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.     

Specific expression pattern of tissue cytokines analyzed through the Surface Acoustic Wave technique is associated with age-related spontaneous benign prostatic hyperplasia in rats

The aim of the study reported herein was to evaluate the suitability of the Surface Acoustic Wave (SAW) technique as a possible diagnostic tool in benign prostatic hyperplasia (BPH). Moreover, for the first time, the BPH model was a totally physiological using naturally aged rats with spontaneous, age-related BPH instead of the pharmacologically induced models usually used. Eighteen male Wistar rats were distributed according to their age: 6 weeks (young), 12 weeks (adult) and 12 months (old) old. Prostate gland was removed and analyzed by mini-arrays, Western blotting (WB) and SAW techniques. Mini-arrays indicated that there were significant differences in the expression of 29/34 inflammation-related cytokines. WB was carried out to confirm the results after selection of 4 cytokines from which one showed no changes, namely PDGF-AA, and the other three, which significantly increase in older animals, were CD86, β-NGF and VEGF. Notwithstanding, WB of old rats yielded confusing results due to an anomalous migration of proteins, dismissing this technique as an useful tool in these animals. Accurate results in old rats were uniquely obtained by using the SAW technique. Thus, SAW analysis showed that there were not differences among groups in the amount of PDGF-AA. On the contrary, SAW analysis showed that amounts of CD86, β-NGF and VEGF in old rats were 2.0, 1.9 and 5.7-fold higher than that from young ones, respectively. These results indicate that SAW is a highly accurate technique for determining changes in the cytokines expression in BPH.     

New quantification method for estradiol in the prostatic tissues of benign prostatic hyperplasia using liquid chromatography-tandem mass spectrometry

Estrogen is suspected to play a role in the pathogenesis of benign prostatic hyperplasia (BPH) and prostate cancer. To clarify the role of estradiol (E2) in the prostatic tissues (prostatic tissue E2) during the development of prostatic disorders, we developed a new sensitive and specific quantification method for prostatic tissue E2 using liquid chromatography-tandem mass spectrometry (LC-MS/MS). For the solid-phase extraction, E2 was purified by anion-exchange through an Oasis MAX cartridge. In addition, after the formation of 3-pentaflurobenzyl-17β-pyridinium-estradiol derivative (E2-PFBPY), E2-PFBPY was purified by cation-exchange through an Oasis WCX cartridge. These processes in the LC-MS/MS method improved the specificity and sensitivity for prostatic tissue E2 measurement, compared to the radioimmunoassay (RIA) method. The validation tests showed that intra-day and inter-day precisions were both within ±15% (except for 15.5% of the inter-day precision of the lowest concentration), with the accuracy ranging from 88 to 110%. The quantification limit of this assay was 0.15 pg/tube in our method, which was 80-fold more sensitive than that of the RIA method. With the use of our present method, the median E2 levels in the prostatic tissues in patients with BPH (n = 20, median age: 71 years) were 12.0 pg/g tissue (95% confidence interval = 9.1-22.6 pg/g tissue). Furthermore, the E2 levels increased significantly with aging. These results showed that our present method would be useful for elucidating the role of prostatic tissue E2 in the development of prostatic disorders with a small amount of tissue samples.     

Tissue and serum levels of principal androgens in benign prostatic hyperplasia and prostate cancer

Androgens are considered to play a substantial role in pathogenesis of both benign prostatic hyperplasia (BPH) and prostate cancer. The importance of determination of androgen levels in tissue and serum for cancer progression and prognosis has been poorly understood. The aim of study was to find out hormonal differences in both diseases, their correlations between intraprostatic and serum levels and predicted value of their investigation. Testosterone, dihydrotestosterone, androstenedione and also epitestosterone were determined in prostate tissue from 57 patients who underwent transvesical prostatectomy for BPH and 121 patients after radical prostatectomy for prostate cancer. In 75 subjects with cancer and 51 with BPH the serum samples were analyzed for testosterone, dihydrotestosterone and SHBG. Significantly higher intraprostatic androgen concentrations, i.e. 8.85+/-6.77 versus 6.44+/-6.43 pmol/g, p<0.01 for dihydrotestosterone, and 4.61+/-7.02 versus 3.44+/-4.53 pmol/g, p<0.05 for testosterone, respectively, were found in patients with prostate cancer than in BPH. Higher levels in cancer tissue were found also for epitestosterone. However, no differences were found in serum levels. Highly significant correlations occurred between all pairs of intraprostatic androgens and also epitestosterone as well as between serum testosterone and dihydrotestosterone (p<0.001) in both BPH and cancer groups. Correlation was not found between corresponding tissue and serum testosterone and dihydrotestosterone, either in benign or cancer samples. The results point to importance of intraprostatic hormone levels for evaluation of androgen status of patients, contrasting to a low value of serum hormone measurement.     

Bee venom suppresses testosterone-induced benign prostatic hyperplasia by regulating the inflammatory response and apoptosis

Benign prostatic hyperplasia (BPH), which is a common disorder in aging men, involves inflammation that is associated with an imbalance between cell proliferation and cell death. Because current BPH drug treatments have undesirable side effects, the development of well-tolerated and effective alternative medicines to treat BPH is of interest. Bee venom (BV) has been used in traditional medicine to treat conditions, such as arthritis and rheumatism, and pain. Although inflammation has been associated with BPH and BV has strong anti-inflammatory effects, the effects of BV on BPH are not fully understood. Therefore, in this study, we evaluated the efficacy of BV against testosterone-induced BPH in rats. BV decreased prostate weight compared to the untreated group. In addition, BV suppressed serum dihydrotestosterone concentration levels and the levels of proliferating cell nuclear antigen in the histological analysis. Furthermore, BV significantly decreased the levels of the apoptotic suppressors, Bcl-2 and Bcl-xL, and increased the levels of the proapoptotic factors, Bax and caspase-3 activation. These results suggested that BV suppressed the development of BPH and has good potential as a treatment for BPH.     

Identification of key genes and pathways in benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is one of the most common causes of lower urinary tract symptoms (LUTS) in elderly man. However, the underlying molecular mechanisms of BPH have not been completely elucidated. We identified the key genes and pathways by using analysis of Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using edgeR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for the DEGs by Database for Annotation, Visualization and Integrated Discovery (DAVID) database and ConsensusPathDB, respectively. Then, protein–protein interaction (PPI) networks were established by the Search Tool for the Retrieval of Interacting Genes (STRING) database and visualized by Cytoscape software. Finally, we identified 660 DEGs ultimately including 268 upregulated genes and 392 downregulated genes. GO analysis revealed that DEGs were mainly enriched in extracellular exosome, identical protein binding, mitochondrial adenosine triphosphate (ATP) synthesis coupled proton transport, extracelluar matrix, focal adhesion, cytosol, Golgi apparatus, cytoplasm, protein binding, and Golgi membrane. Focal adhesion pathway, FoxO signaling pathway, and autophagy pathway were selected. Ubiquitin-conjugating enzyme E2 C (UBE2C), serine/threonine kinase (AKT1), mitogen-activated protein kinase 1 (MAPK1), cyclin B1 (CCNB1), polo-like kinase 1 (PLK1) were filtrated as the hub genes according to the degree of connectivity from the PPI network. The five hub genes including UBE2C, AKT1, MAPK1, CCNB1, PLK1 may play key roles in the pathogenesis of benign prostatic hyperplasia (BPH). Focal adhesion pathway, FoxO signaling pathway, and autophagy pathway may be crucial for the progression of BPH.     

酒精对丙酸睾酮诱导的小鼠前列腺增生的作用

目的：探讨酒精对丙酸睾酮引起的小鼠前列腺增生（BPH）的作用及其生殖毒性。方法：成年雄性昆明系小鼠70只随机分为空白对照组（Control）、阴性对照组（Negative control,sc大豆油25 mg/（kg·d）,ig蒸馏水7.5 ml/（kg·d）,连续处理7 d、21 d）、酒精7 d和21 d组（AL7和AL21,ig 50°白酒7.5 ml/（kg·d）,连续处理7 d、21 d）,丙酸睾酮7 d和21 d组（TP7和TP21,sc丙酸睾酮注射液25 mg/（kg·d）,连续处理7 d、21 d）,丙酸睾酮+酒精7 d组（TP+AL7,sc丙酸睾酮注射液25 mg/（kg·d）,ig50°白酒7.5 ml/（kg·d）,连续处理7 d）,每组10只。末次处理24 h后处死小鼠,计算小鼠前列腺和睾丸系数,检测精子参数,测定睾丸和前列腺组织中自由基水平、抗氧化能力,观察前列腺组织病理学变化。结果：与对照组、TP7 d组、AL7和AL21 d组相比,TP+AL7 d组的前列腺系数显著提高、精子数量和质量显著降低、前列腺和睾丸MDA含量显著升高、SOD和GPx酶活力显著下降（P均< 0.05）;与TP21 d组相比,TP+AL7 d组的前列腺系数无显著差别（P>0.05））。结论：丙酸睾酮和酒精共同处理7 d就可以达到典型的前列腺增生（BPH）状态,并引起睾丸及精子的损伤,导致生殖系统的氧化应激反应增强,说明酒精对丙酸睾酮引起的小鼠前列腺增生有明显的促进作用。     

Central obesity as a risk factor for prostatic hyperplasia

Objective: Obesity‐related metabolic diseases may influence prostatic hyperplasia. This study examined the impact of obesity on prostate volume in men without overt obesity‐related metabolic diseases. Research Methods and Procedures: We recruited 146 men over the age of 40 years who did not have overt obesity‐related diseases, such as diabetes, impaired fasting glucose, hypertension, or dyslipidemia. Transrectal ultrasonography was performed on all subjects. The subjects were divided into three groups according to their BMI: normal (18.5 to 22.9 kg/m²), overweight (23 to 24.9 kg/m²), and obese (≥25 kg/m²), and two groups according to their waist circumference: normal waist (≤90 cm) and central obesity (>90 cm). The classification of the subgroups was based on the Asia‐Pacific criteria of obesity. We compared the prostate volume among subgroups and assessed factors related to prostatic hyperplasia. Results: Mean prostate volume was 18.8 ± 5.0, 21.8 ± 7.2, and 21.8 ± 5.6 mL in the normal, overweight, and obese groups, respectively, and was 20.0 ± 5.9 and 23.7 ± 5.3 mL in the normal waist and central obesity group, respectively. Prostate volume was significantly greater in the obese group than in the normal group (P = 0.03) and in the central obesity group compared with the normal waist group (P = 0.002). Prostate volume was positively correlated with BMI and waist circumference after adjustment for age. After adjusting for confounding factors, central obesity was an independent factor affecting prostatic hyperplasia, which was defined as a prostate volume >20 mL (odds ratio = 3.37, p = 0.037). Relative to men with both low BMI (18.5 to 22.9 kg/m²) and normal waist circumference, those with high BMI (≥25 kg/m²) and central obesity were at significantly increased risk of prostatic hyperplasia (odds ratio = 4.88, p = 0.008). However, those with high BMI (≥25 kg/m²) and normal waist circumference were not at significantly increased risk. Discussion: Prostate volume was greater in the obese and central obesity groups than in the normal group after patients with overt obesity‐related metabolic diseases were excluded. Although both BMI and waist circumference were positively correlated with prostate volume, central obesity was the only independent factor affecting prostate hyperplasia. We suggest that central obesity is an important risk factor for prostatic hyperplasia.     

自发性及睾酮诱导犬前列腺增生模型的比较

目的比较自发性及雄激素诱导犬前列腺增生模型的特点,为更好地评价治疗前列腺增生药物奠定方法学基础。方法成年雄性Beagle犬12只,随机分成2组,B超探测符合要求的老年Beagle犬6只,依次设为对照组、睾酮组和老年犬组（即自发性前列腺增生组）。睾酮组动物去势后,经肌肉注射（im）2.5 mg/kg的睾酮,对照组动物给予等体积溶媒,老年犬组动物不给药,连续4周。每周称重一次,最后一次给药24 h后,B超探测前列腺体积,采血,取血清备用。麻醉处死动物,取前列腺,称干湿重,测量前列腺体积,计算前列腺脏器系数,组织切片,HE染色后镜下观察前列腺病理组织学变化,并进一步利用显微图像软件测量前列腺上皮高度及腺腔面积。利用磁酶免和ELISA方法检测血清及前列腺组织中睾酮（T）、双氢睾酮（DHT）、前列腺特异抗原（PSA）和前列腺酸性磷酸酶（PAP）水平。结果①给药后,各组动物体重增长总体呈平稳趋势。②B超结果显示,去势Beagle犬给予睾酮4周,前列腺体积大于对照组（P〈0.01）,老年犬前列腺体积大于成年犬（P〈0.01）。③解剖结果显示,睾酮组和老年犬组实际前列腺体积均明显大于对照组（P〈0.05）,且老年犬前列腺体积大于睾酮组;睾酮组和老年犬组前列腺湿量和脏器系数均大于对照组（P〈0.05）,且老年犬前列腺湿重和脏器系数均大于睾酮组。④病理形态分析显示,睾酮组犬前列腺镜下主要表现为腺体增生,尤其是腺上皮增生,而老年犬则更多表现为间质增生。显微图像分析结果显示,与正常对照组相比,睾酮组前列腺上皮高度增加（P〈0.01）,腺腔面积增大（P〈0.01）;老年Bea-gle犬同样表现为前列腺上皮高度增加（P〈0.01）,腺腔面积增大（P〈0.05）,但上皮高度要低于睾酮组。⑤激素检测结果显示,与对照组相比,睾酮组血清中T、DHT和PAP水平略升高,前列腺组织中T（P〈0.05）、DHT（P〈0.01）、PAP（P〈0.05）和PSA水平升高明显;老年犬血清中T、DHT和PAP水平略升高,前列腺组织中T升高,但DHT、PAP和PSA水平均较正常组为低。结论自发性和睾酮诱导的犬前列腺增生模型均可用于前列腺增生药物评价,但模型间存在一定的差异性。     

Dose–response effect of Red Maca (Lepidium meyenii) on benign prostatic hyperplasia induced by testosterone enanthate

The main goal of this study was to determine the effect of a freeze-dried aqueous extract of the red variety of Lepidium meyenii (Red Maca) on testosterone-induced benign prostatic hyperplasia (BPH) in adult rats of the Holtzman strain. Rats were treated with freeze-dried aqueous extract of Red Maca at doses of 0, 0.01, 0.05, 0.1, and 0.5 g/kg body wt. A positive control group received Finasteride (0.6 mg/kg body wt.). After treatment, the animals were sacrificed, and the ventral prostate was extracted, and weighed. HPLC was used to determine the presence of glucosinolates in Red Maca. The prostate weight diminished in a dose-dependent fashion in rats treated with Red Maca. The effect of Red Maca was better than that observed with Finasteride. Finasteride, but not Red Maca, reduced seminal vesicles weight. Analysis of the HPLC indicated the presence of benzyl glucosinolate (Glucotropaeolin) with a content of 0.639%. Serum testosterone levels were not affected by Red Maca. Moreover, serum testosterone levels were not related to prostate or seminal vesicles weight in rats treated with vehicle and Red Maca. In conclusion, Red Maca administered orally in rats seems to exert an inhibitory effect at a level post DHT conversion, on the BPH-induced experimentally, although a direct measure of reductase action would still be required.     

A lectin histochemistry comparative study in human normal prostate, benign prostatic hyperplasia, and prostatic carcinoma

The partial oligosaccharide sequences of glycoconjugates and the nature of their glycosidic linkages were investigated in normal human prostate, benign prostatic hyperplasia (BPH) and prostatic carcinoma by means of lectin histochemistry, using light microscopy and Western blot analysis. The labeling pattern of BPH differed from that of normal prostate in having more intense staining with DSA, HPA, UEA-I and AAA, and in showing lesser staining with WGA and SBA. Prostatic carcinoma differed from normal prostates in displaying the more intense labeling with PNA, DSA, SBA, DBA, UEA-I and AAA, and in having lesser labeling with WGA. The main differences in labeling pattern between prostatic carcinoma and BPH were that the latter specimens showed more marked staining with PNA, DSA, DBA, SBA, UEA-I and AAA, and lesser staining with WGA and HPA. The staining patterns of SNA, MAA, ConA, LCA and GNA were similar in all three groups of specimens. For most of the lectins studied, including those showing a similar immunohistochemical staining in the three groups of specimens studied, the Western blot analysis showed differences in the banding pattern among normal, hyperplastic, and carcinomatous prostates. Present results suggest that the glycosylation of proteins was modified in both BPH and prostatic carcinoma. In BPH a strong expression of N-acetylgalactosamine residues occurred, while in prostatic carcinoma an increase of sialic aci, galactose and fucose residues was observed. No changes in mannose residues were detected.     

Protocatechuic acid ameliorates testosterone‐induced benign prostatic hyperplasia through the regulation of inflammation and oxidative stress in castrated rats

Protocatechuic acid (PA) is a polyphenol—recognized for its efficacy as an antioxidant—possesses anticancer, anti‐inflammatory, antioxidant properties. The efficacy of PA in the management of benign prostatic hyperplasia (BPH) has not been investigated. Forty‐two castrated rats (n = 7) were treated as follows: control (corn oil), BPH only received testosterone propionate (TP) (TP 3 mg/kg intraperitoneally), BPH + PA (TP 3 mg/kg + PA 40 mg/kg), BPH + finasteride (Fin) (TP 3 mg/kg + Fin 10 mg/kg), PA only (40 mg/kg: by gavage), and Fin only (10 mg/kg: by gavage) for 4 weeks. In BPH rats, there were significant (P < .05) increases in prostatic (250%) and organosomatic (280%) weights compared with controls. Cotreatment decreased prostatic weights by 19% (PA) and 21% (Fin). Markers of inflammation: myeloperoxidase activities increased in serum (148%) and prostate (70%), as well as nitric oxide levels serum (92%) and prostatic (95%). Proinflammatory cytokines interleukin‐1β and tumor necrosis factor‐α increased by 3.6‐ and 2.8‐fold. Furthermore, prostatic malondialdehyde, superoxide dismutase, and serum total acid phosphatase increased by 97%, 25%, and 48%, respectively. Histology revealed poor architecture and severe proliferation of the prostate in BPH rats. Inflammation and oxidative stress markers, as well as the histological alteration in BPH rats, was attenuated (P < .05) upon cotreatment with PA and comparable with Fin cotreatment. These results suggest that PA mitigates oxido‐inflammatory responses and restored prostatic cytoarchitecture to levels comparable with control in rats induced with BPH.     

Selenium level in benign and cancerous prostate

The dietary microelement selenium (Se) has been proposed as a potential chemopreventive agent for prostate cancer. This element is present in various amounts in all tissues. Little information is available on Se level in patients with prostate gland disorders. The levels of Se in prostatic gland of patients with prostate cancer, benign prostate hyperplasia, and healthy controls were examined. The Se level for benign prostate hyperplasia (156±30.6 ng/g) was the same as in the control group (157±26.0 ng/g), but in the gland of prostate cancer patients (182±34.1 ng/g wet weight), the Se level was significantly (p<0.01) higher than in both healthy controls and benign prostate hyperplasia. Thus, the Se level in human healthy controls is lower than in kidney and liver but higher compared with other tissues.     

Relevance of anti-reactive oxygen species activity to anti-inflammatory activity of components of Eviprostat, a phytotherapeutic agent for benign prostatic hyperplasia

Inflammation is a common finding in benign prostatic hyperplasia (BPH). The phytotherapeutic agent eviprostat is a popular treatment for BPH in Japan and Germany. This agent consists of five components; four are extracted from Chimaphila umbellata, Populus tremula, Pulsatilla pratensis and Equisetum arvense (coded as EVI-1, EVI-2, EVI-3 and EVI-4, respectively) and the fifth is germ oil from Triticum aestivum (coded as EVI-5). In this study, the effects of each component on the reactive oxygen species (ROS), superoxide anion (O2-) and hydroxyl radical (OH*) generated in cell-free systems and human neutrophils, and on carrageenin-induced paw edema in rats were investigated. EVI-1, EVI-2 and EVI-4 suppressed the O2- levels in the xanthine/xanthine oxidase system, and EVI-1, EVI-2, EVI-3 and EVI-4 abolished the OH* produced in a Fenton-type reaction system, so that EVI-1, EVI-2 and EVI-4 possessed inhibitory action with respect to both O2- and OH*. EVI-1, EVI-2 and EVI-4 also reduced ROS levels in phorbol myristate acetate-stimulated neutrophils. The paw swelling was inhibited by a mixture of EVI-1, EVI-2, EVI-3, EVI-4 and EVI-5 (a mixture which is equivalent to eviprostat) or by a mixture of EVI-1, EVI-2 and EVI-4, even though each component alone did not significantly inhibit the swelling. These findings suggest that the suppression of ROS by EVI-1, EVI-2 and EVI-4 may partly contribute to the anti-inflammatory action of eviprostat, and this action may be implicated in its therapeutic effect on BPH.     

Structure and expression of the nerve growth factor gene in Xenopus oocytes and embryos

A large part of the coding portion of the Xenopus nerve growth factor (NGF) gene has been identified and cloned by the use of a chicken cDNA probe and its sequence has been determined. Comparison of the derived amino acid sequence of mature Xenopus NGF with that of other species showed a high conservation, whereas comparison of the prepropeptide showed large divergent regions alternated with short conserved regions. Expression of the NGF gene was examined during development of oocytes and embryos. Surprisingly, NGF mRNA was found in the oocyte; it is present in small previtellogenic as well as in fully grown oocytes. NGF mRNA, passed to the embryo at fertilization, is degraded before the gastrula stage and starts accumulating again around the stage of the neurula. The association of NGF mRNA with polysomes is indicative of NGF synthesis during oogenesis. In fact, by using antibodies against mouse NGF it was possible to reveal NGF molecules present as precursors. These molecules accumulate during oogenesis and are maintained in the embryos up to the blastula stage; a very faint band corresponding to a smaller size peptide is sometimes detected. A maternal role for the NGF can be proposed, although a possible activity of NGF in the oocyte cannot be ruled out.     

Selenium in combination with a tomato lipid extract as a therapy for benign prostatic hyperplasia and its alterations in rats with induced BPH

Benign prostatic hyperplasia (BPH) is the most common adenoma in old men. Tomatoes are a rich source of bioactive compounds that, as well as selenium (Se), possess antioxidant and antiproliferative activity. The aim was to evaluate the therapeutic effect of Se in combination with a tomato extract in aged rats with BPH. Aged male Wistar rats were divided in the following groups (n = 10 rats/group): Control (C), BPH, BPH + Finasteride (BPH + F), BPH + Tomato Lipidic Extract (BPH + E), BPH + Selenium (BPH + S) and BPH plus E plus S (BPH + E + S). After 4 weeks of treatment, prostate weight, diuresis, antioxidants enzymes, prooxidants and inflammatory markers, growth factors and androgens were determined. BPH + E + S reduced prostate weight by 59.29% and inhibited growth by 99.35% compared to BPH + F which only decreased weight and inhibited growth by 15.31% and 57.54%, respectively. Prooxidant markers were higher with BPH + F (49.4% higher vs. BPH), but BPH + E + S decreased these markers (94.27% vs. BPH) and increased antioxidant activity. Finally, diuresis was higher with the BPH + E + S combination and markers of inflammation and growth factors were significantly lower with respect to BPH + F. Our findings provide a beneficial and protective therapeutic option of E + S directed against androgens, oxidative stress and inflammation that regulates cell proliferation in the prostate gland.     

Epidermal growth factor binding and steroid receptor content in human benign prostatic hyperplasia

The receptor for epidermal growth factor (EGF-R) was characterized on membrane fractions from human benign prostatic hyperplasia (BPH). Specific binding of [125I]EGF reached equilibrium after 40 min at 25 degrees C and was stable for up to 120 min. Saturation analysis of EGF-R, performed by incubating the membranes with 0.0156-15 nM [125I]EGF in the presence and in the absence of 100-fold excess of cold EGF for 60 min, revealed the presence of two classes of binding sites with high and low affinities (Kd = 0.35 +/- 0.23 and 9.60 +/- 2.87 nM respectively). Competition experiments revealed that FSH, insulin and calcitonin did not compete with [125I]EGF. The simultaneous determination of EGF-R and that of estradiol (ER), progesterone (PR) and androgen receptors (AR) was performed using the same buffer to homogenate the tissues and to obtain cellular membranes. The steroid receptors (SR) were determined by means of the dextran-coated charcoal method. There was a significant negative correlation between nuclear SR and binding capacity of EGF-R. The presence of specific and high affinity binding sites for EGF and the modulation of the level of these sites by steroid receptors suggest a possible role of EGF in prostatic hyperplasia.     

Effect of castration monotherapy on the levels of adrenal androgens in cancerous prostatic tissues

The mechanism accounting for the development of castration-resistant prostate cancer (CRPC) remains unclear. Studies in CRPC tissues suggest that, after androgen deprivation therapy (ADT), the adrenal androgens may be an important source of testosterone (T) and 5-alpha dihydrotestosterone (DHT) in CRPC tissues. To clarify the role of adrenal androgens in the prostatic tissues (prostatic tissue adrenal androgens) during ADT, we developed a high sensitive and specific quantification method for the levels of androgens in prostatic tissue using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Human prostatic tissues were purified using mixed-mode reversed-phase, strong anion exchange Oasis cartridges (Oasis MAX). Analysis of steroids was performed using LC-MS/MS after picolinic acid derivatization. The validation tests showed that our method of quantitative analysis was precise and sensitive enough for the quantification of dehydroepiandrosterone (DHEA), androstenedione, androstenediol, T, and DHT in the prostatic tissue. The levels of adrenal androgens in prostate cancer tissues after ADT were similar to those in untreated PCa. Especially, DHEA was the most existing androgen precursor in PCa tissues after ADT. The levels of DHEA were high in PCa tissues, irrespective of ADT. We assumed that DHEA played a significant role in the synthesis of T and DHT in PCa tissues after ADT.     

Effects of estrogen deprivation on human benign prostatic hyperplasia

Sex steroids are thought to play an essential role in the pathogenesis of human benign prostatic hyperplasia (BPH). Since recent studies in animal models and in men have shown that estrogens might be causally linked to the onset and maintenance of BPH, we examined the effect of 1-methyl-androsta-1,4-diene-3,17-dione (Atamestane), a newly developed aromatase inhibitor, in men with BPH. In an open multicenter study 49 men (mean age 70.1 years, range 55 to 84) with obstructive BPH were treated with atamestane (3 × 200 mg/day) for 3 months. Of the 49 patients 44 completed the treatment period; the other patients discontinued the study for reasons unrelated to treatment. With treatment BPH-related symptoms such as daytime voiding frequency, nycturia, peak flow and residual urine improved considerably; however, these parameters did not reach statistical significance. The mean prostatic volume decreased significantly from 74.2 ± 31.7 to 64.0 ± 31 ml (mean ± SD). Serum estrogen levels decreased markedly during treatment. In addition intraprostatic estrogen concentration decreased with treatment as compared to estrogen levels in hyperplastic prostates from untreated patients. The following conclusions can be drawn from this study: first, estrogens appear to have an important supportive role in established BPH, and second, estrogen deprivation improved BPH-related symptoms and reduced significantly prostatic volume.