Androgens and estrogens in benign prostatic hyperplasia: past, present and future

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. The precise role of endogenous and exogenous estrogens in directly affecting prostate growth and differentiation in the context of BPH is an understudied area. Estrogens and selective estrogen receptor modulators (SERMs) have been shown to promote or inhibit prostate proliferation signifying potential roles in BPH. Recent research has demonstrated that estrogen receptor signaling pathways may be important in the development and maintenance of BPH and LUTS; however, new models are needed to genetically dissect estrogen regulated molecular mechanisms involved in BPH. More work is needed to identify estrogens and associated signaling pathways in BPH in order to target BPH with dietary and therapeutic SERMs.     

Adénome prostatique, hormones et androgénothérapie

The prostate is an androgen dependent organ. Benign prostatic hyperplasia (BPH) has a high prevalence in histological studies, but all the affected men do not present symptoms. Aging and the presence of androgens are the main determinants of BPH. However, androgen blood levels were not higher in patients with BPH than in the general population. Suppression of androgens induced a decrease in prostatic volume. Androgen replacement therapy resulted in a re-increase of prostatic volume, but during androgen replacement therapy the prostate volume was only slighty increased, it any, thus remaining within normal range. The present review of the literature indicates that BPH is no a contra-indication for androgen replacement therapy in men with partial or complete androgen deficiency. However, it must be noticed that in most of the studies published so far subjects with BPH have been excluded. A specific study involving such patients is to be undertaken.     

Long-Term Experience with 5-alpha-Reductase Inhibitors

Finasteride, a 5-alpha-reductase inhibitor, dramatically suppresses the production of dihydrotestosterone in men; thus, attention has turned to this agent for the treatment of benign prostatic hyperplasia (BPH). A number of randomized clinical trials have studied finasteride's effects on prostate size, BPH symptoms, flow rate, and prostate-specific antigen (PSA) level. Although the decrease in symptoms with finasteride therapy has been modest compared with more invasive treatments, its use has resulted in sustained reductions in prostatic volume and PSA level with minimal adverse effects. Fewer surgeries for BPH, as well as a decreased incidence of acute urinary retention, have also been seen with finasteride therapy. More research is needed to maximize the effectiveness of such medical therapy for BPH.     

Benign prostatic hyperplasia: does prostate size matter?

Recent studies and analyses have confirmed that baseline prostate volume is related to progression of benign prostatic hyperplasia (BPH) as well as to negative outcomes related to BPH, such as acute urinary retention (AUR) and need for surgery, and can also predict response to therapy. Other investigations have determined that prostate-specific antigen (PSA) level has good predictive value for assessing prostate volume. Strong evidence exists that baseline serum PSA level, like baseline prostate volume, predicts future prostate growth. Randomized placebo-controlled finasteride trials have shown that men with larger prostate volumes and higher PSA levels experience a clinically significant response to therapy compared with those with smaller prostate volumes and lower PSA levels. It has also been demonstrated that men with larger prostate glands and higher PSA levels are at increased risk for AUR and BPH-related surgery but that finasteride reduces these risks. Moreover, doxazosin and finasteride, alone and in combination, have been shown to significantly reduce BPH clinical progression.     

Sex steroid receptor expression and localization in benign prostatic hyperplasia varies with tissue compartment

Androgens and estrogens, acting via their respective receptors, are important in benign prostatic hyperplasia (BPH). The goals of this study were to quantitatively characterize the tissue distribution and staining intensity of androgen receptor (AR) and estrogen receptor-alpha (ERα), and assess cells expressing both AR and ERα, in human BPH compared to normal prostate. A tissue microarray composed of normal prostate and BPH tissue was used and multiplexed immunohistochemistry was performed to detect AR and ERα. We used a multispectral imaging platform for automated scanning, tissue and cell segmentation and marker quantification. BPH specimens had an increased number of epithelial and stromal cells and increased percentage of epithelium. In both stroma and epithelium, the mean nuclear area was decreased in BPH relative to normal prostate. AR expression and staining intensity in epithelial and stromal cells was significantly increased in BPH compared to normal prostate. ERα expression was increased in BPH epithelium. However, stromal ERα expression and staining intensity was decreased in BPH compared to normal prostate. Double positive (AR and ERα) epithelial cells were more prevalent in BPH, and fewer double negative (AR and ERα) stromal and epithelial negative cells were observed in BPH. These data underscore the importance of tissue layer localization and expression of steroid hormone receptors in the prostate. Understanding the tissue-specific hormone action of androgens and estrogens will lead to a better understanding of mechanisms of pathogenesis in the prostate and may lead to better treatment for BPH.     

Effects of the aromatase inhibitor testolactone on human benign prostatic hyperplasia

The aromatase inhibitor testolactone was used for endocrine treatment of benign prostatic hyperplasia (BPH). Thirteen patients (mean age 79 years) with complete urinary retention (BPH stage IV) without improvement after 4 weeks of bladder drainage by suprapubic catheter were treated with testolactone 100 mg, b.i.d., for 6 months. Nine men (mean age 80 years) with identical conditions who did not receive hormonal therapy served as controls. Results, treatment group: In 7 patients spontaneous micturation reoccurred after an average treatment period of 8 weeks (group A); 6 patients continued to need the catheter (group B). Prostatic volume decreased in all patients, and an average volume reduction of 26% was found in group A, whereas in group B the decrease averaged 15%. Finally, the testosterone/estradiol ratio significantly increased in all patients during treatment. Control group: Prostatic volume did not change nor did spontaneous micturation occur during the whole observation period.     

Aromatase and other inhibitors in breast and prostatic cancer

Estrogens have an important role in the growth of breast and other hormone-sensitive cancers. We have shown that 4-hydroxyandrostenedione (4-OHA) selectively blocks estrogen synthesis by inhibiting aromatase activity in ovarian and peripheral tissues and reduces plasma estrogen levels in rat and non-human primate species. In postmenopausal men and women, estrogens are mainly of peripheral origin. When postmenopausal breast cancer patients were administered either by daily oral or parenteral weekly treatment with 4-OHA, plasma estrogen concentrations were significantly reduced. Complete or partial response to treatment occurred in 34% of 100 patients with advanced breast cancer, while the disease was stabilized in 12%. We recently studied the effects of 4-OHA and other aromatase inhibitors, 10-propargylestr-4-ene-3,17-dione (PED) and imidazo[1,5-]3,4,5,6-tetrahydropyrin-6-yl-(4-benzonitrile) (CGS 16949A) as well as 5-reductase inhibitors, N,N-diethyl-4-methyl-3-oxo-4-aza-5-androstane-17β-carboxyamide (4-MA) and 17β-hydroxy-4-aza-4-methyl-19norandrost-5-en-3-one (L651190) in prostatic tissue from 11 patients with prostatic cancer and six patients with benign prostatic hypertrophy (BPH), and from normal men at autopsy. We attempted to measure aromatase activity in tissue incubation by quantitating ³H₂O released during aromatization of androstenedione or testosterone labeled at the C-1 position. The amount of ³H₂O released from all samples was at least twice that of the heat inactivated tissue samples. The ³H₂O release was significantly inhibited by 4-OHA and 4-MA, but not by the other aromatase inhibitors. However, when HPLC and TLC were used to isolate steroid products, no estrone or estradiol was detected in the incubates. Furthermore, no aromatase mRNA was detected following amplification by PCR. The 4-OHA was found to inhibit 5-reductase in both BPH and cancer tissue, although to a lesser extent than 4-MA. The other aromatase inhibitors were without effect. Although a mechanism involving intraprostatic aromatase is not likely, inhibitors may act to reduce peripherally-formed estrogens. In postmenopausal breast cancer, the results indicate that 4-OHA is of significant benefit.     

Medical treatment of benign prostatic hyperplasia

Medical therapy for the treatment of benign prostatic hyperplasia (BPH) became an accepted standard of care in the 1990s following the reports of randomized, double-blind, placebo-controlled studies showing that finasteride, a 5-α reductase inhibitor, and terazosin, an α-blocker, significantly improved lower urinary tract symptoms and increased peak urinary flow rates in men with BPH. This article reviews novel approaches to the pharmacological treatment of BPH.     

Management of benign prostatic hyperplasia with particular emphasis on aromatase inhibitors

The pathogenesis of human benign prostatic hyperplasia (BPH) has not been fully elucidated. There is, however, evidence that estrogens—besides other factors—might play an important role for the growth of the prostate. Consequently, estrogen deprivation might be a new, useful principle for a conservative treatment of BPH. Atamestane, a new, highly selective steroidal aromatase inhibitor has been proven to be successful in antagonizing experimentally-induced estrogen-related stromal overgrowth of the prostate in dogs and monkeys. Double-blind placebo controlled studies are now underway in Europe and the U.S.A. It is anticipated that these studies will give us a definite answer of the clinical validity of this concept in BPH patients in the near future. However, it is very important to take into consideration that for an effective treatment of BPH, a reduction of both the glandular and stromal elements has to be achieved. In other words, both androgens and estrogens seem to be involved in the regulation of (over)growth of the prostate. Therefore, a combination of an androgen and estrogen deprivation might be a more promising approach than any single treatment.     

Landmark studies impacting the medical management of benign prostatic hyperplasia

The treatment of benign prostatic hyperplasia (BPH) has changed dramatically over the past 10 years. Phase 3 studies of the safety and effectiveness of alpha-blockers (eg, terazosin and doxazosin) and 5-alpha-reductase inhibitors (eg, finasteride) for the treatment of BPH began to appear in the literature in 1992. This article reviews the results of landmark studies of these agents, either separately as monotherapy or as combined therapy, for the treatment of BPH. The relationship between prostate size and lower urinary tract symptoms (LUTS) is discussed. Although prostate volume is not as strongly correlated with these symptoms as was once believed, it has been shown to be an important predictor of risk for developing acute urinary retention. alpha-Blockers represent an effective treatment for LUTS independent of prostate volume; the clinical benefit of finasteride for LUTS is limited primarily to men with large prostates. Finasteride decreases the risk of progression to acute urinary retention and the requirement for surgical intervention; this benefit is greatest in men with enlarged prostates.     

5-alpha-Reductase Inhibitors Prevent the Progression of Benign Prostatic Hyperplasia

Lower urinary tract symptoms (LUTS) associated with clinical benign prostatic hyperplasia (BPH) are a common occurrence in aging men, causing bother and interference with daily activities and affecting disease-specific quality of life. There is increasing evidence to suggest that, in many patients, the signs and symptoms of BPH are progressive. Progression can be measured as continued growth of the prostate gland; worsening of symptoms, bother, or quality of life; deterioration of urinary flow rate; episodes of acute urinary retention (AUR); and need for prostate-related surgery. Furthermore, it has become clear that the risk of disease progression increases with age as well as with increasing prostate volume and serum prostate-specific antigen (PSA) level. The 5-alpha-reductase inhibitor finasteride has been shown not only to improve symptoms, bother, and quality of life but also to prevent progression to AUR and surgery, with a relative risk reduction of over 50%. As the risk for such progression is higher in patients with larger glands or higher serum PSA values at baseline, it is in those patients that finasteride induces an even greater risk reduction, making it a cost-effective treatment choice for patients with LUTS associated with prostatic enlargement.     

Validity of the "bother score" in the evaluation and treatment of symptomatic benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is a condition that is common among older men. It causes a variety of clinically significant lower urinary tract signs and symptoms. BPH is rarely life-threatening; the decision to seek treatment is frequently based on the degree to which patients find the symptoms bothersome and disruptive of daily activities. Recently developed reliable and valid outcome measures to evaluate treatments for BPH are clinical tools that urologists can use to determine the extent of bother and make treatment decisions. A single question used to determine the "bother score" provides a widely used and statistically valid measure of the need for treatment of BPH. Validation data support the argument that the bother score is a statistically reliable measure of treatment outcome in patients with BPH who view their symptoms as bothersome.     

Use of Tregs as a cell‐based therapy via CD39 for benign prostate hyperplasia with inflammation

Benign prostatic hyperplasia (BPH) occurs most commonly among older men, often accompanied by chronic tissue inflammation. Although its aetiology remains unclear, autoimmune dysregulation may contribute to BPH. Regulatory T cells (Tregs) prevent autoimmune responses and maintain immune homeostasis. In this study, we aimed to investigate Tregs frequency, phenotype, and function in BPH patients and to evaluate adoptive transfer Tregs for immunotherapy in mice with BPH via CD39. Prostate specimens and peripheral blood from BPH patients were used to investigate Treg subsets, phenotype and Treg‐associated cytokine production. Sorted CD39^+/? Tregs from healthy mice were adoptively transferred into mice before or after testosterone propionate administration. The Tregs percentage in peripheral blood from BPH patients was attenuated, exhibiting low Foxp3 and CD39 expression with low levels of serum IL‐10, IL‐35 and TGF‐β. Immunohistochemistry revealed Foxp3+ cells were significantly diminished in BPH prostate with severe inflammatory. Although the Tregs subset was comprised of more effector/memory Tregs, CD39 was still down‐regulated on effector/memory Tregs in BPH patients. Before or after testosterone propionate administration, no alterations of BPH symptoms were observed due to CD39‐ Tregs in mice, however, CD39⁺Tregs existed more potency than Tregs to regulate prostatic hyperplasia and inhibit inflammation by decreasing IL‐1β and PSA secretion, and increasing IL‐10 and TGF‐β secretion. Furthermore, adoptive transfer with functional Tregs not only improved prostate hyperplasia but also regulated muscle cell proliferation in bladder. Adoptive transfer with Tregs may provide a novel method for the prevention and treatment of BPH clinically.     

Medical therapy for benign prostatic hyperplasia: new terminology, new concepts, better choices

This article discusses 3 areas of medical therapy for benign prostatic hyperplasia (BPH) that are undergoing extensive research and evaluation: 1) the use of muscarinic receptor antagonists to treat lower urinary tract symptoms (LUTS) in men with BPH; 2) the definition of an "enlarged prostate"; and 3) sexual function and LUTS. Fears of worsening obstructive symptoms or causing acute urinary retention often keep practitioners from prescribing muscarinic receptor antagonists to men who might have concomitant bladder outlet obstruction; a multicenter, multinational, double-blind study showed that tolterodine is safe for men with low postvoid residual volumes. Most urologists accept that a prostate volume of more than 40 mL is consistent with an enlarged prostate; there is more debate regarding prostate volumes of 30 to 40 mL. Recently presented data suggest that combination medical therapy might be effective for men having prostates with volumes of more than 25 mL. The association between voiding and sexual function has been increasingly recognized and investigated, and there seem to be common pathophysiologic mechanisms governing both conditions. Targeted treatment algorithms addressing both conditions seem warranted.     

The role of estrogens and estrogen receptors in normal prostate growth and disease

Estrogens have significant direct and indirect effects on prostate gland development and homeostasis and have been long suspected in playing a role in the etiology of prostatic diseases. Direct effects are mediated through prostatic estrogen receptors alpha (ERalpha) and beta (ERbeta) with expression levels changing over time and with disease progression. The present review examines the evidence for a role of estrogens and specific estrogen receptors in prostate growth, differentiation and disease states including prostatitis, benign prostatic hyperplasia (BPH) and cancer and discusses potential therapeutic strategies for growth regulation via these pathways.     

17beta-estradiol affects proliferation and apoptosis of rat prostatic smooth muscle cells by modulating cell cycle transition and related proteins

Abundant evidence indicates that estrogens have an important role in the pathology of benign prostatic hyperplasia (BPH). To investigate the effect of 17beta-estradiol (E2) on the proliferation and apoptosis of prostatic smooth muscle cells (PSMCs), rat PSMCs were obtained and exposed to gradient concentrations (0.1-100 nmol/l) of E2 over varying amounts of time. The progression of cell cycle, cellular apoptosis, cyclin D1, Bcl-2 and Bax proteins were detected. The data show that the effect of E2 on rat PSMCs is bilateral: it promotes cell proliferation by enhancing the expression of cyclin D1, which accelerates G1 to S phase transition; on the other hand, it induces apoptosis of the cells by up-regulating the expression of Bax. We thus suggest that an increase in estrogen may exert a launching effect in the pathology of BPH.     

Estrone sulfate (E1S), a prognosis marker for tumor aggressiveness in prostate cancer (PCa)

Seeking insight into the possible role of estrogens in prostate cancer (PCa) evolution, we assayed serum E₂, estrone (E₁), and estrone sulfate (E₁S) in 349 PCa and 100 benign prostatic hyperplasia (BPH) patients, and in 208 control subjects in the same age range (50–74 years).

E₁ (pmol/L ± S.D.) and E₁S (nmol/L ± S.D.) in the PCa and BPH patients (respectively 126.1 ± 66.1 and 2.82 ± 1.78, and 127.8 ± 56.4 and 2.78 ± 2.12) were significantly higher than in the controls (113.8 ± 47.6 and 2.11 ± 0.96). E₂ was not significantly different among the PCa, BPH, and control groups. These assays were also carried out in PCa patients after partition by prognosis (PSA, Gleason score (GS), histological stage, and surgical margins (SM)). Significantly higher E₁S levels were found in PCa with: PSA > 10 ng/L (3.05 ± 1.92) versus PSA ≤ 10 ng/mL (2.60 ± 1.55), stage pT3-T4 (2.99 ± 1.80) versus pT2 (2.58 ± 1.58), and positive (3.26 ± 1.95) versus negative margins (2.52 ± 1.48). E₁ was higher in poor- than in better-prognosis PCa. E₂ was significantly higher in PCa with GS ≥ 4 + 3 (109.5 ± 43.8) versus GS ≤ 3 + 4 (100.6 ± 36.5) and increased significantly when GS increased from 3 + 3 to 4 + 4. Estrogens, especially E₁S appeared to be possible markers of PCa progression.

Attempting to identify potential sources of E₂ in PCa according to prognosis, as well as in BPH, we found a significant correlation coefficient between E₁S and E₂ (0.266–0.347) in poor-prognosis PCa and no correlation in BPH (0.026) and better-prognosis PCa (0.013–0.104).

It is as though during progression of PCa from good to poor prognosis there were a shift in the E₁ to E₂ metabolic pathway from predominantly oxidative to predominantly reductive.     

Effect of sorghum ethyl-acetate extract on benign prostatic hyperplasia induced by testosterone in Sprague–Dawley rats

ABSTRACT

Benign prostatic hyperplasia (BPH) is commonly observed in men > 50 years worldwide. Phytotherapy is one of the many treatment options. Sorghum (Sorghum bicolor L.) contains various health-improving phytochemicals with antioxidant and inhibitory activities on cell proliferation, both in vitro and in vivo. To confirm the effects of Donganme sorghum ethyl-acetate extract (DSEE) on BPH, we induced BPH in Spragye–Dawley rats using exogenous testosterone. We measured prostate weight, examined prostrates histopathologically, and analyzed mRNAs associated with male hormones and proteins associated with cell proliferation in the prostate. DSEE inhibited weight gain of the prostate; decreased mRNA expressions of androgen receptor and 5α-reductase II; and improved histopathological symptoms, the protein-expressed ratio of Bax/Bcl-2, and the oxidative status of BPH induced by testosterone in SD rats. Therefore, DSEE may have potential as a preventive or therapeutic agent against BPH.     

ESTROGEN METABOLISM IN MEN

In studies of men''s capacity for estrogen inactivation in health and disease, it was observed that patients with prostatic cancer had enhanced ability to inactivate estrogenic hormones. This ability might well lead to excessive androgen stimulation, thereby providing favorable hormonal environment for the development of prostatic cancer. Extension or regression of the malignant process did not affect this peculiar pattern of estrogen metabolism. It is possible, therefore, that the pattern may not be related to the cancer process itself but to some inherent tendency in the individual. Upon speculation as to whether or not this tendency is found in the liver, which is known to be the principal site of estrogen inactivation, studies of patients with liver damage were carried out and the results indicated that the liver possesses a tremendous reserve for inactivation of the estrogens in men.Studies on estrogen concentration in the bile indicated that estrogens are not eliminated rapidly from the human body through the biliary tract. However, this does not hold true for experimental animals.Observations on endogenous estrogen excretion in men did not support the concept that benign prostatic hypertrophy is due to an elevated estrogen-androgen ratio.     

Estrogen metabolism in men

In studies of men's capacity for estrogen inactivation in health and disease, it was observed that patients with prostatic cancer had enhanced ability to inactivate estrogenic hormones. This ability might well lead to excessive androgen stimulation, thereby providing favorable hormonal environment for the development of prostatic cancer. Extension or regression of the malignant process did not affect this peculiar pattern of estrogen metabolism. It is possible, therefore, that the pattern may not be related to the cancer process itself but to some inherent tendency in the individual. Upon speculation as to whether or not this tendency is found in the liver, which is known to be the principal site of estrogen inactivation, studies of patients with liver damage were carried out and the results indicated that the liver possesses a tremendous reserve for inactivation of the estrogens in men. Studies on estrogen concentration in the bile indicated that estrogens are not eliminated rapidly from the human body through the biliary tract. However, this does not hold true for experimental animals. Observations on endogenous estrogen excretion in men did not support the concept that benign prostatic hypertrophy is due to an elevated estrogen-androgen ratio.