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.     

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.     

Effects of Panax ginseng on the nerve growth factor expression in testosterone induced benign prostatic hyperplasia

The prostatic hyperplasia in benign prostatic hyperplasia (BPH) leads to obstructive micturition symptoms. Previous studies showed that pontine micturition center (PMC), ventrolateral periaqueductal gray (vlPAG), and medial preopticnucleus (MPA) regions in the brain have been known to regulate the urinary bladder function. The present study shows the influences of Panax ginseng on nerve growth factor (NGF) expressions in PMC, vlPAG, and MPA regions in the brain. Wistar rats were used for the present study. The rats split into four groups; 4 groups (n = 6) in control group, BPH-induced group, BPH-induced and P. ginseng-treated group, and BPH-induced and finasteride-treated group. BPH in rats was induced by testosterone and the animals were evaluated for NGF expression in PMC, vlPAG, and MPA regions in the brain. The NGF expression was identified using immunohistochemistry (IHC). The NGF expression by IHC showed spots with dark brown color. In our results, NGF expressions in PMC, vlPAG, and MPA regions in the brainstem of the BPH-induced group showed increase than the control animal. These increased NGF expressions in three regions were decreased using treatment with P. ginseng (200 mg/kg). These results suggest that P. ginseng has therapeutic effects on the symptoms of BPH and is associated with the regulation of NGF expression in the brain. In conclusion, the administration of P. ginseng helps nerve growth factor activation.     

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.     

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.     

Pathological and molecular mechanisms of prostate carcinogenesis: implications for diagnosis, detection, prevention, and treatment

Prostate cancer is an increasing threat throughout the world. As a result of a demographic shift in population, the number of men at risk for developing prostate cancer is growing rapidly. For 2002, an estimated 189,000 prostate cancer cases were diagnosed in the U.S., accompanied by an estimated 30,200 prostate cancer deaths [Jemal et al., 2002]. Most prostate cancer is now diagnosed in men who were biopsied as a result of an elevated serum PSA (>4 ng/ml) level detected following routine screening. Autopsy studies [Breslow et al., 1977; Yatani et al., 1982; Sakr et al., 1993], and the recent results of the Prostate Cancer Prevention Trial (PCPT) [Thompson et al., 2003], a large scale clinical trial where all men entered the trial without an elevated PSA (<3 ng/ml) were subsequently biopsied, indicate the prevalence of histologic prostate cancer is much higher than anticipated by PSA screening. Environmental factors, such as diet and lifestyle, have long been recognized contributors to the development of prostate cancer. Recent studies of the molecular alterations in prostate cancer cells have begun to provide clues as to how prostate cancer may arise and progress. For example, while inflammation in the prostate has been suggested previously as a contributor to prostate cancer development [Gardner and Bennett, 1992; Platz, 1998; De Marzo et al., 1999; Nelson et al., 2003], research regarding the genetic and pathological aspects of prostate inflammation has only recently begun to receive attention. Here, we review the subject of inflammation and prostate cancer as part of a "chronic epithelial injury" hypothesis of prostate carcinogenesis, and the somatic genome and phenotypic changes characteristic of prostate cancer cells. We also present the implications of these changes for prostate cancer diagnosis, detection, prevention, and treatment.     

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.     

右美托咪啶对经尿道前列腺电切阴茎勃起的影响*

目的:探究右美托咪定(DEX)对经尿道前列腺电切术(TURP)后阴茎勃起的影响。方法:选取2017年1月至2018年3月于我院确诊为良性前列腺增生并行经TURP的86例患者,按照随机数字表法均分为实验组和对照组,每组43例。其中,实验组于手术初始即使用输液泵持续输注右美托咪定(输注剂量0.5μg/kg)直至手术结束,对照组患者于手术开始时即开始使用输液泵持续输注等量的生理盐水直至手术结束。于麻醉前(T1)、麻醉插管后导尿前(T2)、DEX或生理盐水泵入10 min时(T3)、手术开始后导尿时(T4)四个时间点比较两组患者的平均脉压差(MAP)、心率(HR)、阴茎勃起发生率及术后膀胱刺激征的发生率。结果:T1、T2、T3时刻,两组间HR和MAP水平比较差异无统计学意义(P0.05),T4时,对照组HR和MAP均选择低于实验组,差异具有统计学意义(P0.05);两组患者T1及T2时阴茎勃起率比较差异无统计学意义(P0.05),对照组T3、T4阴茎勃起率分别为27.91%、74.42%,实验组患者T3、T4阴茎勃起率分别为6.98%、11.63%,差异具有统计学意义(P0.05)。实验组术后膀胱刺激征出现率为9.30%,低于对照组的32.56%,差异具有统计学意义(P0.05)。结论:右美托咪定用于TURP术中可以有效稳定患者术中血流动力学,并降低患者术后阴茎异常勃起率,且术后患者膀胱刺激征发生率显著降低。     

Oxytocin,oxytocin-associated neurophysin and the oxytocin receptor in the human prostate

Oxytocin has been implicated in the regulation of prostate growth. However, the cellular localisation of oxytocin in the normal and diseased human prostate is not known. Oxytocin, oxytocin-associated neurophysin and oxytocin receptor were detected by immunohistochemistry in tissues from patients undergoing routine prostatectomy and in normal human prostate epithelial and stromal cell lines. Western blot analysis detected a single band at 14 kDa with neurophysin antiserum and a 66-kDa band with oxytocin receptor antiserum in epithelial and stromal cell lines. Similar sized bands were also detected in extracts of hyperplastic and adenocarcinomic prostate tissues. Oxytocin, oxytocin-associated neurophysin and oxytocin receptor were present in stromal and epithelial cell lines and in tissue from patients with benign prostatic hyperplasia. The peptides were localised predominantly to the epithelial cells, although discrete areas of stromal staining were also observed. There was a significant difference in the intensity of oxytocin-staining between tissue displaying benign prostatic hyperplasia and invasive carcinoma, with less immunoreactivity being present in the malignant epithelial cells. Thus, oxytocin and its neurophysin and receptor are present in epithelial and stromal cells of the human prostate. Oxytocin expression is reduced with tumour progression and may provide a marker for invasive disease.This work was supported by a Project Grant (007756) from the Wellcome Trust and from Lottery Health Research     

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.     

血糖与前列腺癌患者的关系

目的:探讨前列腺活检患者的血糖与前列腺癌患者的关系。方法:前瞻性收集416例初次经直肠超声引导下前列腺穿刺活检患者的血糖、前列腺特异性抗原(PSA)和Gleason评分等临床资料,所有患者以血糖浓度6.1 mmol/L为界分成两组,比较高血糖组和正常血糖组前列腺癌检出率和Gleason评分的差异。结果:416例前列腺活检患者中,检出前列腺癌165例,高血糖组38例(40.00%),正常血糖组127例(39.56%),差异无统计学意义(P0.05);低级别前列腺癌(Gleason7分)患者的构成比分别为0.184、0.071,差异有统计学意义(P0.05),Spearman等级相关分析显示前列腺癌患者的血糖值与Gleason评分呈负相关(r=-0.228,P0.05)。结论:血糖对前列腺活检患者中前列腺癌检出率没有影响,但提高了低级别前列腺癌患者的构成比,血糖是影响前列腺癌Gleason评分的一个独立因素。     

经尿道等离子前列腺剜除术与经尿道前列腺电切术治疗良性前列腺增生症的临床疗效对比研究

摘要 目的：对比经尿道等离子前列腺剜除术（TUKEP）与经尿道前列腺电切术（TURP）治疗良性前列腺增生症（BPH）的临床疗效。方法：回顾性分析我院2018年1月1日至2021年3月17日期间收治的200例BPH患者的临床资料。根据手术方式的不同将患者分为A组（n=83）和B组（n=117）,A组手术方式为TURP,B组手术方式为TUKEP,比较两组围术期指标,随访6个月,对比两组性功能、尿流动力学变化及并发症发生情况。结果：B组手术时间、术中出血量、尿管留置时间、住院时间、术后冲洗时间短于A组（P<0.05）。术后6个月,两组患者的最大尿流速（Qmax）、膀胱顺应性（BC）升高,剩余尿量（PVR）降低（P<0.05）,且B组患者的Qmax、BC高于A组,PVR低于A组（P<0.05）。术后6个月,两组患者的勃起功能评分表（IIEF-5）、射精功能评分表（CIPE-5）评分降低（P<0.05）,但B组、A组IIEF-5、CIPE-5评分组间对比无明显统计学差异（P>0.05）。B组的并发症发生率小于A组（P<0.05）。结论：TUKEP、TURP治疗BPH,疗效相当,TUKEP在缩短手术时间、尿管留置时间、术后冲洗时间、住院时间,降低术中出血量,减少并发症发生率,改善尿流动力学方面更有优势。     

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.     

Inhibition of prostate growth and inflammation by the vitamin D receptor agonist BXL-628 (elocalcitol)

The prostate is a target organ of vitamin D receptor (VDR) agonists and represents an extra-renal site of 1,25-dihydroxyvitamin D₃ synthesis, but its capacity to respond to VDR agonists has, so far, been almost exclusively probed for the treatment of prostate cancer. We have analyzed the capacity of VDR agonists to treat benign prostatic hyperplasia (BPH), a complex syndrome characterized by a static component related to prostate overgrowth, a dynamic one responsible for urinary irritative symptoms, and an inflammatory component. Preclinical data demonstrate that VDR agonists, and notably BXL-628 (elocalcitol), reduce the static component of BPH by inhibiting the activity of intra-prostatic growth factors downstream of the androgen receptor, and the dynamic component by targeting bladder cells. In addition, BXL-628 inhibits production of proinflammatory cytokines and chemokines by human BPH cells. These data have led to a proof-of-concept clinical study that has successfully shown arrest of prostate growth in BPH patients treated with BXL-628, with excellent safety. We have documented the anti-inflammatory effects of BXL-628 also in animal models of autoimmune prostatitis, observing a significant reduction of intra-prostatic cell infiltrate following administration of this VDR agonist, at normocalcemic doses, in mice with already established disease. These data extend the potential use of VDR agonists to novel indications that represent important unmet medical needs, and provide a sound rationale for further clinical testing.     

Selenium concentration in the prostate

Samples of healthy tissue were taken from each of six prostatectomy specimens (55–72 yr), digested with acids, and analyzed for selenium by atomic fluorescence spectroscopy. The concentrations for five specimens were 1.32±0.09 μg Se/g dry wt (range 1.24–1.42) and 0.213±0.012 μg Se/g wet wt (range 0.200–0.229). The other specimen, from a 58-yr-old man who was the only one within this study to take a 200-μg Se/d dietary supplement, contained 2.72 μg Se/g dry wt and 0.421 μg Se/g wet wt.     

Zinc and cadmium analysis in human prostate neoplasms

The objective of this study was to test the hypothesis that prostatic cancer is associated with the changes of zinc (Zn) and cadmium (Cd) concentration. Normal prostate, benign prostatic hyperplasia (BPH), and prostatic carcinoma (PCA) were analyzed for Zn and Cd by atomic absorption spectrometry. Cd level was measured using a graphite furnace and Zn level was measured by flame mode. Metal content was assessed in whole tissues and in nuclear, plasma membrane, and cytosolic fractions. An increase of Zn content in BPH, but a decrease in PCA as compared to normal tissue, was observed. Cd concentration appeared to be higher in BPH and PCA than in normal tissue. No correlation between Zn and Cd level was found in BPH specimens obtained from the same patients. Probability values ofp ≤0.05 were considered to indicate significant differences. Obtained results seem to support the hypothesis of Cd carcinogenicity and preventing function of Zn in prostatic cancer. Plasma membrane fraction corresponding to lysosomal, mitochondrial, and microsomal subcellular compartments are probably critical in Zn and Cd participation in human prostate neoplasms.