α/α homodimers and estrogens that promote their dimerization and activity are considered growth promoting, whereas ER-β/β dimerization is generally considered growth inhibitory. The role of ER-α/β heterodimerization is less understood. One possibility is that an ER within a heterodimer may act in a dominant fashion: for example, in ER-α/β heterodimers, if ER-α acts dominantly, then ER-α target genes will be transcribed and visa-versa
if ER-β is dominant acting. Alternatively, ER-α/β heterodimers may serve to activate transcription of a unique set of genes altogether [145
]. Thus, dimer states may dictate proliferation and differentiation in estrogen target tissues in the prostate. Which ER acts as the dominant receptor in a heterodimer is likely dependent upon the cell type, interactions with cofactors, and the stage of progression (e.g. normal or diseased cell). For many years the difficulty of evaluating dimerization states lay within the inability of methodologies to accurately determine dimerization states particularly in vivo
. Fluorescence resonance energy transfer (FRET) has typically been used to determine receptor dimerization in vitro
, however due to technical inaccuracies, including photobleaching and autofluorescence, other techniques have evolved including bioluminescence resonance energy transfer (BRET) [145
]. Use of BRET reduces these problems associated with FRET, resulting in lowered background, increased sensitivity and quantification. Thus, in vitro
and in vivo
analyses of homodimerization and heterodimerization may be measured. The balance of homodimers and heterodimers within the same cell may hold the key to estrogen regulation in cell biological processes including the pathogenesis of BPH. Moreover, identifying the dominant acting ER partner in ER-α/β heterodimers may lead to the identification of new and unique target genes involved in estrogen hormone action. To date dimerization analyses in BPH disease progression is unknown, however the elucidation of dimerization states will provide a better understanding of the molecular mechanism involved in estrogen hormone action and may pave the way for future therapies for BPH and other estrogen mediated diseases.
Estrogens in BPH
The most compelling implication of estrogens in the pathogenesis of BPH is that treatment of male dogs with androgens and estrogens leads to earlier and more extensive BPH and obstructive voiding [49
]. In humans, as serum androgens decline with advancing age, serum levels of E2
remain relatively constant but the net effect is an increased serum E2
to T ratio, which is associated with the development of BPH and LUTS [39
]. Some studies have demonstrated correlation of serum estrogens with prostate volume and other features of BPH [152
] while others have failed to demonstrate this relationship [155
]. There is evidence for a correlation between transition zone volume and total prostate volume with serum estrone [154
]. Furthermore, a study of 49 men who underwent radical prostatectomy for low volume prostate cancer demonstrated that the volume of BPH histology in these specimens correlates with serum free T, E2
, and estrone levels [156
]. A strong trend for increased risk of surgical intervention for BPH was found across quintiles for serum E2
concentrations in the Physician's Health Study [157
Estrogen hormone action in the prostate is dependent upon types of estrogens and also the type of estrogen receptor. In this regard, stromal cells from normal prostates may respond differently to estrogenic ligands than BPH stromal cells. In an in vitro
study of cells isolated from normal organ donors or from BPH specimens, normal stromal cells predominantly used rapid E2
signaling, mediated by G-protein coupled receptor-30 (GPR30), but BPH stromal cells used classical ER-signaling, which was inhibited by treatment with ER antagonist [158
]. This suggests that the mechanism of estrogen regulated cell growth and the role of stromal cells may be different in normal versus BPH prostates. Elucidation of the estrogen-regulated pathways in BPH may lead to better therapies targeted towards stromal components of the prostate.
Stromal-epithelial interactions in BPH
Given the important role of the stroma in prostate organogenesis, epithelial identity, and cancer progression, its role in BPH seems likely [21
]. Furthermore, steroid hormones have important roles in prostate growth and maturation and prostate development is mediated by androgen-regulated stromal factors [21
]. The role of estrogens and stromal-epithelial interactions in the prostate is less clear. Prins and colleagues suggested that estrogen imprinting and prostate pathologies are mediated through stromal ER-α [132
]. This conclusion is consistent with ER-α localization in the normal prostate, where ER-α is found primarily in the nuclei of stromal cells; however, ER-α is also found in epithelial cells [62
]. The estrogen regulated stromal-epithelial interactions involved in prostatic growth are complicated in part due to the variable temporal and spatial localization of ERs within the prostate (). If estrogen mediated glandular growth events are controlled via the stroma it is likely that estrogen regulated stromal factors, also known as “estromedins”, are the primary mediators. Alternatively, ER-α may affect stromal cell proliferation directly and hence affect stromal BPH nodular growth. If estrogen mediated events are controlled by epithelia, then estrogens may mediate epithelial proliferation directly or alternatively affect epithelial estromedins which may promote stromal hyperplasias. ER-β is found almost exclusively in the nuclei of prostatic epithelial cells [167
]. However, in estrogen-treated mice, the localization of ER-α in the prostatic epithelium increases, while epithelial ER-β decreases suggesting that estrogens may mediate epithelial proliferative effects directly through ER-α (stromal, epithelial, or both) and less through ER-β [62
]. In support of this idea, ER-α but not ER-β, is necessary for prostate proliferation in estrogen treated mice [62
]. Determination of estrogen hormone action in BPH remains to be elucidated.
Tissue specific estrogen hormone action