Pathogenesis Of Benign Prostatic Hyperplasia Research Articles

LU Yonghui's clinical experience of hierachical acupuncture at acupoints of conception vessel in treatment of benign prostatic hyperplasia

The paper introduces professor LU Yonghui 's academic thought and clinical experience in treating benign prostatic hyperplasia (BPH). It is believed that the pathogenesis of BPH includes retarded qi movement of triple energizers and dysfunction of the bladder in qi activity, resulting in impairment of water metabolism, and difficulty in micturition occurs. In treatment, acupuncture is delivered at the muscle region (membrane) of the body to promote qi circulation. The needles are inserted at the acupoints of conception vessel to different depths. The shallow insertion is operated at Qihai (CV 6) and Guanyuan (CV 4) to benefit qi movement of triple energizers, the moderate insertion is at Zhongji (CV 3), the front-mu point of the bladder, to benefit the intersections (membranes) of triple energizers, and the deep insertion is at Qugu (CV 2) to work at the internal organ, regulate qi, remove obstruction. As a result, the qi movement of triple energizers is improved, the function of the bladder in qi activity recovered, urination ameliorated and the retention of urine cured.

Potential role of oxidative stress in pathogenesis of benign prostatic hyperplasia in male dogs.

The pathogenesis of benign prostatic hyperplasia (BPH) in dogs is still not fully understood. Some studies suggest that oxidative stress may have a potential role in the pathogenesis of BPH in dogs. Age-related hormonal changes may activate a chronic inflammatory response in the prostate. This causes the generation of reactive oxygen species (ROS) and results in oxidative stress. Excessive production of ROS results in DNA damage and hyperplastic transformation of prostatic cells. The use of antioxidants for improvement of treatment outcomes for canine PBH has been discussed. Further research is needed on the importance of oxidative stress in the development of BPH in dogs and the usefulness of antioxidants in the supportive treatment of this condition.

Research Progress on the Treatment of Benign Prostatic Hyperplasia with Classical Prescriptions

AbstractThe main pathogenesis of benign prostatic hyperplasia (BPH) includes deficiency of healthy qi, blood stasis, and fluid retention. The root cause of BPH is the deficiency of healthy qi, for which Jingui Shenqi Pill and Zhenwu Decoction are used to nourish kidney qi and warm yang to promote diuresis. Blood stasis is the key pathogeneses of BPH, for which Guizhi Fuling Pill and Didang Decoction are used to dissipate blood stasis, relieve obstruction of orifices and facilitate bowel movement. Fluid retention is the most urgent symptom of BPH, for which Wuling Powder and Danggui Shaoyao Powder are used to transform qi and promote diuresis, addressing the urgent symptoms.

Untargeted metabolomics reveals that declined PE and PC in obesity may be associated with prostate hyperplasia.

Recent studies have shown that obesity may contribute to the pathogenesis of benign prostatic hyperplasia (BPH). However, the mechanism of this pathogenesis is not fully understood. A prospective case-control study was conducted with 30 obese and 30 nonobese patients with BPH. Prostate tissues were collected and analyzed using ultra performance liquid chromatography ion mobility coupled with quadrupole time-of-flight mass spectrometry (UPLC-IMS-Q-TOF). A total of 17 differential metabolites (3 upregulated and 14 downregulated) were identified between the obese and nonobese patients with BPH. Topological pathway analysis indicated that glycerophospholipid (GP) metabolism was the most important metabolic pathway involved in BPH pathogenesis. Seven metabolites were enriched in the GP metabolic pathway. lysoPC (P16:0/0:0), PE (20:0/20:0), PE (24:1(15Z)/18:0), PC (24:1(15Z)/14:0), PC (15:0/24:0), PE (24:0/18:0), and PC (16:0/18:3(9Z,12Z,15Z)) were all significantly downregulated in the obesity group, and the area under the curve (AUC) of LysoPC (P-16:0/0/0:0) was 0.9922. The inclusion of the seven differential metabolites in a joint prediction model had an AUC of 0.9956. Thus, both LysoPC (P-16:0/0/0:0) alone and the joint prediction model demonstrated good predictive ability for obesity-induced BPH mechanisms. In conclusion, obese patients with BPH had a unique metabolic profile, and alterations in PE and PC in these patients be associated with the development and progression of BPH.

FERTILITY FACTORS. D-HORMONE IN PREVENTION OF REPRODUCOPATHIES CAUSED BY BENIGN PROSTATIC HYPERPLASIA (Literature review)

In accordance with the statistical data, the spreading of benign prostatic hyperplasia (BPH) is increasing, because modern stressful lifestyle causes sex hormones disbalances and other dyshormonal conditions which lead to pathologies’ development at younger ages. The pathogenesis of BPH is connected with disturbances of regulation in the hypothalamo-hypophyseal system and with the changes of the regulatory signals intensity which go to the reproductive organs. The central pathogenic links of this pathology’ development are: the declining of efficacy of hypothalamus functioning regulation which carries out on the basis of feedback; the changes of the pituitary gland cells sensitivity to the releasing hormones of hypothalamus and disbalance of sex hormones. In addition to gonadotropins prolactin has a significant impact on the BPH development. Its hypersecretion causes the development of hyperplastic age-related changes in prostate gland. The introduction of dopamine receptors antagonists such as sulpiride causes the increasing of prolactin concentration and declining of gonadotropins releasing. “Sulpiride model” is broadly used in the experimental endocrinology for studying prostate-active drugs and is characterized by sex hormones disbalance' and inflammation processes’ development. The development of the pathology is linked with the disturbance of testosterone synthesis in the testicles, insufficiency of prostate gland functioning and increasing of prolactin and estradiol concentrations which provoke proliferative changes. The androgens disbalance is the main cause of BHP development, therefore, the “Testosterone model” based on testosterone’ and estradiol’ slow releasing implants is broadly used for modeling of urination disturbance in rats which imitates the same condition in elderly men with benign prostatic hyperplasia. The prostatitis, which developed under the condition of BHP, causes the disturbances of spermatogenesis during experimental modeling and in the clinical practice when spermatopathies, sexual disturbances and hypofertility are diagnosed in patients. The traditional BHP therapeutic methods are not always effective and the new therapeutic approaches of hypofertility caused by prostate gland pathologies are developed by investigators. Thus, there are data about correlation between increased vitamin D consumption and decreasing of BHP spreading, between gland volume and cells proliferation in patients with this pathology. Vitamin D level influences the quantity and quality of ejaculate. The deficiency of vitamin D is associated with lower proportion of sex hormones in young men and choriogonin sensitivity of Leydig's cells to be diminished. It has been experimentally shown that cholecalciferol regulates steroid hormones genesis, mitigates the age-related declining of testicles activity, protects the testicles in old animals and the unchanged spermatogenesis in normal males which received vitamin D3 can be considered to be the result of estrogens and androgens balance. The androgens receptors as well as vitamin D receptors have been found in prostate gland in health males and in those with hyperplasia. In addition to its classical function in calcium homeostasis and bones health, vitamin D inhibits tumor growth in different tissues including prostate gland. Vitamin D metabolites have been determined to be anti-inflammatory, proapoptotic and antiproliferative. D-hormone application potentiates the specific properties of prostate gland protectors, recovers reproductive capacity under the condition of experimental chronic prostatitis of inflammatory genesis as well as traumatic. All facts listed above allow to confirm the positive role of D-hormone in the regulation of prostate gland and reproductive function in patients with BHP and recovering of fertility under the condition of this pathology. The literature search for this review has been carried out on databases PubMed, Science Direct, Europa PMC, BMC, MedLine etc.

Hypoxia activates the hypoxia-inducible factor-1α/vascular endothelial growth factor pathway in a prostatic stromal cell line: A mechanism for the pathogenesis of benign prostatic hyperplasia

Abstract Background The development of benign prostatic hyperplasia (BPH) is closely related to hypoxia in the prostatic stroma, and the hypoxia-inducible factor-1α/vascular endothelial growth factor (HIF-1α/VEGF) pathway has been shown to significantly activate in response to hypoxia. The underlying mechanism for activation of this pathway in the pathogenesis of BPH remains unclear. Materials and methods We constructed HIF-1α overexpression and knockdown BPH stromal (WPMY-1) and epithelial (BPH-1) cell lines, which were cultured under different oxygen conditions (hypoxia, normoxia, and hypoxia + HIF-1α inhibitor). Quantitative real-time polymerase chain reaction (qPCR) and Western blotting were applied to detect the expression of the HIF-1α/VEGF pathway. Cell proliferation and apoptosis were analyzed by Cell Counting Kit-8 and flow cytometry. We used the miRWalk 2.0 database and Western blotting to predict the potential miRNA that selectively targets the HIF-1α/VEGF pathway, and verified the prediction by qPCR and dual-luciferase assays. Results In a BPH stromal cell line (WPMY-1), the expression of VEGF was in accordance with HIF-1α levels, elevated in the overexpression cells and decreased in the knockdown cells. Hypoxia-induced HIF-1α overexpression, which could be reversed by a HIF-1α inhibitor. Moreover, the HIF-1α inhibitor significantly depressed cellular proliferation and promoted apoptosis in hypoxic conditions, assessed by Cell Counting Kit-8 and flow cytometry. However, in the BPH epithelial cell line (BPH-1), the expression level of HIF-1α did not influence the expression of VEGF. Finally, a potential miRNA, miR-17-5p, regulating the HIF-1α/VEGF pathway was predicted from the miRWalk 2.0 database and Western blotting, and verified by qPCR and dual-luciferase assay. Conclusions In hypoxia, activation of the HIF-1α/VEGF pathway plays a crucial role in regulating cell proliferation in a BPH stromal cell line. Regulation by miR-17-5p may be the potential mechanism for the activation of this pathway. Regulation of this pathway may be involved in the pathogenesis of BPH.

Diacerein provokes apoptosis, improves redox balance, and downregulates PCNA and TNF-α in a rat model of testosterone-induced benign prostatic hyperplasia: A new non-invasive approach.

One of the most prevalent chronic conditions affecting older men is benign prostatic hyperplasia (BPH), causing severe annoyance and embarrassment to patients. The pathogenesis of BPH has been connected to epithelial proliferation, inflammation, deranged redox balance, and apoptosis. Diacerein (DIA), the anthraquinone derivative, is a non-steroidal anti-inflammatory drug. This study intended to investigate the ameliorative effect of DIA on the prostatic histology in testosterone-induced BPH in rats. BPH was experimentally induced by daily subcutaneous injection of testosterone propionate for four weeks. The treated group received DIA daily for a further two weeks after induction of BPH. Rats' body and prostate weights, serum-free testosterone, dihydrotestosterone, and PSA were evaluated. Prostatic tissue was processed for measuring redox balance and histopathological examination. The BPH group had increased body and prostate weights, serum testosterone, dihydrotestosterone, PSA, and oxidative stress. Histologically, there were marked acinar epithelial and stromal hyperplasia, inflammatory infiltrates, and increased collagen deposition. An immunohistochemical study showed an increase in the inflammatory TNF-α and the proliferative PCNA markers. Treatment with DIA markedly decreased the prostate weight and plasma hormones, improved tissue redox balance, repaired the histological changes, and increased the proapoptotic caspase 3 expression besides the substantial reduction in TNF-α and PCNA expression. In conclusion, our study underscored DIA's potential to alleviate the prostatic hyperplastic and inflammatory changes in BPH through its antioxidant, anti-inflammatory, antiproliferative, and apoptosis-inducing effects, rendering it an effective, innovative treatment for BPH.

Salvia miltiorrhiza Bunge Ameliorates Benign Prostatic Hyperplasia through Regulation of Oxidative Stress via Nrf-2/HO-1 Activation.

Oxidative stress is a key factor in the pathogenesis of benign prostatic hyperplasia (BPH) that leads to inflammation. This study aimed to evaluate the ameliorative effects of Salvia miltiorrhiza Bunge extract (HLT-101) on BPH through the regulation of oxidative stress and inflammation. A testosterone propionate (TP)-induced BPH rat model was orally administered HLT-101 (20, 40, or 80 mg/kg), and its effects on oxidative stress- and inflammation-related gene expression were examined. Further, HLT-101 was assessed for its effect on reactive oxygen species (ROS) levels and Nrf-2/HO-1 signaling pathways in BPH-1 cells. HLT-101 decreased testosterone-induced excessive free radical production and inflammatory factor activation. Moreover, HLT-101 treatment significantly decreased the intracellular ROS level in the TNF-α and IFN-γ treated BPH-1 cells through the activation of Nrf-2. In addition, HLT-101 treatment inhibited the NF-κB pathway and androgen receptor (AR) signaling, which is highly linked to the pathogenesis of BPH. Therefore, HLT-101 has the potential to be an effective treatment reagent for BPH because of its ability to reduce inflammation and oxidative stress via Nrf-2/HO-1 signaling.

Serum Testosterone and Dihydrotestosterone and Incidence and Progression of Lower Urinary Tract Symptoms: Results From the REDUCE Study.

Though the pathogenesis of benign prostatic hyperplasia is unclear, it was previously believed that increasing androgen levels contributed, though not all data support this idea. We tested if elevated serum testosterone or dihydrotestosterone were risk factors for lower urinary tract symptoms incidence in asymptomatic men and for lower urinary tract symptoms progression in symptomatic men. A post hoc analysis of REDUCE was performed in 3009 asymptomatic men and in 2145 symptomatic men. REDUCE was a randomized trial of dutasteride for prostate cancer prevention in men with an elevated prostate-specific antigen and negative prestudy biopsy. We estimated multivariable adjusted hazard ratios and 95% confidence intervals using Cox models to test the association between quintiles of serum testosterone and dihydrotestosterone at baseline and lower urinary tract symptoms incidence and progression and tested for interaction by treatment arm (dutasteride vs placebo). In asymptomatic men, there was no evidence serum testosterone or dihydrotestosterone were related to lower urinary tract symptoms incidence (P = .9, P = .4). In symptomatic men, there was no evidence serum testosterone or dihydrotestosterone were related to lower urinary tract symptoms progression (P = .9, P = .7). Results were similar in both placebo and dutasteride arms (all P interaction ≥ .3). In REDUCE, higher serum testosterone and higher serum dihydrotestosterone were not associated with either lower urinary tract symptoms incidence in asymptomatic men or lower urinary tract symptoms progression in symptomatic men. These data do not support the hypothesis that serum androgens in middle-aged men are associated with lower urinary tract symptoms.

Mechanism of RhoA regulating benign prostatic hyperplasia: RhoA-ROCK-β-catenin signaling axis and static & dynamic dual roles

BackgroundThe pathogenesis of benign prostatic hyperplasia (BPH) has not been fully elucidated. Ras homology family member A (RhoA) plays an important role in regulating cell cytoskeleton, growth and fibrosis. The role of RhoA in BPH remains unclear.MethodsThis study aimed to clarify the expression, functional activity and mechanism of RhoA in BPH. Human prostate tissues, human prostate cell lines, BPH rat model were used. Cell models of RhoA knockdown and overexpression were generated. Immunofluorescence staining, quantitative real time PCR (qRT-PCR), Western blotting, cell counting kit-8 (CCK-8), flow cytometry, phalloidine staining, organ bath study, gel contraction assay, protein stability analysis, isolation and extraction of nuclear protein and cytoplasmic protein were performed.ResultsIn this study we found that RhoA was localized in prostate stroma and epithelial compartments and was up-regulated in both BPH patients and BPH rats. Functionally, RhoA knockdown induced cell apoptosis and inhibited cell proliferation, fibrosis, epithelial-mesenchymal transformation (EMT) and contraction. Consistently, overexpression of RhoA reversed all aforementioned processes. More importantly, we found that β-catenin and the downstream of Wnt/β-catenin signaling, including C-MYC, Survivin and Snail were up-regulated in BPH rats. Downregulation of RhoA significantly reduced the expression of these proteins. Rho kinase inhibitor Y-27632 also down-regulated β-catenin protein in a concentration-dependent manner. However, overexpression of β-catenin did not affect RhoA-ROCK levels, suggesting that β-catenin was the downstream of RhoA-ROCK regulation. Further data suggested that RhoA increased nuclear translocation of β-catenin and up-regulated β-catenin expression by inhibiting its proteasomal degradation, thereby activating Wnt/β-catenin signaling. Overexpression of β-catenin partially reversed the changes in cell growth, fibrosis and EMT except cell contraction caused by RhoA downregulation. Finally, Y-27632 partially reversed prostatic hyperplasia in vivo, further suggesting the potential of RhoA-ROCK signaling in BPH treatment.ConclusionOur novel data demonstrated that RhoA regulated both static and dynamic factors of BPH, RhoA-ROCK-β-catenin signaling axis played an important role in the development of BPH and might provide more possibilities for the formulation of subsequent clinical treatment strategies.

Association Between Neutrophil-to-Lymphocyte Ratio and Benign Prostatic Hyperplasia: Results from the TCLSIH Cohort Study.

The prevalence of benign prostatic hyperplasia (BPH) in the general Chinese adult male population has risen sharply over the past few decades. Increasing evidence suggests that inflammation plays an important role in the pathogenesis of BPH. To better understand the role of inflammation in the pathogenesis of BPH, we can use the neutrophil-to-lymphocyte ratio (NLR) because it is a simple and effective marker of inflammation and immunity. This study aims to prospectively investigate the association between NLR levels and the prevalence of BPH in a general Chinese adult male population. This study included a total of 15,783 male participants free from BPH at baseline. NLR was measured according to the complete blood count. BPH was defined as total prostate volume (TPV) ≥30 mL, and TPV was determined by transabdominal ultrasonography. Multivariable Cox proportional hazards models were fitted to calculate hazards ratios (HRs) and corresponding 95% confidence intervals (CIs) for BPH risk with NLR levels. During a median follow-up of 2.7 years, 5078 BPH cases were documented. After adjusting for age, body mass index, smoking, alcohol, education, occupation, income, physical activity, total energy intake, personal and family history of disease, and inflammation markers, the multivariable-adjusted HRs of BPH were 1.00 (reference), 1.08 (95% CIs 0.99, 1.17), 1.10 (95% CIs1.02, 1.19), and 1.12 (95% CIs1.03, 1.21), respectively, for participants with NLR in the first, second, third, and fourth quartiles (P for trend <0.01). Higher NLR levels were associated with a higher risk of BPH in Chinese adult male population. Our findings support the notion that NLR levels may be an important target for BPH prevention and intervention.

Mechanism of Androgen-Independent Stromal Proliferation in Benign Prostatic Hyperplasia.

Benign prostatic hyperplasia (BPH) is a chronic proliferative disease showing stromal-dominant proliferation. However, the detailed proliferation mechanism has remained unclear. Although aging and androgen have been reported as definitive risk factors for BPH, recent studies have focused on the involvement of androgen-independent factors. Androgen-independent factors include ischemia, oxidative stress, metabolic syndrome, infection, autoimmune reactions, and inflammation, with inflammation in BPH tissues playing a central role in the BPH proliferative process. Inflammation in BPH tissues by various factors finally leads to tissue remodeling and stromal proliferation through the wound healing process of the prostate. To elucidate the proliferative mechanism of BPH, a study using whole-genome gene expression analysis in a stromal-dominant BPH rat model was performed and showed that immune response-related pathways and complement classical pathways are activated. Furthermore, expression analysis using this BPH rat model showed that the autoimmune reaction triggered complement pathway activation in the proliferative process of BPH. BPH is a multifactorial disease, and understanding the role of androgen-independent factors including immune responses contributes to elucidating the pathogenesis of BPH. Androgen-independent factors may lead to new therapeutic targets for BPH, and further development of this research is expected.

Multidirectional Effects of Terpenoids from Sorbus intermedia (EHRH.) PERS Fruits in Cellular Model of Benign Prostate Hyperplasia.

Benign prostatic hyperplasia (BPH) is a common urological disease affecting aging men. Its pathogenesis is regarded as complex and multifactorial, with sex hormones and inflammation as key contributory factors. In the current study, we investigated the anti-BPH potential of terpenoids present in the fruits of Sorbus intermedia (EHRH.) PERS. Not only the effects on testosterone-stimulated normal prostate epithelial PNT2 cells, namely suppression of 5-α-reductase activity, PSA secretion, and cell proliferation, were determined but also the inhibitory activity on heat-induced protein denaturation, hyaluronidase, as well as IL-6, TNF-α, and NO release in LPS-treated macrophages. Sorbus terpenoids significantly inhibited 5-α-reductase activity and reduced PSA secretion in PNT2 cells, reversing the stimulatory effect of testosterone. PNT2 cell proliferation was also found to be attenuated. Subsequently, all compounds reduced the release of pro-inflammatory mediators in RAW 264.7 cells. In addition, ursolic acid (UA) and its aldehyde (UAL) were the most potent hyaluronidase inhibitors of all compounds, with IC50 values of 225.75 µg/mL and 369.77 µg/mL, respectively. For better understanding and interpretation of the overall effect of Sorbus terpenoids on different aspects of BPH pathogenesis and development, cluster analysis was applied.

Benign Prostatic Hyperplasia in a 13-Year-Old Boy

Benign prostatic hyperplasia (BPH) is most common in men 40 years and above. It rarely occurs in childhood. As a result of the scarcity of cases, the pathogenesis is not clear, and treatment of BPH in this age group is challenging. This report focuses on a 13-year-old patient diagnosed with a histologically confirmed BPH, having presented with a 2-year history of recurrent hematuria and acute urinary retention. Magnetic resonance imaging (MRI) revealed a 287 g prostatic mass, with no signs of malignancy nor metastasis detected. A decision for open suprapubic prostatectomy was made. Postoperative follow-up at 1 year was uneventful. The possible causes of juvenile BPH have been postulated as gonadotropin supplementation for cryptorchidism and human chorionic gonadotropin-containing agent use by the mother during pregnancy. Our case had a history of the right inguinal undescended testis with scrotal orchidopexy done at 11 years of age. However, the patient had no history of human chorionic gonadotropin use, endocrinologic abnormality, or other possible contributing factors. His antenatal history was normal, with no use of human chorionic gonadotropin by the mother. Due to the very few reported cases, there is insufficient data to help understand the pathogenesis of childhood BPH.

Simvastatin ameliorates testosterone-induced prostatic hyperplasia in rats via modulating IGF-1/PI3K/AKT/FOXO signaling

Benign prostatic hyperplasia (BPH) is characterized by non-malignant enlargement of prostate cells causing many lower urinary tract symptoms. BPH pathogenesis includes androgens receptors signaling pathways, oxidative stress, apoptosis, and possibly changes in IGF-1/PI3K/AKT/FOXO pathway. Altogether, modulating IGF-1/PI3K/AKT/FOXO signaling along with regulating oxidative stress and apoptosis might preserve prostatic cells from increased proliferation. Beyond statins' common uses, they also have anti-inflammatory, antioxidant, and anti-tumor effects. This study aims to determine simvastatin's beneficial effect on testosterone-induced BPH. Rats were randomly allocated into four groups, 9 rats each. The control group received olive oil subcutaneously and distilled water orally for 30 consecutive days. The second group received simvastatin (20 mg/kg, p.o.) dissolved in distilled water. The BPH-induced group received testosterone enanthate (3 mg/kg, s.c.) dissolved in olive oil, and the BPH-induced treated group received both simvastatin and testosterone. Testosterone significantly increased prostate index and severity of histopathological alterations in prostate tissues as well as 5-alpha reductase enzyme level in contrast to simvastatin treatment that reversed the testosterone-induced alterations in these parameters. Likewise, testosterone up-regulated IGF-1/PI3K/AKT signaling pathway and down-regulated FOXO transcription factor. It also decreased apoptotic markers level in prostatic tissue BAX, caspase-3, and caspase-9, while it elevated Bcl-2 level. In addition, it alleviated reduced GSH and GPX5 levels and SOD activity. Simvastatin treatment significantly opposed testosterone's effect on all aforementioned parameters. In conclusion, this study demonstrates that simvastatin is a possible treatment for BPH which may be attributed to its effect on IGF-1/PI3K/AKT/FOXO signaling pathway as well as anti-oxidant and apoptotic effects.

Targeting benign prostate hyperplasia treatments: AR/TGF-β/NOX4 inhibition by apocynin suppresses inflammation and proliferation

IntroductionApocynin (Apo), an NADPH oxidase (NOX) inhibitor, has been widely used to treat various inflammatory diseases. However, the therapeutic effects of Apo on benign prostatic hyperplasia (BPH), a multifactorial disease associated with chronic inflammation and hormone imbalance, remain unknown. ObjectivesThe link between androgen signaling, reactive oxygen species (ROS), and prostate cell proliferation may contribute to the pathogenesis of BPH; therefore, the aim of this study was to identify the specific signaling pathway involved and to demonstrate whether the anti-oxidant Apo plays a role in the prevention and treatment of BPH. MethodsIngenuity pathway analysis and si-RNA transfection were conducted to demonstrate the androgen receptor (AR) and NOX4 linkage in BPH. Pathological markers of BPH were measured by H&E staining, immunoblotting, ELISA, qRT-PCR, and immunofluorescence to examine the effect of Apo. Rats stimulated with testosterone and BPH-1 cells were used as BPH models. ResultsAR and NOX4 network-mediated oxidative stress was upregulated in the BPH model. Next, we examined the effects of Apo on oxidative stress and chronic prostatic inflammation in BPH mouse models. In a testosterone-induced BPH rat model, Apo alleviated pathological prostate enlargement and suppressed androgen/AR signaling. Apo suppressed the upregulation of proinflammatory markers and promoted the expression of anti-oxidant factors. Furthermore, Apo regulated the TGF-β/Glut9/activin pathway and macrophage programming. In BPH-1 cells, Apo suppressed AR-mediated proliferation and upregulation of TGFB and NOX4 expression by alleviating oxidative stress. Apo activated anti-oxidant and anti-inflammatory systems and regulated macrophage polarization in BPH-1 cells. AR knockdown partially abolished the beneficial effects of Apo in prostate cells, indicating AR-dependent effects of Apo. ConclusionIn contrast with existing BPH therapies, Apo may provide a new application for prostatic disease treatment, especially for BPH, by targeting the AR/TGF-β/NOX4 signaling pathway.

PD02-06 SERUM TESTOSTERONE AND DIHYDROTESTOSTERONE AND INCIDENCE AND PROGRESSION OF LOWER URINARY TRACT SYMPTOMS IN REDUCTION BY DUTASTERIDE OF PROSTATE CANCER EVENTS TRIAL

You have accessJournal of UrologyCME1 Apr 2023PD02-06 SERUM TESTOSTERONE AND DIHYDROTESTOSTERONE AND INCIDENCE AND PROGRESSION OF LOWER URINARY TRACT SYMPTOMS IN REDUCTION BY DUTASTERIDE OF PROSTATE CANCER EVENTS TRIAL James Daniels, James Mirocha, Daniel Moreira, Gerald Andriole, and Stephen Freedland James DanielsJames Daniels More articles by this author , James MirochaJames Mirocha More articles by this author , Daniel MoreiraDaniel Moreira More articles by this author , Gerald AndrioleGerald Andriole More articles by this author , and Stephen FreedlandStephen Freedland More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003219.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Benign prostatic hyperplasia (BPH) is common in older men, with many developing lower urinary tract symptoms (LUTS) that impair quality of life. Though the pathogenesis of BPH is unclear, it was previously believed that increasing androgen levels had a role, though not all data support this idea. We tested if elevated serum testosterone and elevated serum DHT are risk factors for LUTS incidence in asymptomatic men and for LUTS progression in symptomatic men. METHODS: A post-hoc analysis of REDUCE was carried out in 3009 asymptomatic men with baseline International Prostate Symptom Score (IPSS) <8 and in 2145 symptomatic men with baseline IPSS≥8 not taking α-blockers or 5α-reductase inhibitor medications. The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial was a randomized trial of dutasteride for prostate cancer prevention in men with an elevated PSA and negative pre-study biopsy. IPSS was measured every 6 months over the 4-year study. We estimated multivariable adjusted hazard ratios (adj-HRs) and 95% confidence intervals (CIs) using Cox models to test the association between quintiles of serum testosterone and quintiles of serum dihydrotestosterone (DHT) at baseline and LUTS incidence and progression. Among asymptomatic men, incident LUTS was defined as the first report of medical treatment, surgery or sustained clinically significant LUTS (i.e., 2 reports of IPSS>14). Among symptomatic men, LUTS progression was defined as an IPSS increase of ≥4 points from baseline, any surgical procedure for BPH, or the start of a new BPH medication. RESULTS: In asymptomatic men, relative to the lowest quantile, all quintiles of serum testosterone and all quintiles of DHT were unrelated to LUTS incidence (all p≥0.25). In symptomatic men, relative to the lowest quantile, all quintiles of serum testosterone and all quintiles of DHT were unrelated to LUTS progression (all p≥0.17). There was no significant interaction between treatment with dutasteride and serum testosterone or DHT when predicting LUTS; as such, data were not stratified by treatment assignment. CONCLUSIONS: In the REDUCE study, higher serum testosterone and higher serum DHT were not associated with either incident LUTS in asymptomatic men or progression of LUTS in symptomatic men. These data do not support the hypothesis that serum androgen levels in middle-aged men are associated with LUTS. Source of Funding: Dr. Daniels is funded by the NIH grants TL1 DK132768 and U2C DK129496 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e71 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information James Daniels More articles by this author James Mirocha More articles by this author Daniel Moreira More articles by this author Gerald Andriole More articles by this author Stephen Freedland More articles by this author Expand All Advertisement PDF downloadLoading ...

Docking and Molecular Dynamics Identify Leads against 5 Alpha Reductase 2 for Benign Prostate Hyperplasia Treatment

Steroid 5 alpha-reductase 2 (5αR-2) is a membrane-embedded protein that together with other isoforms plays a key role in the metabolism of steroids. This enzyme catalyzes the reduction of testosterone to the more potent ligand, dihydrotestosterone (DHT) in the prostate. Androgens, testosterone, and DHT play important roles in prostate growth, development, and function. At the same time, both testosterone and DHT have been implicated in the pathogenesis of benign prostate hyperplasia (BPH). Inhibition of the DHT formation, therefore, provides a therapeutic strategy that offers the possibility of preventing, delaying, or treating BPH. Currently, two steroidal drugs that inhibit 5αR-2, dutasteride and finasteride, have been approved for clinical use. These two come at a high cost and also portray undesirable sexual side effects which necessitate the need to find new chemotherapeutic alternatives for the disease. Based on the aforementioned, finasteride and dutasteride were subjected to scaffold hopping, fragment-based de novo design, molecular docking, and molecular dynamics simulations employing databases like ChEMBL, DrugBank, PubChem, ChemSpider, and Zinc15 in the identification of potential hits targeting 5αR-2. Altogether, ten novel compounds targeting 5αR-2 were identified with binding energies lower or comparable to finasteride and dutasteride, the main inhibitors for this target. Molecular docking and molecular dynamics simulations studies identify amino acid residues Glu57, Phe219, Phe223, and Leu224 to be critical for ligand binding and complex stability. The physicochemical and pharmacological profiling suggests the potential of the hit compounds to be drug-like and orally active. Similarly, the quality parameter assessments revealed the hits possess LELP greater than 3 implying their promise as lead-like molecules. The compounds A5, A9, and A10 were, respectively, predicted to treat prostate disorders with Pa (0.188, 0.361, and 0.270) and Pi (0.176, 0.050, and 0.093), while A8 and A9 were found to be associated with BPH treatment with Pa (0.09 and 0.127) and Pi (0.077 and 0.033), respectively. Structural similarity searches via DrugBank identified the drugs faropenem, acemetacin, estradiol valerate, and yohimbine to be useful for BPH treatment suggesting the de novo designed ligands as potential chemotherapeutic agents for treating this disease.

Genetically elevated bioavailable testosterone level was associated with the occurrence of benign prostatic hyperplasia.

Recent studies identified several risk factors of benign prostatic hyperplasia (BPH), including dyslipidemia, type 2 diabetes mellitus, hypertension, and obesity. But they were not so reliable and some studies contradicted with one another. Hence, a reliable method is urgently needed to explore exact factors that facilitated BPH development. The study was based on Mendelian randomization (MR) design. All participants were from the most recent genome-wide association studies (GWAS) with large sample size. The causal associations between nine phenotypes (total testosterone level, bioavailable testosterone level, sex hormone-binding globulin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, type 2 diabetes mellitus, hyper-tension, and body mass index) and BPH outcome were estimated. Two sample MR, bidirectional MR, and multivariate MR (MVMR) were performed. Increase in bioavailable testosterone level was able to induce BPH based on nearly all combination methods [beta (95% confidence interval (CI)): 0.20 (0.06-0.34) for inverse variance weighted (IVW)]. The other traits seemed to interact with testosterone level and did not cause BPH generally. Higher triglycerides level was likely to raise bioavailable testosterone level [beta (95% CI): 0.04 (0.01-0.06) for IVW]. In MVMR model, bioavailable testosterone level was still associated with BPH occurrence [beta (95% CI) 0.27 (0.03-0.50) for IVW]. We for the first time validated the central role of bioavailable testosterone level in the pathogenesis of BPH. The complex associations between other traits and BPH should be further investigated.

A Novel Insight into the Immune-Related Interaction of Inflammatory Cytokines in Benign Prostatic Hyperplasia.

Benign prostatic hyperplasia (BPH) is a common male condition that impacts many men's quality of life by generating lower urinary tract symptoms (LUTS). In recent years, inflammation has become very common in the prostate, and BPH with inflammation has a higher International Prostate Symptom Score (IPSS) score and an enlarged prostate. Chronic inflammation leads to tissue damage and the release of pro-inflammatory cytokines, which play an important role in the pathogenesis of BPH. We will focus on current advancements in pro-inflammatory cytokines in BPH, as well as the future of pro-inflammatory cytokine research.