Human Benign Prostatic Hyperplasia Tissue Research Articles

ChemInform Abstract: New Nonsteroidal Steroid 5α-Reductase Inhibitors. Syntheses and Structure-Activity Studies on Carboxamide Phenylalkyl-Substituted Pyridones and Piperidones.

In the search for nonsteroidal inhibitors of 5 alpha-reductase for the treatment of benign prostatic hyperplasia (BPH), we synthesized diisopropyl (1a-8a) and tert-butyl (1b-8b) benzamides, as well as ethyl benzoates (1c, 3c), which were substituted in 4 position via variable alkyl spacer (n = 0: 1-4, n = 1: 5, 7 and n = 3: 6, 8) with a 1-methyl-2-pyridone (1, 2, 5, 6) or a 1-methyl-2-piperidone (3, 4, 7, 8) moiety mimicking steroidal ring A. The directly connected benzamides (1a-4a, 1b-4b) and benzoates (1c, 3c) were obtained by palladium-catalysed coupling reaction of diethyl(3-pyridyl)-borane with 4-bromobenzoic acid derivatives, followed by alpha-oxidation of the 1-methyl-pyridinium salt and subsequent separation of the regioisomers. Catalytic hydrogenation of the pyridones (1, 2) led to the piperidones (3, 4). The preparation of the benzamides with a methylene (5, 7) and a propylene spacer (6, 8), respectively, started with the reduction of the keto group of 5-benzoyl-1,2-dihydro-1-methyl-2(1H)-pyridone and catalytic hydrogenation of the alkene obtained by Wittig reaction of 5-formyl-1,2-dihydro-1-methyl-2(1H)-pyridone with (2-phenylethyl)triphenylphosphonium bromide, respectively. The phenyl ring was functionalized by Friedel-Crafts reaction, haloform cleavage to give the acid, formation of the acid chloride, and subsequent treatment with the appropriate amines. Again, catalytic hydrogenation of the pyridones (5, 6) led to the piperidones (7, 8). The 5 alpha-reductase inhibitory properties were determined using rat ventral prostate, as well as human BPH tissue as enzyme source, 1 beta-2 beta-[3H]testosterone as substrate and a HPLC procedure for the separation of dihydrotestosterone (DHT). Tested at a concentration of 100 microM, the inhibition values of 1-8 ranged from 0-79%. Significant differences were observed between rat and human enzyme. The most active compound was ethyl 4-(1-methyl-2-oxopiperid-5-yl)benzoate 3c (68%) for the human enzyme and N,N-bis(1-methylethyl)-4-[3-(1,2-dihydro-1-methyl-2-oxopyrid-5-yl) propyl] benzamide 6a (79%) for the rat enzyme.

Functional role of PKC in contraction of cultured human prostatic stromal cells

The contractile activity of prostatic stromal cells contributes to symptoms of benign prostatic hyperplasia (BPH). However, the mechanisms for this contraction have not yet been fully elucidated. In this study, we investigated the role of protein kinase C (PKC) in prostatic contraction by measuring the isometric tension development of cultured human prostatic stromal cells (CHPSCs) derived from BPH patients. Fresh human BPH tissue was used only in a Western blot analysis. A ring preparation made of CHPSCs and collagen gel could develop an isometric tension during activation with various agonists. Phorbol 12,13 dibutyrate (PDBu), a PKC activator, induced a relaxation. A Western blot analysis revealed the expression of PKC-potentiated protein phosphatase-1 inhibitory protein (CPI-17) in both CHPSCs and fresh human BPH tissue to be much lower than that in the rabbit aorta. When CPI-17 was over-expressed, PDBu induced a large contraction, but the agonist-induced contraction did not become larger than expected. In alpha-toxin permeabilized preparations, PDBu induced a relaxation in control CHPSCs, while it induced a contraction at a constant [Ca2+]i in CPI-17 over-expressing CHPSCs. These results indicated that the activation of PKC in CHPSCs induces a relaxation probably due to low expression level of CPI-17 and also that the PKC-CPI-17 pathway does not appear to play a major role in the agonist-induced contraction even when CPI-17 was over-expressed.

Combination Therapy with Rofecoxib and Finasteride in the Treatment of Men with Lower Urinary Tract Symptoms (LUTS) and Benign Prostatic Hyperplasia (BPH)

Purpose: Cyclooxygenase-2 (COX-2) is expressed in human BPH tissue and displays either a pro-inflammatory effect or a proliferative effect on prostate cells. The aim of this study is to analyze whether combination therapy with rofecoxib, a COX-2 inhibitor, and finasteride offers an advantage compared to finasteride monotherapy in patients with BPH. Materials and Methods: This is a single centre unblinded trial. Forty-six consecutive men with LUTS and BPH were entered into the study and were randomized to receive rofecoxib 25 mg/day plus finasteride 5 mg/day (group B) versus finasteride 5 mg/day alone (group A) for 24 weeks. Inclusion criteria included also a prostate size greater than 40 cc. The efficacy and safety of treatments were assessed at baseline and at week 4, 12 and 24. Results: In our population, both treatments (groups A and B) produced statistically significant improvements in total IPSS and Q max from baseline during follow-up, although they were very low in particular for the finasteride alone group at 4 weeks. We found that finasteride monotherapy produces very little improvement at the 1 month interval. In comparing group A with group B, a significantly higher improvement in IPSS ( p = 0.0001) and Q max ( p = 0.03) was obtained in group B at 4 weeks interval (% cases with IPSS reduction >4 points: group B = 34.7, group A = 0; % cases with Q max improvement >3 ml/s: group B = 8.7, group A =0), whereas at week 24, the differences between the two treatments were not significant ( p > 0.05). Conclusions: In our population, the advantage of the combination therapy compared to finasteride alone is significant in a short-term interval (4 weeks). It can be hypothesized that the association of rofecoxib with finasteride induces a more rapid improvement in clinical results until the effect of finasteride becomes predominant.

Kinetics of acetyl coenzyme A: arylamine N-acetyltransferase from rapid and slow acetylator human benign prostatic hyperplasia tissues.

N-acetyltransferase (NAT) activity was determined in 40 human benign prostatic hyperplasia tissues using 2-aminofluorene (AF) and p-aminobenzoic acid (PABA) as substrates. These were then assayed by high performance liquid chromatography for determining the amounts of acetylated AF and PABA and non-acetylated AF and PABA. The activities (mean +/- SD) of AF-NAT from human benign prostatic hyperplasia tissues were divided into rapid (2.06 +/- 0.08 nmol/min per milligram protein), intermediate (1.25 +/- 0.26 nmol/min per milligram protein), and slow (0.58 +/- 0.30 nmol/min per milligram protein) acetylator groups. The activities (mean +/- SD) of PABA-NAT from human benign prostatic hyperplasia tissues were also divided into rapid (2.00 +/- 0.00 nmol/min per milligram protein), intermediate (1.25 +/- 0.18 nmol/min per milligram protein), and slow (0.48 +/- 0.29 nmol/min per milligram protein) acetylator groups. Kinetic constants for arylamine NAT activities were determined for each of these acetylator groups. Apparent differences in Km and Vmax for AF were found. Therefore, there seems to be a polymorphism in NAT activity with two rapid, five intermediate, and 33 slow acetylators among the 40 samples assayed. This is the first demonstration of acetyl CoA-arylamine NAT activity in human benign prostatic hyperplasia tissues.

New nonsteroidal steroid 5 alpha-reductase inhibitors. Syntheses and structure-activity studies on carboxamide phenylalkyl-substituted pyridones and piperidones.

In the search for nonsteroidal inhibitors of 5 alpha-reductase for the treatment of benign prostatic hyperplasia (BPH), we synthesized diisopropyl (1a-8a) and tert-butyl (1b-8b) benzamides, as well as ethyl benzoates (1c, 3c), which were substituted in 4 position via variable alkyl spacer (n = 0: 1-4, n = 1: 5, 7 and n = 3: 6, 8) with a 1-methyl-2-pyridone (1, 2, 5, 6) or a 1-methyl-2-piperidone (3, 4, 7, 8) moiety mimicking steroidal ring A. The directly connected benzamides (1a-4a, 1b-4b) and benzoates (1c, 3c) were obtained by palladium-catalysed coupling reaction of diethyl(3-pyridyl)-borane with 4-bromobenzoic acid derivatives, followed by alpha-oxidation of the 1-methyl-pyridinium salt and subsequent separation of the regioisomers. Catalytic hydrogenation of the pyridones (1, 2) led to the piperidones (3, 4). The preparation of the benzamides with a methylene (5, 7) and a propylene spacer (6, 8), respectively, started with the reduction of the keto group of 5-benzoyl-1,2-dihydro-1-methyl-2(1H)-pyridone and catalytic hydrogenation of the alkene obtained by Wittig reaction of 5-formyl-1,2-dihydro-1-methyl-2(1H)-pyridone with (2-phenylethyl)triphenylphosphonium bromide, respectively. The phenyl ring was functionalized by Friedel-Crafts reaction, haloform cleavage to give the acid, formation of the acid chloride, and subsequent treatment with the appropriate amines. Again, catalytic hydrogenation of the pyridones (5, 6) led to the piperidones (7, 8). The 5 alpha-reductase inhibitory properties were determined using rat ventral prostate, as well as human BPH tissue as enzyme source, 1 beta-2 beta-[3H]testosterone as substrate and a HPLC procedure for the separation of dihydrotestosterone (DHT). Tested at a concentration of 100 microM, the inhibition values of 1-8 ranged from 0-79%. Significant differences were observed between rat and human enzyme. The most active compound was ethyl 4-(1-methyl-2-oxopiperid-5-yl)benzoate 3c (68%) for the human enzyme and N,N-bis(1-methylethyl)-4-[3-(1,2-dihydro-1-methyl-2-oxopyrid-5-yl) propyl] benzamide 6a (79%) for the rat enzyme.

A prospective randomized trial evaluating tissue effects of finasteride therapy in benign prostatic hyperplasia.

Finasteride is widely used for the treatment of benign prostatic hyperplasia (BPH). Its therapeutic efficacy is believed to be mediated through selective inhibition of prostatic 5alpha-reductase (type II). This prospective, controlled, randomized study examines various relationships between changes in tissue 5alpha-reductase isozyme activity, epithelial proliferative index and morphology in men with BPH treated with finasteride for 6 months, and correlates these with clinical response. Thirty-one patients presenting with symptomatic bladder outflow obstruction were prospectively randomized to receive either finasteride or placebo (2:1) for 24 weeks. Of these, 27 men aged 55-80 y (median 69 y) completed the study, including 18 patients on treatment. Symptom score determination, uroflow and prostate volume were assessed at baseline and end of study. Prostatic tissue was obtained by ultrasound-guided needle biopsy at baseline and by transurethral resection (TURP) at end of study for biochemical and morphometric analysis. Epithelial proliferation was examined quantitatively in the resected tissue using MIB-1 antibody to Ki-67 and counting the percentage of positively staining cells. Type II 5alpha-reductase activity was strongly inhibited by finasteride in resected BPH tissue, with over 100-fold decrease in V(max) (P=0.001), whereas the type I isozyme was inhibited 5-fold (P=0.005). Selective inhibition of type II 5alpha-reductase was demonstrated in all treated patients. No significant difference in epithelial proliferation was observed between the finasteride and placebo groups. Epithelial proliferation was, however, greater in prostatic tissue with histological manifestation of inflammation (2.02% vs 0.89%, P=0.001). Positive correlation between the total epithelial volume and the ratio of transition zone volume/total prostate volume was observed in the placebo group (r=0.834), whereas there was no such correlation in men taking finasteride (r=-0.300), consistent with a reduction in epithelial content in the treatment group. Improvement in uroflow and reduction in prostatic volume in patients treated with finasteride did not reach statistical significance. This study shows that finasteride causes inhibition of 5alpha-reductase activity in human BPH tissue with selectivity for the type II isozyme. In spite of this, no significant effects in epithelial proliferation or tissue morphology were demonstrated. The presence of inflammation was, however, associated with significantly greater proliferative activity. The power of this study was limited by the small number of recruited patients, and a larger study would be required for further investigation of morphological changes induced by finasteride in BPH tissue and their biochemical basis.

α1- and α2-Adrenoceptors in BPH

The dynamic obstruction of the bladder outlet secondary to benign prostatic hyperplasia (BPH), and the contractile properties of the human prostate are mediated primarily by α₁-adrenoceptors. There are now at least three subtypes (A, B, and D) of α₁-adrenoceptors, and recent work revealed that α_1A-adrenoceptor and α_1B-adrenoceptor may have a prime role for prostatic obstruction, and contraction of artery, respectively. Very recently, the presence of a low affinity α₁-adrenoceptor for prazosin, named α_1L, in the human BPH tissue has been determined. Because the DNA sequence of α_1L-adrenoceptor has not yet been cloned, the α_1L-adrenoceptor may be another form of the α_1A-adrenoceptor, or another pharmacologically distinct α₁-adrenoceptor which mediates the norepinephrine-induced contraction of the prostatic smooth muscle. Furthermore, the contribution of α₁-adrenoceptors in the prostate to symptoms (not only obstructive, but irritative symptoms) which are elicited by prostatic obstruction remains to be determined.

CAN THE INTRAPROSTATIC CONCENTRATION OF EPIDERMAL GROWTH FACTOR INFLUENCE THE VARIANCE OF SERUM PROSTATE SPECIFIC ANTIGEN LEVELS IN PATIENTS WITH BENIGN PROSTATIC HYPERPLASIA?

Except for prostate volume, little is known about the factors influencing serum prostate specific antigen (PSA) levels. Considering that dihydrotestosterone and epidermal growth factor are regulators of the proliferation and differentiation in the epithelial component of human prostate tissue and that PSA is produced only by the epithelial cells of the gland, studies were performed on patients with a histological diagnosis of benign prostatic hyperplasia (BPH) to establish whether a significant association exists between the intraprostatic concentration of dihydrotestosterone or epidermal growth factor and serum PSA levels.A total of 20 patients with BPH who had not been previously treated were part of a larger study on the correlation among PSA, prostate volume and age, and were evaluated according to the algorithm in the guidelines of the international consultation on BPH. All men underwent open suprapubic prostatectomy to enucleate the entire adenoma and in each case sections were made in the periurethral, subcapsular and intermediate zones of the BPH tissue. Dihydrotestosterone and epidermal growth factor concentrations were evaluated by radioimmunoassay in the periurethral zone and in total BPH tissue.In these 20 patients with BPH serum PSA levels were significantly associated with epidermal growth factor but not with dihydrotestosterone concentrations in total BPH tissue (r = 0.7762, p = 0.00002836 and r = 0.3923, p = 0.0956307, respectively). A stronger association was found between PSA levels and the periurethral concentration of epidermal growth factor and dihydrotestosterone (r = 0.8117, p = 0.000005 and r = 0.5656, p = 0.0098326, respectively). On the contrary, epidermal growth factor and dihydrotestosterone were not significantly associated with prostate volume (p = 0.957415 and p = 0.531439, respectively).To our knowledge this study is the first report in the literature to demonstrate an association between serum PSA, and dihydrotestosterone and epidermal growth factor levels, particularly in the periurethral zone of human BPH tissue. These data suggest the importance of epidermal growth factor and dihydrotestosterone in influencing serum PSA levels.

Can the intraprostatic concentration of epidermal growth factor influence the variance of serum prostate specific antigen levels in patients with benign prostatic hyperplasia?

Except for prostate volume, little is known about the factors influencing serum prostate specific antigen (PSA) levels. Considering that dihydrotestosterone and epidermal growth factor are regulators of the proliferation and differentiation in the epithelial component of human prostate tissue and that PSA is produced only by the epithelial cells of the gland, studies were performed on patients with a histological diagnosis of benign prostatic hyperplasia (BPH) to establish whether a significant association exists between the intraprostatic concentration of dihydrotestosterone or epidermal growth factor and serum PSA levels. A total of 20 patients with BPH who had not been previously treated were part of a larger study on the correlation among PSA, prostate volume and age, and were evaluated according to the algorithm in the guidelines of the international consultation on BPH. All men underwent open suprapubic prostatectomy to enucleate the entire adenoma and in each case sections were made in the periurethral, subcapsular and intermediate zones of the BPH tissue. Dihydrotestosterone and epidermal growth factor concentrations were evaluated by radioimmunoassay in the periurethral zone and in total BPH tissue. In these 20 patients with BPH serum PSA levels were significantly associated with epidermal growth factor but not with dihydrotestosterone concentrations in total BPH tissue (r = 0.7762, p = 0.00002836 and r = 0.3923, p = 0.0956307, respectively). A stronger association was found between PSA levels and the periurethral concentration of epidermal growth factor and dihydrotestosterone (r = 0.8117, p = 0.000005 and r = 0.5656, p = 0.0098326, respectively). On the contrary, epidermal growth factor and dihydrotestosterone were not significantly associated with prostate volume (p = 0.957415 and p = 0.531439, respectively). To our knowledge this study is the first report in the literature to demonstrate an association between serum PSA, and dihydrotestosterone and epidermal growth factor levels, particularly in the periurethral zone of human BPH tissue. These data suggest the importance of epidermal growth factor and dihydrotestosterone in influencing serum PSA levels.

Coexpression of gonadotropic hormones and their corresponding FSH- and LH/CG-receptors in the human prostate.

Benign prostatic hyperplasia (BPH) affects the majority of elderly men, and prostate cancer is the most common male cancer. Prostatic growth and function are thought to be regulated by steroid hormones, primarily androgens and estrogens, but nonandrogenic hormones must also be considered. The increasing evidence of para/autocrine functions of the gonadotropic glycoprotein-hormones (GPH), their allocation to the superfamily of cystine-knot growth factors, and luteinizing hormone (LH)/chorionic gonadotropin (CG)-receptor (R) gene expression in nongonadal tissues led us to investigate intraprostatic GPH and GPH-R gene expression. RT-PCR and subsequent Southern hybridization and/or restriction enzyme analysis of BPH and prostatic adenocarcinoma demonstrated that all three human (h) gonadotropic hormones, i.e., follicle-stimulating hormone (FSH), LH, and CG, as well as the corresponding FSH-R and LH/CG-R, are transcribed intraprostatically. Significant amounts of the alpha and beta subunits of hCG were secreted by short-term primary cultures of human BPH tissues, as detected by highly sensitive and specific time-resolved immunofluorometric assays (IFMAs). Our data suggest that prostatic- and pituitary-derived GPH act directly on the prostatic gland, particularly FSH via the FSH-R, thereby possibly modulating locally acting key hormones and growth factors involved in BPH development.

Differential expression of acidic and basic fibroblast growth factors in benign prostatic hyperplasia identified by immunohistochemistry.

To detect the expression and to determine the relative cellular locations of the two peptide growth factors, acidic fibroblast growth factor (a-FGF) and basic (b)-FGF in tissues from human benign prostatic hyperplasia (BPH). A series of 50 sequential and unselected cases of human BPH tissues, obtained after transurethral prostatectomy, was examined. Adjacent sections of formalin-fixed and paraffin wax-embedded tissues were stained immunohistochemically for expression of a-FGF and b-FGF using well-characterized and commercially available antibodies. The stained tissue sections were assessed for the cellular distribution of immunohistochemical products and analysed according to the relative intensity of staining as well as the spatial relationships of positively stained cells. Acidic-FGF was weakly expressed with a pancytoplasmic distribution within luminal glandular epithelial cells in regions of prostatic intra-epithelial neoplasia (both PIN I and II) but not by non-dysplastic normal or hyperplastic tissues. No expression of a-FGF was detected in basal epithelial cells or in the stromal compartment of any tissue examined. In contrast, b-FGF was strongly expressed within the cytoplasm of all basal epithelial cells, but not by luminal epithelial cells, in morphologically normal regions of all cases examined. Basal expression of b-FGF was diminished, or absent, in regions of mild epithelial dysplasia, particularly those strongly expressing a-FGF. Extensive nuclear and cytoplasmic expression of b-FGF occurred predominantly in smooth muscle-type stromal cells but not in all types of stromal cells. This study confirmed both a differential and a reciprocal expression of a- and b-FGF in non-dysplastic prostatic hyperplasia and in mildly dysplastic regions of prostatic tissues. While only small amounts of a-FGF were expressed in BPH, exclusively in the luminal epithelial compartment, its consistent appearance in PIN I and II suggests that it might contribute to the early stages of PIN. Conversely, b-FGF may be an important mediator of stromal-epithelial interaction during the pathogenesis of BPH. These results provide new information about the relative expression of these growth factors, particularly in the architectural relationships between different cell-types within normal and non-malignant prostatic tissues.

Effect of finasteride on the concentrations of testosterone, dihydrotestosterone and 3α-androstanediol in human benign prostatic hyperplasia tissue : S. Monti, P. A. Varasano, S. Lanzara, C. Tosti-Croce, G. D'Eramo, F. Di Silverio, and F. Sciarra. Departments of Medical Physiopathology, III Endocrinology, and Urology, University of Rome La Sapienza, Rome, Italy

Effect of finasteride on the concentrations of testosterone, dihydrotestosterone and 3α-androstanediol in human benign prostatic hyperplasia tissue : S. Monti, P. A. Varasano, S. Lanzara, C. Tosti-Croce, G. D'Eramo, F. Di Silverio, and F. Sciarra. Departments of Medical Physiopathology, III Endocrinology, and Urology, University of Rome La Sapienza, Rome, Italy

Growth factors in benign prostatic hyperplasia (BPH) and prostate carcinoma

It has been stated that, although steroid hormones are a necessary prerequisiste for prostate cell proliferation, cell division is not an inevitable consequence of the presence of hormones. The possibility that diffusible trophic factors play an important role in the normal and pathologic regulatory process within the prostate, offers a new and exciting research initiative. In order to better clarify the relationships between Epidermal growth factor (EGF), its receptor (EGFr) and steroid receptors at target tissue levels, we have demonstrated a statistically significant linear correlation between irEGF and nuclear androgen receptor (nAR) levels in human BPH tissue. Moreover we started an investigation to analyse the stroma-epithelium ratio and to verify EGF, EGFr, AR, DHT concentrations in the periurethral, central and peripheral zone of human BPH tissue. In all BPH zones the quantitative method of image analysis showed a higher percentage content of stroma than of epithelium. The highest levels of EGF, DHT and stroma content were present in the periurethral zone, where BPH begins. Both androgen and antiandrogen treatment enhance the proliferation rate of prostate cancer cell line LNCaP. After prolonged R1881 administration, a marked increase of EGF release was observed, completely blocked by the addition of OH-flutamide. The role of Transforming growth factor beta 1 (TGF beta1) in prostate cancer has been also demonstrated in prostate cancer tissue of patients submitted to radical prostatectomy.

Studies on the mechanisms of action of fibroblast growth factors in stromal cells in hyperplastic human prostate

Stromal-epithelial cell interaction is very important for the development of human benign prostatic hyperplasia (BPH). Growth factors and their receptors in the prostate are thought to mediate the cell communication and play some roles in the development of BPH. Among many growth factors, fibroblast growth factor (FGF) family members have received the most intensive study, and mRNAs for acidic FGF (aFGF), basic FGF (bFGF) and keratinocyte growth factor (KGF) have been identified in rat or human prostate. However, synthesis sites and roles of them in stromal-epithelial cell interaction remain to be undefined. In the present study, to define the mechanisms for the regulation of prostatic cell growth by stromal cells in human BPH, we established the method for isolation and culture of epithelial cells as well as stromal cells from human BPH tissue. Using these primary cultured prostatic cells, we evaluated the effects of stromal cell conditioned medium (SCM) and stromal cell extract (SCE) on the growth of stromal cells and epithelial cells by [3H]-thymidine incorporation assay. We also examined the expression of mRNAs for aFGF, bFGF, KGF, FGF receptor 1 (FGFR1) and FGFR2 in epithelial and stromal cells using Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) analysis. As the results, both SCM and SCE stimulated the growth of stromal cells, and the growth promoting effects of them to stromal cells were completely suppressed by anti-bFGF neutralizing antibody, but not by anti-aFGF neutralizing antibody at all. SCM also stimulated the growth of epithelial cells. The growth promoting effect of it to epithelial cells was not completely suppressed by anti-bFGF neutralizing antibody, and not by anti-aFGF neutralizing antibody at all. Furthermore, RT-PCR analysis demonstrated the expression of mRNAs for bFGF, KGF and FGFR1 in stromal cells and that of FGFR2 in epithelial cells. These findings suggest that bFGF produced by stromal cells acts on stromal cells through FGFR1 by an autocrine mechanism, KGF produced by stromal cells acts on epithelial cells through FGFR2 by a paracrine manner in human BPH. These mechanisms for the regulation of cell growth by stromal cells were thought to contribute to the development of human BPH.

Transrectal hyperthermia-induced histological and ultrastructural changes of human benign prostatic hyperplasia tissue.

This prospective study evaluated the tissutal, cellular and intracellular effects of transrectal microwave hyperthermia on human benign prostatic hyperplasia. Forty-eight patients with benign prostatic hyperplasia underwent ten 60-min-long sessions of transrectal hyperthermia with an intraprostatic calculated temperature of 42 +/- 0.5 degrees C. Ultrasound-guided transperineal biopsies of the prostate were taken before and 1 month after completion of treatment. Postoperatively, morphometric analysis of bioptic specimens showed a statistically significant (p < 0.01) increase in the number of intraprostatic arterioles and capillary-like vessels. Diffused inflammatory infiltrates were also noted. Postoperative integrity of intracellular organelles and cellular membranes was evidenced by transmission electron microscopy. Our regimen of transrectal prostatic hyperthermia did not cause any irreversible histological or ultrastructural damage to the prostatic tissue. Hyperthermia-induced increase in blood flow could enhance drug delivery to the prostate gland.

Formula omitted] biosynthesis of FSH like peptide by the human prostate

Human benign prostatic hyperplasia tissue is able to synthesize immunoreactive FSH (IR FSH) in vitro . The prostatic FSH is similar to pituitary FSH as evident by co-elution on Sephadex G-100. High performance gel filtration chromatography and Western blot analysis. Immunocytochemical localization studies indicate positive staining in the cytoplasm of prostatic epithelial cells. There is a two fold increase in the concentration of immunoreactive FSH in benign hyperplastic tissue as compared to normal prostate.

Prostatic growth effects of rat urogenital sinus and human prostatic tissue in the rat

It is known that fetal urogenital sinus (UGS) implanted into one ventral lobe of an adult mouse prostate produces a significantly increased DNA content in that lobe. In our study, we attempted to determine whether that growth was of host or of graft tissue. UGS from fetal rats and ventral prostate from adult rats were implanted in various sites in syngeneic Fischer rats, alone or as a recombinant tissue complex. Human benign prostatic hyperplasia (BPH) tissue was implanted into the ventral prostate of adult, male, hooded nude rats to determine whether it stimulated prostatic growth. All UGS-implanted in situ ventral lobes enlarged. Mean DNA content of UGS and ventral prostate implanted together in the flank was not different from the mean DNA content of UGS and ventral prostate implanted separately in the flank (P = 0.69). Mean DNA content of in situ control ventral lobe and of UGS grown singly in the flank was less than that of a UGS-implanted in situ ventral lobe (P less than 0.01). Thus overgrowth in the UGS-implanted in situ ventral prostate was location-dependent, but which tissue(s) enlarged remains unclear. Implanted human BPH tissue did not stimulate rat prostatic growth.

Divergent Effects of Interferons on the Growth of Human Benign Prostatic Hyperplasia Cells in Primary Culture

Epithelial cells from human benign prostatic hyperplasia tissues were grown in primary cultures for up to 21 days and the effects of interferons on the growth of the cells were investigated. Interferon-α (Wellferon) showed growth inhibition both in the presence and in the absence of 3 × 10-10M testosterone propionate (TP) whereas interferon-γ stimulated growth in a dose dependent manner under similar conditions. Interferon-β had little effect on growth at the dose levels used in the study. The growth inhibition by interferon-α can be induced after stimulation of growth is achieved either with TP or with interferon-γ. Implications of these findings for clinical use of these lymphokines is discussed.

Localization of epidermal growth factor receptors in the human prostate by biochemical and immunocytochemical methods

The receptor for epidermal growth factor (EGF) was characterized in the particulate fraction from human benign prostatic hyperplasia (BPH) and was present in 85% of tissues analysed. The uptake of 125I-labelled EGF by BPH was dependent on both time and temperature, with maximum specific uptake achieved after incubation for 90 min at 37 degrees C. Binding characteristics revealed two classes of binding sites of higher (mean dissociation constant (Kd) +/- S.D. = 0.8 +/- 0.2 nmol/l) and lower (Kd = 7.6 +/- 2.8 nmol/l) affinities. Competition studies demonstrated the specificity of the receptor assay since the binding of labelled EGF was abolished with excess unlabelled EGF but not with excess unlabelled human GH, human insulin, venom nerve growth factor, human FSH, human LH and human prolactin. There was a complex biphasic relationship between specific binding and protein concentration in the range 0.1-8 mg/ml. Subcellular fractionation of BPH homogenates demonstrated that the bulk of the specific binding was confined to the 800 g (crude heavy pellet) and 15,000 g (mitochondrial pellet) fractions. The 105,000 g (microsomal pellet) and the 105,000 g (cytosol fraction) exhibited low and variable binding capacities for the growth factor. The presence of EGF receptor was also confirmed by immunocytochemical staining of frozen sections from BPH using monoclonal antibody specific for EGF receptors. A positive correlation between 125I-labelled EGF binding and the intensity of staining was found. The presence of a specific EGF-binding receptor protein in human BPH tissues suggests that EGF may play a role in the pathogenesis of human BPH.

Spontaneous bacterial peritonitis.

<h3>Abstract</h3> Benign prostatic hyperplasia (BPH) is ostensibly linked to autoimmune (AI) diseases, but whether the prostate is a target of systemic inflammation associated with AI conditions is unknown. Prostatic inflammation is linked to fibrosis, hyperplasia, and reduced responses to BPH-related medical therapies. This study was conducted to determine if AI disease correlates with BPH diagnosis and whether systemic targeting of an inflammatory mediator limits prostatic inflammation and hyperplasia. Patient medical records (n=112,152) were evaluated to determine BPH prevalence among different AI diseases. Inflammatory cells from human BPH tissues were analyzed by single-cell (sc)RNA-seq and the tumor necrosis factor (TNF)α-antagonist etanercept was tested in two murine models of prostatic enlargement. BPH prevalence was significantly higher among patients with AI disease compared to unaffected individuals. However, AI patients treated with TNFα-antagonists had a significantly reduced incidence of BPH. Data from scRNA- seq identified macrophages as a dominant source of TNFα and <i>in vitro</i> assays confirmed that TNFα stimulates BPH-derived fibroblast proliferation. In the AI patient cohort and murine models, systemic treatment with TNFα-antagonists decreased prostatic epithelial proliferation, macrophage infiltration, and epithelial NFκB activation compared to control tissues. These studies are the first to show that patients with AI diseases have a heightened susceptibility to BPH and that the TNFα-signaling axis is important for BPH pathogenesis. Macrophage-secreted TNFα may mechanistically drive BPH via chronic activation of the signaling axis and NFκB. TNFα blockade appears to be a promising new pharmacological approach to target inflammation and suppress BPH. <h3>One sentence summary</h3> Patient data and mouse models suggest that repurposing tumor necrosis factor alpha blockade reduces inflammation-mediated prostatic hyperplasia.