Etiology Of Benign Prostatic Hyperplasia Research Articles

Spatial transcriptomics identifies candidate stromal drivers of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is the nodular proliferation of the prostate transition zone in older men, leading to urinary storage and voiding problems that can be recalcitrant to therapy. Decades ago, John McNeal proposed that BPH originates with the "reawakening" of embryonic inductive activity by adult prostate stroma, which spurs new ductal proliferation and branching morphogenesis. Here, by laser microdissection and transcriptional profiling of the BPH stroma adjacent to hyperplastic branching ducts, we identified secreted factors likely mediating stromal induction of prostate glandular epithelium and coinciding processes. The top stromal factors were insulin-like growth factor 1 (IGF1) and CXC chemokine ligand 13 (CXCL13), which we verified by RNA in situ hybridization to be coexpressed in BPH fibroblasts, along with their cognate receptors (IGF1R and CXCR5) on adjacent epithelium. In contrast, IGF1 but not CXCL13 was expressed in human embryonic prostate stroma. Finally, we demonstrated that IGF1 is necessary for the generation of BPH-1 cell spheroids and patient-derived BPH cell organoids in 3D culture. Our findings partially support historic speculations on the etiology of BPH and provide what we believe to be new molecular targets for rational therapies directed against the underlying processes driving BPH.

Analysis of platelet and monocyte-to-lymphocyte ratio and diabetes mellitus with benign prostatic enlargement.

The etiology of benign prostatic hyperplasia (BPH) is still elusive. The aim of this study was to provide preventive and prognostic parameters associated with diabetes mellitus with benign prostatic enlargement (BPE). Diabetic patients were collected retrospectively from February 2021 to December 2022, including monocyte-to-lymphocyte ratio (MLR). Diabetic patients were divided into two groups by whether the prostate volume was greater than or equal to 30 ml, which were diabetes mellitus without BPE (DM) and diabetes mellitus with BPE (DM+BPE). The baseline characteristics were compared, the risk and protective factors associated with DM+BPE were determined using univariate and multivariate logistic regression, and the parameters associated with prostate volume were determined using correlation analysis. Of the 671 patients collected, age and prostate volume were significantly higher in the DM+BPE than in the DM; MLR was higher in the DM+BPE than in the DM; and platelet was significantly lower in the DM+BPE than in the DM. Univariate logistic regression showed that age was a risk factor, while protective factors for DM+BPE were lymphocytes and platelet. Multifactorial logistic regression showed that age was a risk factor, while platelet was the protective factor for DM+BPE. In the total overall (n=671), prostate volume was positively correlated with age. Prostate volume was negatively correlated with lymphocytes and platelet. In DM+BPE (n=142), prostate volume was positively correlated with age and MLR. Platelet was a protective factor for DM+BPE and was negatively correlated with prostate volume, whereas MLR was positively correlated with prostate volume in DM+BPE.

Biochemical evaluation of Ceiba pentandra leaf on the amelioration of testosterone induced-benign prostatic hyperplasia in Wister rats

Benign prostatic hyperplasia (BPH) is a considerable public health problem prevalent among older men. Despite its eminent prevalence, the etiology of BPH is not well understood. Accumulating evidence indicates that modifiable risk factors of cardiovascular disease may also increase the risk of BPH and potentially contribute to BPH development. This study evaluated the ameliorative effect of Ceiba pentandra leaf on some lipids profile indices and bilirubin concentration of rats induced BPH. Thirty six Wistar rats were divided randomly into six groups (n = 6). All the experimental groups except the normal control were induced benign prostatic hyperplasia using testosterone propionate and estradiol valerate at a dose of 400 µg and 80 µg respectively, for 21 days. After induction, rats in the negative control (BPH Control) group received no treatment. Rats in the standard control group received finasterides (1mg/kg body weight), while rats in the low dose extract, medium dose extract and high dose extract groups received the plant extract according to their body weights in kilogram at 500 mg/kg, 1000 mg/kg, and 1500 mg/kg respectively. Normal Control group received only feed without any special treatment. The animals in all the groups were allowed access to water and feed ad libitum for 28 days. The rats were anaesthetized after treatment period. Blood samples were collected and serum harvested for analyses using standard methods. Result showed that Ceiba pentandra leaf had ameliorative effect on the lipids profile analyzed.

Ethanol extract of Ceiba pentandra leaf ameliorates some lipids profile indices of Wistar rat’s induced benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is a considerable public health problem prevalent among older men. Despite its eminent prevalence, the etiology of BPH is not well understood. Accumulating evidence indicates that modifiable risk factors of cardiovascular disease may also increase the risk of BPH and potentially contribute to BPH development. This study evaluated the ameliorative effect of Ceiba pentandra leaf on some lipids profile indices of rats induced BPH. Thirty six Wistar rats were divided randomly into six groups (n = 6). All the experimental groups except the normal control were induced benign prostatic hyperplasia using testosterone propionate and estradiol valerate at a dose of 400 µg and 80µg respectively, for 21 days. After induction, rats in the negative control (BPH Control) group received no treatment. Rats in the standard control group received finasterides (1mg/kg body weight), while rats in the low dose extract, medium dose extract and high dose extract groups received the plant extract according to their body weights in kilogram at 500 mg/kg, 1000 mg/kg, and 1500 mg/kg respectively. Normal Control group received only feed without any special treatment. The animals in all the groups were allowed access to water and feed ad libitum for 28 days. The rats were anaesthetized after treatment period. Blood samples were collected and serum harvested for analyses using standard methods. Result showed that Ceiba pentandra leaf had ameliorative effect on the lipids profile analyzed.

Prostatic Therapeutic Efficacy of LENILUTS®, a Novel Formulation with Multi-Active Principles.

Lower Urinary Tract Symptoms (LUTs) in men are usually associated to benign prostatic hyperplasia (BPH), a non-malignant prostate enlargement. Unfortunately, BPH etiology is still unclear. Recent works highlighted a relevant inflammation role in BPH onset and development. Consequently, to complement the 5-α reductase (and α-adrenergic receptor agonists-based therapy, an anti-inflammatory therapy should be devised. To reduce potential adverse effects of multi-drug treatment, plant extract-based therapies are becoming increasingly common. Serenoa repens, the main phytotherapic treatment for BPH, is not sufficient to front the multi-faceted etiology of BPH. In response to this, a novel, multiple phytotherapic agents-based formulation, LENILUTS®, was developed. In the present work, we compared, using an in vitro approach, the prostatic safety and efficacy of LENILUTS® with a commercial formulation, based only on Serenoa repens, and a 5αR inhibitor, Dutasteride. Furthermore, preliminary in vitro experiments to investigate the active principles, bioaccessibility and bioavailability of LENILUTS® were performed. Our results showed a better prostatic safety and therapeutic efficacy of LENILUTS® compared to the commercial formulation and Dutasteride, with increased anti-inflammatory, and pro-apoptotic activity, and a stronger inhibitory effect on the release of the key enzyme 5αR and Prostatic-Specific Antigen (PSA). The limited bioaccessibility and bioavailability of the active principles of LENILUTS® were highlighted. Considering the results obtained, the LENILUTS® formulation is more promising for BPH and LUTs therapy compared to formulations based on Serenoa repens only, but further efforts should be made to improve the bioaccessibility and bioavailability of the active principles.

The Etiology and Pathophysiology Genesis of Benign Prostatic Hyperplasia and Prostate Cancer: A New Perspective.

Background: The etiology of benign prostatic hyperplasia and prostate cancer are unknown, with ageing being the greatness risk factor. Methods: This new perspective evaluates the available interdisciplinary evidence regarding prostate ageing in terms of the cell biology of regulation and homeostasis, which could explain the timeline of evolutionary cancer biology as degenerative, inflammatory and neoplasm progressions in these multifactorial and heterogeneous prostatic diseases. Results: This prostate ageing degeneration hypothesis encompasses the testosterone-vascular-inflamm-ageing triad, along with the cell biology regulation of amyloidosis and autophagy within an evolutionary tumorigenesis microenvironment. Conclusions: An understanding of these biological processes of prostate ageing can provide potential strategies for early prevention and could contribute to maintaining quality of life for the ageing individual along with substantial medical cost savings.

Age-Related Changes in Zinc, Copper and Selenium Levels in the Human Prostate.

Pathophysiological changes in the prostate gland—benign prostatic hyperplasia (BPH) and prostatic adenocarcinoma (PCa)—are closely related to the age of men. In the prostate gland, zinc is of particular importance for its proper functioning, especially with regard to the effects of hormonal disorders. The aim of this study was to evaluate zinc, copper and selenium concentrations in different parts of the prostate gland in relation to age and the nature of pathological changes. Zinc and copper were determined by the AAS method and selenium by the spectrofluorometric method. The concentration of zinc in the central part of the prostate increases with age, and in patients over 36 years it is twice as high as in the peripheral part, where no increase in the level of this element was observed with the age of patients. The above data confirm a possible influence of zinc on the formation of PCa (located mostly in the peripheral part of the prostate, with low levels of zinc) and BPH in the central part where the levels of this element are the highest. The results apparently confirm the disturbed homeostasis of zinc and other essential elements in the etiology of BPH and PCa.

The concentration of androgens and estrogens in benign prostatic hyperplasia

Background. The etiology of benign prostatic hyperplasia (BPH) has not been fully studied. The main role in the induction of prostate tissue proliferation is assigned to the metabolism of testosterone. Recently, it has been reported that one of the risk factors for BPH is a chronic violation of the blood supply to the prostate.The study objective is to determine the level of reproductive hormones in blood serum and prostate tissue when creating a model of chronic ischemia.Materials and methods. The model of chronic pelvic ischemia was created in 10 white non-linear mature rats by partial ligation of the inferior vena cava. The control group of the study consisted of 10 male rats of the same age. After 1.5 months, we performed a hormonal study in all rats (n = 20) determining the concentration of testosterone, dihydrotestosterone and estradiol in the blood and prostate tissue. Also, in all animals (n = 20), a morphological study of the prostate was performed.Results. We’ve found a significant increase in prostate mass in the main group of rats by 16.4 % (p <0.05). Animals with BPH and impaired blood supply to the prostate had changes in their hormonal status: increased levels of testosterone (p <0.05) and dihydrotestosterone (p >0.05) in the prostate tissue.Conclusion. Long-term ischemic disorders in the prostate may be a trigger factor for the development of BPH due to an increase in the concentration of testosterone.

Profile of Diabetes Mellitus in Benign Protate Hyperplation’s Patients with Urinary Retention in Dr. Soetomo 2016

Introduction: Benign prostatic hyperplasia (BPH) develops inevitably related to age in almost all men starting around the age of 40 years. LUTS is the most common manifestation of BPH. There were several risk factors that play a role in the BPH and LUTS, one of which is diabetes mellitus. The incidence of diabetes mellitus is increasing throughout the world. In 2015, it was estimated that 30.3 million Americans (9.4%) and 3.4 million Canadians (9.3%) were diagnosed with diabetes. About 5% - 10% are diagnosed with type I, and around 90% - 95% are diagnosed with type II. The burden of the disease caused by diabetes is quite high and continues to increase in every country. It is estimated that the global prevalence of people with diabetes in 2013 as many as 382 million people will increase to 592 million by 2035. The exact etiology of BPH is still unknown. Acute urinary retention (AUR) is the most frequent urological emergency. This study aims to find out the number of occurrences of diabetes mellitus in BPH patients with urinary retention in Dr. Soetomo General Hospital from January to December 2016. Methods: This research used descriptive research design. Population in this study was BPH patients with acute urinary retention in Dr. Soetomo General Hospital in 2016. The total sampling method was used. The variable studied was diabetes mellitus. The data was obtained from the patient's medical record. Results: In this study, 62 subjects were found with 11 subjects with positive diabetes mellitus (17.7%) and 43 subjects with negative diabetes mellitus (69.4%). Conclusion: From the results of the study, it was found that there were 17.7% of BPH patients with acute urinary retention who had diabetes mellitus.

Upregulation of Oxytocin Receptor in the Hyperplastic Prostate.

Background: The etiology of benign prostatic hyperplasia (BPH) is complex, both age and androgen are thought to be important. However, the failure of androgen blockade treatments suggests other paracrine/autocrine factors involved in BPH. Oxytocin was found to have a paracrine/autocrine role in prostate in recent years. The influence of BPH on prostatic oxytocin receptor (OTR) expression has never been studied.Material and methods: A testosterone-estradiol induced rat model of BPH was employed and human hyperplastic prostate specimens were harvested. Expressions of OTR, α1-adrenoreceptor subtypes and nitric oxide synthase isoforms were determined via real-time RT-PCR. OTR was further analyzed with Western-Blotting and histological examination. Subsequently, rat epithelial cells, human stromal cells and epithelial cells were cultured in vitro and treated with gradient concentrations of OT from 1 to 5 days. Cell proliferation was tested by Cell Counting Kit-8 and Flow Cytometry.Results: The rat BPH model was validated with significant increased prostate weight. H-E stain revealed a different histopathology between human and rat BPH. Masson's trichrome staining demonstrated that smooth muscle (SM) cells, epithelium cells and collagen fibers were simultaneously augmented in this rat BPH model and human BPH samples. OTR mainly localized in epithelium in rat prostate whereas it mainly localized in stroma in human prostate. OTR gene was upregulated 3.3-fold in rat BPH and 3.0-fold in human BPH, along with increased expression of 2.0-fold α1aARs and 3.0-fold eNOS for rat BPH and 5.0-fold α1aARs for human BPH. The expression of OTR protein was upregulated 1.4-fold in rat BPH and 3.9-fold in human BPH, respectively. Increased concentrations of exogenous OT can accelerate proliferation of rat epithelial cells and human stromal cells but has no impact on human epithelial cells in vitro. Flow Cytometry showed oxytocin could significantly increase G2/M period cell number.Conclusions: Our novel data demonstrates a significant and previously undocumented upregulation of OTR in both rat and human BPH. Moreover, exogenous OT accelerates proliferation of rat prostate epithelial cells and human prostate stromal cells. It is suggested OTR is involved in the development of BPH and OT regulatory system could be a potential new target for the BPH treatment.

Growth hormone-releasing hormone antagonists reduce prostatic enlargement and inflammation in carrageenan-induced chronic prostatitis.

Inflammation plays a key role in the etiology of benign prostatic hyperplasia (BPH) through multiple pathways involving the stimulation of proliferation by cytokines and growth factors as well as the induction of the focal occurrence of epithelial-to-mesenchymal transition (EMT). We have previously reported that GHRH acts as a prostatic growth factor in experimental BPH and in autoimmune prostatitis models and its blockade with GHRH antagonists offer therapeutic approaches for these conditions. Our current study was aimed at the investigation of the beneficial effects of GHRH antagonists in λ-carrageenan-induced chronic prostatitis and at probing the downstream molecular pathways that are implicated in GHRH signaling. To demonstrate the complications triggered by recurrent/chronic prostatic inflammation in Sprague-Dawley rats, 50 μL 3% carrageenan was injected into both ventral prostate lobes two times, 3 weeks apart. GHRH antagonist, MIA-690, was administered 5 days after the second intraprostatic injection at 20 μg daily dose for 4 weeks. GHRH-induced signaling events were identified in BPH-1 and in primary prostate epithelial (PrEp) cells at 5, 15, 30, and 60 min with Western blot. Inflammation induced prostatic enlargement and increased the area of the stromal compartment whereas treatment with the GHRH antagonist significantly reduced these effects. This beneficial activity was consistent with a decrease in prostatic GHRH, inflammatory marker COX-2, growth factor IGF-1 and inflammatory and EMT marker TGF-β1 protein levels and the expression of multiple genes related to EMT. In vitro, GHRH stimulated multiple pathways involved in inflammation and growth in both BPH-1 and PrEp cells including NFκB p65, AKT, ERK1/2, EGFR, STAT3 and increased the levels of TGF-β1 and Snail/Slug. Most interestingly, GHRH also stimulated the transactivation of the IGF receptor. The study demonstrates that GHRH antagonists could be beneficial for the treatment of prostatic inflammation and BPH in part by inhibiting the growth-promoting and inflammatory effects of locally produced GHRH.

Diet-Induced Hyperinsulinemia as a Key Factor in the Etiology of Both Benign Prostatic Hyperplasia and Essential Hypertension?

Benign prostatic hyperplasia and hypertension are common age-related comorbidities. Although the etiology of benign prostatic hyperplasia (BPH) is still largely unresolved and poorly understood, a significant age-independent association was found between BPH and hypertension, indicating a common pathophysiological factor for both diseases. It has previously been suggested that the development of essential hypertension may be related to diet-induced hyperinsulinemia. This study follows the question, whether BPH may develop due to the same mechanism, thereby explaining the well-known comorbidity of these 2 disorders. The scientific evidence presented shows that BPH and hypertension share the same pathophysiological changes, with hyperinsulinemia as the driving force. It further shows that significant dietary changes during human history cause disruption of a finely tuned metabolic balance that has evolved over millions of years of evolution: high-insulinemic food, typical of current “Western” diets, has the potential to cause hyperinsulinemia and insulin resistance, as well as an abnormally increased activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, alterations that play a pivotal role in the pathogenesis of BPH and hypertension.

Comparison of 66 chemical element contents in normal and benign hyperplastic prostate

ObjectiveThe aim of this study was to clarify the differences between the prostatic levels of chemical elements in patients with benign prostatic hyperplasia (BPH) and healthy male. MethodsWe evaluated the prostatic level of 66 chemical elements in 43 patients with BPH and 37 healthy males. Measurements were performed using five instrumental analytical methods. ResultsIn the hyperplastic prostates, we have observed a significant increase in the mean level of Bi, Cr, Hg, K, Sb, and Se accompanied a significant decrease in the mean level of Al, Ce, Cs, Dy, Er, Gd, Ho, La, Mo, Nd, Pb, Pr, Sm, Sn, Tb, Tm, U, and Y. No differences were found in the mean prostatic level of other chemical elements including Ag, Al, Au, B, Ba, Be, Br, Ca, Cd, Co, Cu, Fe, Li, Mg, Mn, Na, Nb, Ni, P, Rb, S, Sc, Si, Th, Ti, Tl, Yb, Zn, and Zr between BPH patients and healthy males. ConclusionsThe finding of chemical element contents and correlation between pairs of chemical element mass fractions indicates that there is a great disturbance of prostatic chemical element metabolism in BPH gland. Trace elements Bi, Cr, Hg, K, Sb, and Se may be regarded as the possible tissue biomarkers of hyperplastic transformation of prostate gland. Obtained data did not confirm a critical role of Cd and Pb accumulation in the pathogenesis of BPH. A potential age-related Zn, Fe, and Se deficiency in the prostate tissue has not been found as being involved in the etiology of BPH.

Serotonin regulates prostate growth through androgen receptor modulation

Aging and testosterone almost inexorably cause benign prostatic hyperplasia (BPH) in Human males. However, etiology of BPH is largely unknown. Serotonin (5-HT) is produced by neuroendocrine prostatic cells and presents in high concentration in normal prostatic transition zone, but its function in prostate physiology is unknown. Previous evidence demonstrated that neuroendocrine cells and 5-HT are decreased in BPH compared to normal prostate. Here, we show that 5-HT is a strong negative regulator of prostate growth. In vitro, 5-HT inhibits rat prostate branching through down-regulation of androgen receptor (AR). This 5-HT’s inhibitory mechanism is also present in human cells of normal prostate and BPH, namely in cell lines expressing AR when treated with testosterone. In both models, 5-HT’s inhibitory mechanism was replicated by specific agonists of 5-Htr1a and 5-Htr1b. Since peripheral 5-HT production is specifically regulated by tryptophan hydroxylase 1(Tph1), we showed that Tph1 knockout mice present higher prostate mass and up-regulation of AR when compared to wild-type, whereas 5-HT treatment restored the prostate weight and AR levels. As 5-HT is decreased in BPH, we present here evidence that links 5-HT depletion to BPH etiology through modulation of AR. Serotoninergic prostate pathway should be explored as a new therapeutic target for BPH.

Molecular Analysis of the SRD5A1 and SRD5A2 Genes in Patients with Benign Prostatic Hyperplasia with Regard to Metabolic Parameters and Selected Hormone Levels.

Introduction: The etiology of benign prostatic hyperplasia (BPH) has not so far been fully explicated. However, it is assumed that changes in the levels of hormones associated with aging can contribute to the development of prostatic hyperplasia. Dihydrotestosterone combines with the androgen receptor (AR) proteins of the prostate gland. Enzyme activity is based on two isoenzymes: type 1 and type 2. 5α-reductase type 1 is encoded by the SRD5A1 gene, and type 2 is encoded by the SRD5A2 gene. The aim of our study was to determine the frequency of the SRD5A1 (rs6884552, rs3797177) and SRD5A2 (rs523349, rs12470143) genes’ polymorphisms, and to assess the relationships between the genotypes of the tested mutations, and the levels of biochemical and hormonal parameters in patients with BPH. Material and Methods: The study involved 299 men with benign prostatic hyperplasia. We determined the serum levels of particular biochemical parameters—fasting plasma glucose (FPG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides (TG)—by the spectrophotometric method, using ready reagent kits. The ELISA method was used to determine the levels of the following hormonal parameters and proteins: total testosterone (TT), free testosterone (FT), insulin (I), luteinizing hormone (LH), and sex hormone binding protein (SHBG). Metabolic syndrome was diagnosed. Genotyping was performed by real-time PCR. Results: We analyzed the relationships between the incidence of particular diseases and the genotypes of the SRD5A1 and SRD5A2 polymorphisms among patients with BPH. The BPH patients with the CC genotype of the SRD5A2 rs523349 and rs12470143 polymorphisms were considerably less frequently diagnosed with metabolic syndrome (MetS) (p = 0.022 and p = 0.023 respectively). Our analysis revealed that homozygotes with the CC of the SDR5A2 rs12470143 polymorphism had visibly higher HDL levels than those with the TT and CT genotypes (p = 0.001). Additionally, we found that the patients with the CC genotype of the SDR5A2 rs12470143 polymorphism had considerably higher FT levels (p = 0.001) than the heterozygotes with the CT and the homozygotes with the TT of the genetic variant analyzed in our study. Furthermore, the patients with at least one G allele of the SRD5A2 rs523349 polymorphism had significantly lower SGBG levels (p = 0.022) compared with the homozygotes with the CC genotype. The presence of at least one A allele (AA + AG genotypes) of the SRD5A1 rs3797177 polymorphism entailed notably lower serum insulin levels than those observed in homozygotes with the GG genotype (p = 0.033). Conclusions: The study described in this article shows that selected SRD5A1 and SRD5A2 polymorphisms can alter the levels of metabolic and hormonal parameters in patients with BPH. Special attention should be paid to the SDR5A2 rs12470143 polymorphism, which is associated with a change in lipid profile, as well as with the inheritance and incidence rate of MetS among these patients. An analysis of the frequency of this polymorphism among BPH patients could be useful in estimating the risk of getting ill, and planning therapies of concomitant diseases for BPH patients.

Genetic variants in 5p13.2 and 7q21.1 are associated with treatment for benign prostatic hyperplasia with the α-adrenergic receptor antagonist

Background: The etiology of benign prostatic hyperplasia (BPH) has not been well established. The preferred medical treatment for many men with symptomatic benign prostatic hyperplasia is either an α-adrenergic receptor antagonist (α-blocker), or a 5α-reductase inhibitor. Single nucleotide polymorphism (SNP) is a powerful tool for successful implementation of individualized treatment.Methods: Eighteen SNPs associated with drug efficacy in a Chinese population were genotyped in 790 BPH cases (330 aggressive and 460 non-aggressive BPH cases) and 1008 controls. All BPH patients were treated with α-adrenergic blockers for at least 9 months. We tested the associations between tagging single nucleotide polymorphism and BPH risk/aggressiveness, clinical characteristics at baseline, including the International Prostate Symptom Score (IPSS) and total prostate volume, and changes in clinical characteristics after treatment.Results: There were nine SNPs associated with BPH risk, clinical progression and therapeutic effect. (1) There were nine tSNPs been chosen in CYP3A4, CYP3A5 and RANBP3L genes. (2) The SNP, rs16902947 in RANBP3L at 5p13.2 (p = .01), was significantly associated with BPH. (3) We found two SNPs, rs16902947 in RANBP3L at 5p13.2 (p = .0388) and rs4646437 in CYP3A4 at 7q21.1 (p = .0325), associated with drug effect. (4) Allele “G” for rs16902947 was found to be risk alleles for BPH risk (OR= 2.357, 95%CI 1.01–1.48). The “A” allele of rs4646437 was associated with lower IPSS at baseline (β= −0.4232, p= .03255).Conclusions: rs16902947, rs16902947 and rs4646437 single nucleotide polymorphisms are significantly associated with the clinical characteristics of benign prostatic hyperplasia and the efficacy of benign prostatic hyperplasia treatment.

A genetic variant near GATA3 implicated in inherited susceptibility and etiology of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS).

Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common conditions. Little is known about their etiologies except that studies have suggested a substantial heritable component. Our objective is to provide a comprehensive, genome-wide evaluation of inherited risks and possible mechanisms of etiology in BPH. We performed a three-stage, genome-wide association study (GWAS) of men from three independent populations, the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, the CLUE II cohort, and a Finnish hospital-based population. DNA samples were genotyped using the Illumina HumanOmniExpress BeadChip in REDUCE and CLUE II, and using the Sequenom iPLEX system for the confirmation stage in the Finnish population. A logistic regression model was used to evaluate the association between each SNP and BPH/LUTS. Fourteen SNPs reached P < 5.0 × 10-4 in the meta-analysis of the two GWASs (CLUE II and REDUCE). A total of 773 SNPs were chosen for the confirmation step in the Finish cohort. Only one SNP (rs17144046) located ∼489 kb downstream of GATA3 remained significant after correction for multiple testing (P < 6.5 × 10-5 ). This SNP marginally reached the GWAS significance level after performing a meta-analysis of the three stages (P-meta = 8.89 × 10-7 ). Expression quantitative trait loci (eQTL) analyses showed that the risk allele (G) of rs17144046 was significantly associated with increased expression of GATA3 (P = 0.017). Reported studies indicated a close correlation between GATA3 and BPH pathogenesis and progression. Rs17144046 located near GATA3 was significantly associated with BPH/LUTS in three independent populations, but did not reach a stringent GWAS significance level. Genetic variants of GATA3 may play a role in the inherited susceptibility and etiology of BPH/LUTS. Further research in this area is needed.

MP17-14 DEPLETION OF PERIPHERAL SEROTONIN SYNTHESIS INDUCES BENIGN PROSTATIC GROWTH IN MICE: MORE EVIDENCE FOR THE NEW “NEUROENDOCRINE THEORY” IN BPH ETIOLOGY

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology1 Apr 2017MP17-14 DEPLETION OF PERIPHERAL SEROTONIN SYNTHESIS INDUCES BENIGN PROSTATIC GROWTH IN MICE: MORE EVIDENCE FOR THE NEW “NEUROENDOCRINE THEORY” IN BPH ETIOLOGY Paulo Mota, Emanuel Carvalho-Dias, Alice Miranda, Olga Martinho, Cristina Nogueira-Silva, Natalia Alenina, Michael Bader, Riccardo Autorino, Estevão Lima, and Jorge Correia-Pinto Paulo MotaPaulo Mota More articles by this author , Emanuel Carvalho-DiasEmanuel Carvalho-Dias More articles by this author , Alice MirandaAlice Miranda More articles by this author , Olga MartinhoOlga Martinho More articles by this author , Cristina Nogueira-SilvaCristina Nogueira-Silva More articles by this author , Natalia AleninaNatalia Alenina More articles by this author , Michael BaderMichael Bader More articles by this author , Riccardo AutorinoRiccardo Autorino More articles by this author , Estevão LimaEstevão Lima More articles by this author , and Jorge Correia-PintoJorge Correia-Pinto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.603AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Ageing and testosterone cause almost inexorably benign prostatic hyperplasia (BPH) in Human males, however the etiology of BPH is unknown. Serotonin (5-HT) is produced by neuroendocrine prostatic cells and is present in high concentration in normal prostatic transition zone. In BPH neuroendocrine cells and 5-HT are significantly decreased comparatively to normal prostatic transition zone. Previously, we have demonstrated in several in vitro models that 5-HT inhibitis non-malignant prostatic growth through androgen receptor down-regulation and we suggested a new Neuroendocrine Theory for BPH etiology. Here, we investigated in vivo the effects of peripheral inhibition of 5-HT synthesis on mice prostate gland. METHODS peripheral 5-HT synthesis is critical dependent of the presence of TPH1, so we used transgenic mice depleted from TPH1 (Tph1-/-) to study the in vivo effect of peripheral serotonin depletion. Male wild-type and Tph1-/- mice were sacrificed at different time points: 7, 12, 16 and 20 weeks-old. For pharmacological studies, wild-type and Tph1-/- mice with 19 week-old were treated with daily intraperitoneal injections of 0,9% saline or 5-HT (100 mg/Kg) during 10 consecutive days.Prostate gland mass was determined and proceeded for histology, western blotting, immunofluorescence and qRT-PCR of AR expression. RESULTS We showed that Tph1 knockout mice depleted from peripheral 5-HT have significant higher prostate mass comparatively to wild-type (p < 0,001) and 5-HT treatment of Tph1 knockout mice restores prostate mass to levels of wild-type (p < 0,001) (figure A and B). We demonstrated also that the benign prostatic growth in Tph1 knockout mice is associated with up-regulation of AR and 5-HT treatment restores de expression of AR (p<0,05) (Figure C and D). CONCLUSIONS In vivo, 5-HT depletion induces benign prostatic growth in mice trough AR up-regulation. 5-HT depletion in transition zone of aging human male could be the etiologic factor for BPH etiology. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e216-e217 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Paulo Mota More articles by this author Emanuel Carvalho-Dias More articles by this author Alice Miranda More articles by this author Olga Martinho More articles by this author Cristina Nogueira-Silva More articles by this author Natalia Alenina More articles by this author Michael Bader More articles by this author Riccardo Autorino More articles by this author Estevão Lima More articles by this author Jorge Correia-Pinto More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Antagonists of growth hormone-releasing hormone inhibit proliferation induced by inflammation in prostatic epithelial cells

The etiology of benign prostatic hyperplasia (BPH) is multifactorial, and chronic inflammation plays a pivotal role in its pathogenesis. Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide that has been shown to act as paracrine/autocrine factor in various malignancies including prostate cancer. GHRH and its receptors are expressed in experimental models of BPH, in which antagonists of GHRH suppressed the levels of proinflammatory cytokines and altered the expression of genes related to epithelial-to-mesenchymal transition (EMT). We investigated the effects of GHRH antagonist on prostatic enlargement induced by inflammation. Autoimmune prostatitis in Balb/C mice was induced by a homogenate of reproductive tissues of male rats. During the 8-wk induction of chronic prostatitis, we detected a progressive increase in prostatic volume reaching 92% at week 8 compared with control (P < 0.001). Daily treatment for 1 mo with GHRH antagonist MIA-690 caused a 30% reduction in prostate volume (P < 0.05). Conditioned medium derived from macrophages increased the average volume of spheres by 82.7% (P < 0.001) and elevated the expression of mRNA for N-cadherin, Snail, and GHRH GHRH antagonist reduced the average volume of spheres stimulated by inflammation by 75.5% (P < 0.05), and TGF-β2 by 91.8% (P < 0.01). The proliferation of primary epithelial cells stimulated by IL-17A or TGF-β2 was also inhibited by 124.1% and 69.9%, respectively. GHRH stimulated the growth of BPH-1 and primary prostate spheres. This study provides evidence that GHRH plays important roles in prostatic inflammation and EMT and suggests the merit of further investigation to elucidate the effects of GHRH antagonists in prostatitis and BPH.

The role of sex steroid hormones in benign prostatic hyperplasia

Introduction: The etiology of benign prostatic hyperplasia (BPH) remains a mystery to scientists; estrogen/androgen imbalance in aged men has been implicated.Methods: Thirty (30) apparently healthy men and newly diagnosed BPH patients were recruited from the Ghana Police Hospital. Lower urinary tract syndrome (LUTS) and prostate volume were assessed via the prostate symptom score sheet (IPSS) and abdominopelvic scan, respectively. Laboratory assays for total prostate specific antigen (tPSA) and hormones [androstenedione (AED), testosterone (T), dihydrotestosterone (DHT), androstanedioladiol (3α-adiol), androstanediol (3β-diol), estrone (E1) and estradiol (E2)] were performed via ELISA techniques. Non-parametric analyses were employed. p < 0.05 was considered significant.Results: AED was significantly higher in controls compared to the BPH patients. AKRIC2 (3α-diol/DHT) was significantly higher in the BPH group (p < 0.001) whiles AKRIC1 (3β-diol/DHT) was significantly lower. Estradiol was significantly higher in BPH (p= 0.029). Age correlated negatively with T, while a negative correlation was observed between TIPSS and 3β-diol and AKRIC1. Also, prostate volume correlated negatively with fT.tPSA correlated positively with E2 and aromatase activity (E2/T) and negatively with fT. On multiple linear regression, DHT and 3β-diol remained independent predictors for TIPSS and fT for tPSA.Conclusion: Estrogens and androstanediols seem to play a role in BPH development.