Androgen Receptor Roles in the Development of Benign Prostate Hyperplasia
2013; Elsevier BV; Volume: 182; Issue: 6 Linguagem: Inglês
10.1016/j.ajpath.2013.02.028
ISSN1525-2191
AutoresKouji Izumi, Atsushi Mizokami, Wen‐Jye Lin, Kuo‐Pao Lai, Chawnshang Chang,
Tópico(s)Hormonal and reproductive studies
ResumoBenign prostate hyperplasia (BPH) is a major cause of lower urinary tract symptoms, with an increased volume of transitional zone and associated with increased stromal cells. It is known that androgen/androgen receptor (AR) signaling plays a key role in development of BPH, and that blockade of this signaling decreases BPH volume and can relieve lower urinary tract symptoms, but the mechanisms of androgen/AR signaling in BPH development remain unclear, and the effectiveness of current drugs for treating BPH is still limited. The detailed mechanisms of androgen/AR signaling need to be clarified, and new therapies are needed for better treatment of BPH patients. This review focuses on roles of AR in epithelial and stromal cells in BPH development. In epithelial cells, AR may contribute to BPH development via epithelial cell–stromal cell interaction with alterations of epithelial–mesenchymal transition, leading to proliferation of stromal cells. Data from several mouse models with selective knockout of AR in stromal smooth-muscle cells and/or fibroblasts indicate that the AR in stromal cells can also promote BPH development. In prostatic inflammation, AR roles in infiltrating macrophages and epithelial and stromal cells have been linked to BPH development, which has led to discovery of new therapeutic targets. For example, targeting AR with the novel AR degradation enhancer, ASC-J9 offers a potential therapeutic approach against BPH development. Benign prostate hyperplasia (BPH) is a major cause of lower urinary tract symptoms, with an increased volume of transitional zone and associated with increased stromal cells. It is known that androgen/androgen receptor (AR) signaling plays a key role in development of BPH, and that blockade of this signaling decreases BPH volume and can relieve lower urinary tract symptoms, but the mechanisms of androgen/AR signaling in BPH development remain unclear, and the effectiveness of current drugs for treating BPH is still limited. The detailed mechanisms of androgen/AR signaling need to be clarified, and new therapies are needed for better treatment of BPH patients. This review focuses on roles of AR in epithelial and stromal cells in BPH development. In epithelial cells, AR may contribute to BPH development via epithelial cell–stromal cell interaction with alterations of epithelial–mesenchymal transition, leading to proliferation of stromal cells. Data from several mouse models with selective knockout of AR in stromal smooth-muscle cells and/or fibroblasts indicate that the AR in stromal cells can also promote BPH development. In prostatic inflammation, AR roles in infiltrating macrophages and epithelial and stromal cells have been linked to BPH development, which has led to discovery of new therapeutic targets. For example, targeting AR with the novel AR degradation enhancer, ASC-J9 offers a potential therapeutic approach against BPH development. Benign prostatic hyperplasia (BPH) is the most common male benign proliferative disease, and approximately 8 million patients are estimated to visit physicians with the diagnosis of primary or secondary BPH.1Wei J.T. Calhoun E. Jacobsen S.J. Urologic diseases in America project: benign prostatic hyperplasia.J Urol. 2005; 173: 1256-1261Crossref PubMed Scopus (457) Google Scholar The incidence of gross enlargement of the prostate gland has been reported as 40% in 70-year-old men, and microscopic foci of the prostate gland are present in up to 80% of these men.2Ekman P. BPH epidemiology and risk factors.Prostate Suppl. 1989; 2: 23-31Crossref PubMed Scopus (50) Google Scholar BPH patients often have lower urinary tract symptoms, and need to be treated with surgery or medication. Although transurethral resection of the prostate is the most common surgical treatment for BPH worldwide, the procedure can lead to complications (eg, bleeding, urethral stricture, incontinence) and may have limitations for people of advanced age.3Ahyai S.A. Gilling P. Kaplan S.A. Kuntz R.M. Madersbacher S. Montorsi F. Speakman M.J. Stief C.G. Meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement.Eur Urol. 2010; 58: 384-397Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar, 4Smith R.D. Patel A. Transurethral resection of the prostate revisited and updated.Curr Opin Urol. 2011; 21: 36-41Crossref PubMed Scopus (37) Google Scholar, 5Kavanagh L.E. Jack G.S. Lawrentschuk N. Prevention and management of TURP-related hemorrhage.Nat Rev Urol. 2011; 8: 504-514Crossref PubMed Scopus (25) Google Scholar Although α-blockers are frequently prescribed for treatment of BPH and have a quick onset of action, within 3 to 5 days,6Kapoor A. Benign prostatic hyperplasia (BPH) management in the primary care setting.Can J Urol. 2012; 19: 10-17PubMed Google Scholar these drugs alone fail to shrink BPH volume and are often insufficient to eliminate symptoms.7Lepor H. Kazzazi A. Djavan B. alpha-Blockers for benign prostatic hyperplasia: the new era.Curr Opin Urol. 2012; 22: 7-15Crossref PubMed Scopus (75) Google Scholar In contrast, 5-α reductase inhibitors (5-ARIs), which suppress testosterone conversion into dihydrotestosterone (DHT), have greater efficacy in reducing BPH volume, and clinical data indicate that the combination of 5-ARIs with α-blockers leads to the best symptomatic response to date.8Emberton M. Fitzpatrick J.M. Rees J. Risk stratification for benign prostatic hyperplasia (BPH) treatment.BJU Int. 2011; 107: 876-880Crossref PubMed Scopus (27) Google Scholar, 9Barkin J. Benign prostatic hyperplasia and lower urinary tract symptoms: evidence and approaches for best case management.Can J Urol. 2011; 18: 14-19PubMed Google Scholar The above clinical data suggest that androgen/androgen receptor (AR) signaling plays key roles in development of BPH and that targeting androgen/AR signaling could be a major therapeutic approach for BPH. Nevertheless, the detailed mechanisms of androgen/AR signaling, and especially the pathogenic roles of AR in BPH,10van der Sluis T.M. Meuleman E.J. van Moorselaar R.J. Bui H.N. Blankenstein M.A. Heijboer A.C. Vis A.N. Intraprostatic testosterone and dihydrotestosterone. Part II: concentrations after androgen hormonal manipulation in men with benign prostatic hyperplasia and prostate cancer.BJU Int. 2012; 109: 183-188Crossref PubMed Scopus (23) Google Scholar are still unclear. In this review, we focus on the roles of AR in promoting prostate stromal cell growth11Bierhoff E. Vogel J. Benz M. Giefer T. Wernert N. Pfeifer U. Stromal nodules in benign prostatic hyperplasia.Eur Urol. 1996; 29: 345-354Crossref PubMed Scopus (69) Google Scholar and prostate epithelial cell growth with increased epithelial–mesenchymal transition (EMT).12Alonso-Magdalena P. Brössner C. Reiner A. Cheng G. Sugiyama N. Warner M. Gustafsson J.A. A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasia.Proc Natl Acad Sci USA. 2009; 106: 2859-2863Crossref PubMed Scopus (123) Google Scholar We also discuss how AR regulates development of BPH through the inflammatory environment with macrophage infiltration, and address potential new therapeutic approaches, such as targeting AR with the newly identified AR degradation enhancer ASC-J9 and/or targeting specific inflammatory cytokines downstream of AR. The hormone dependency of development of BPH is well documented, and androgen concentration or AR activity in BPH patients has been a subject of study since 1895.13White JW. I. The results of double castration in hypertrophy of the prostate.Ann Surg. 1895; 22: 1-80Crossref PubMed Google Scholar One study in the 1980s found little difference in AR expression in prostate tissues isolated from either BPH patients or unaffected control subjects.14Elhilali M. Lehoux J.G. Carmel M. Madarnas P. Mongeau C. Beauchesne C. Tétreault L. Bénard B. Nuclear androgen receptors of human prostatic tissue–a quantitative histological study.Arch Androl. 1983; 10: 21-27Crossref PubMed Scopus (7) Google Scholar However, the serum concentration of testosterone and DHT may change with age, with reduced serum testosterone in healthy old men, relative to that in healthy younger men. In contrast, DHT levels are elevated, and serum DHT in BPH patients is significantly higher than that in unaffected men at a similar age.15Horton R. Hsieh P. Barberia J. Pages L. Cosgrove M. Altered blood androgens in elderly men with prostate hyperplasia.J Clin Endocrinol Metab. 1975; 41: 793-796Crossref PubMed Scopus (80) Google Scholar, 16Hammond G.L. Kontturi M. Vihko P. Vihko R. Serum steroids in normal males and patients with prostatic diseases.Clin Endocrinol (Oxf). 1978; 9: 113-121Crossref PubMed Scopus (83) Google Scholar Similar conclusions were also obtained recently in a large cross-sectional study that included 505 men aged 40 to 79 years (mean, 58 years); higher serum DHT levels and DHT/testosterone ratios were associated with larger prostate volume and higher prevalence of BPH.17Liao C.H. Li H.Y. Chung S.D. Chiang H.S. Yu H.J. Significant association between serum dihydrotestosterone level and prostate volume among Taiwanese men aged 40–79 years.Aging Male. 2012; 15: 28-33Crossref PubMed Scopus (28) Google Scholar Tang et al18Tang J. Yang J.C. Zhang Y. Liu X. Zhang L. Wang Z. Li J. Luo Y. Xu J. Shi H. Does benign prostatic hyperplasia originate from the peripheral zone of the prostate? A preliminary study.BJU Int. 2007; 100: 1091-1096Crossref PubMed Scopus (10) Google Scholar found no difference in AR expression between the peripheral zone (PZ) and the transitional zone (TZ) in BPH. In other studies, although nucleic AR expression was detected in both epithelial and stromal cells of hyperplastic nodules, higher nuclear AR expression was detected in prostate epithelial cells than in stromal cells.19Kyprianou N. Davies P. Association states of androgen receptors in nuclei of human benign hypertrophic prostate.Prostate. 1986; 8: 363-380Crossref PubMed Scopus (17) Google Scholar, 20Peters C.A. Barrack E.R. Androgen receptor localization in the human prostate: demonstration of heterogeneity using a new method of steroid receptor autoradiography.J Steroid Biochem. 1987; 27: 533-541Crossref PubMed Scopus (17) Google Scholar Others found higher 5-α reductase activity in stromal cells than in epithelial cells, with AR distributed evenly between epithelial and stromal cells.21Krieg M. Bartsch W. Thomsen M. Voigt K.D. Androgens and estrogens: their interaction with stroma and epithelium of human benign prostatic hyperplasia and normal prostate.J Steroid Biochem. 1983; 19: 155-161Crossref PubMed Scopus (87) Google Scholar, 22Tunn S. Hochstrate H. Grunwald I. Flüchter S.H. Krieg M. Effect of aging on kinetic parameters of 5 alpha-reductase in epithelium and stroma of normal and hyperplastic human prostate.J Clin Endocrinol Metab. 1988; 67: 979-985Crossref PubMed Scopus (50) Google Scholar Importantly, the primitive BPH nodules found in the periurethral area of the TZ had higher concentrations of androgens and higher nuclear AR expression than those in other prostate regions. These findings suggest that androgen/AR signaling may play important roles in promoting the proliferation of epithelial and stromal cells in the periurethral area of the TZ, thus leading to development of BPH with urinary obstruction (Figure 1).23Monti S. Di Silverio F. Toscano V. Martini C. Lanzara S. Varasano P.A. Sciarra F. Androgen concentrations and their receptors in the periurethral region are higher than those of the subcapsular zone in benign prostatic hyperplasia (BPH).J Androl. 1998; 19: 428-433PubMed Google Scholar Castrated BPH patients showed a marked decrease of prostatic volume after 2 to 3 months, and this volume reduction correlated well with a relief of lower urinary tract symptoms.24Schroeder F.H. Westerhof M. Bosch R.J. Kurth K.H. Benign prostatic hyperplasia treated by castration or the LH-RH analogue buserelin: a report on 6 cases.Eur Urol. 1986; 12: 318-321Crossref PubMed Scopus (52) Google Scholar, 25Bianchi S. Gravina G. Podestà A. Barletta D. Franchi F. Kicovic P. Luisi M. 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Fatal and nonfatal hepatotoxicity associated with flutamide.Ann Intern Med. 1993; 118: 860-864Crossref PubMed Scopus (192) Google Scholar and have been replaced by the 5-ARIs, which have better efficacy in suppressing development of BPH. A study of BPH patients treated for 1 year with finasteride, a 5-ARI for 5-α reductase type 2, showed a significant decrease in the size of the periurethral area, as well as total prostate gland size, suggesting that suppression of testosterone conversion into DHT could lead to a significant decrease in the size of the prostate.29Tempany C.M. Partin A.W. Zerhouni E.A. Zinreich S.J. Walsh P.C. The influence of finasteride on the volume of the peripheral and periurethral zones of the prostate in men with benign prostatic hyperplasia.Prostate. 1993; 22: 39-42Crossref PubMed Scopus (76) Google Scholar The efficacy and safety profiles of finasteride in BPH patients over a 12-month period also showed a 74% reduction in serum DHT levels, a 21% reduction in prostate volume, and a significant improvement in urinary obstructive symptoms.30Finasteride (MK-906) in the treatment of benign prostatic hyperplasia. The Finasteride Study Group.Prostate. 1993; 22: 291-299Crossref PubMed Scopus (208) Google Scholar, 31Grino P. Stoner E. Finasteride for the treatment and control of benign prostatic hyperplasia: summary of phase III controlled studies. The Finasteride Study Group.Eur Urol. 1994; 25: 24-28Crossref PubMed Scopus (21) Google Scholar However, finasteride treatment led to a 55% decrease of DHT in epithelial cells of the TZ, with little effect on stromal cells,32Marks L.S. Partin A.W. Gormley G.J. Dorey F.J. Shery E.D. Garris J.B. Subong E.N. Stoner E. deKernion J.B. Prostate tissue composition and response to finasteride in men with symptomatic benign prostatic hyperplasia.J Urol. 1997; 157: 2171-2178Crossref PubMed Scopus (67) Google Scholar even though 5-α reductase type 2 is expressed in both stromal and epithelial cells in the prostate. In contrast, another 5-ARI, dutasteride, inhibiting both type 2 and type 1 of 5-α reductases (the latter expressed predominantly in epithelial cells33Shirakawa T. Okada H. Acharya B. Zhang Z. Hinata N. Wada Y. Uji T. Kamidono S. Gotoh A. Messenger RNA levels and enzyme activities of 5 alpha-reductase types 1 and 2 in human benign prostatic hyperplasia (BPH) tissue.Prostate. 2004; 58: 33-40Crossref PubMed Scopus (24) Google Scholar), showed a greater decrease in DHT (98.4 ± 1.2%) than did finasteride (70.8 ± 18.3%).34Clark R.V. Hermann D.J. Cunningham G.R. Wilson T.H. Morrill B.B. Hobbs S. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor.J Clin Endocrinol Metab. 2004; 89: 2179-2184Crossref PubMed Scopus (374) Google Scholar Taken together, these clinical studies suggest that androgen/AR may contribute to the increase of prostate volume, and 5-ARIs with suppression of testosterone conversion into DHT are effective medicines for reducing BPH size. Although 5-ARIs have been shown to reduce the volume of BPH, these may have some limitations. The Combination of Avodart and Tamsulosin (CombAT) study, with 4844 BPH patients, showed that combined therapy with both dutasteride and the α-blocker tamsulosin was significantly superior to either monotherapy in reducing the relative risk of BPH progression and symptoms.35Roehrborn C.G. Siami P. Barkin J. Damião R. Major-Walker K. Nandy I. Morrill B.B. Gagnier R.P. Montorsi F. CombAT Study GroupThe effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study.Eur Urol. 2010; 57 ([Erratum appeared in Eur Urol 2010, 58:801]): 123-131Abstract Full Text Full Text PDF PubMed Scopus (550) Google Scholar Later analysis, however, found that combined therapy was better than dutasteride monotherapy in men with prostate volumes of ≥30 to <58 mL, but not in men with a prostate volume of <30 or ≥58 mL.36Montorsi F. Roehrborn C. Garcia-Penit J. Borre M. Roeleveld T.A. Alimi J.C. Gagnier P. Wilson T.H. The effects of dutasteride or tamsulosin alone and in combination on storage and voiding symptoms in men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH): 4-year data from the Combination of Avodart and Tamsulosin (CombAT) study.BJU Int. 2011; 107: 1426-1431Crossref PubMed Scopus (54) Google Scholar The benefit of combination therapy is thus greatest only in patients with larger BPH volumes, and α-blockers alone may be sufficient to alleviate lower urinary tract symptoms in patients with smaller BPH volumes; however, transurethral resection of the prostate may be needed for patients with the largest BPH volumes (approximately 60 mL).6Kapoor A. Benign prostatic hyperplasia (BPH) management in the primary care setting.Can J Urol. 2012; 19: 10-17PubMed Google Scholar Importantly, 5-ARIs have been reported to produce significant adverse sexual reactions, including decreased libido, erectile dysfunction, or ejaculation problems.37Traish A.M. Hassani J. 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Increased prostate cell proliferation and loss of cell differentiation in mice lacking prostate epithelial androgen receptor.Proc Natl Acad Sci USA. 2007; 104 ([Erratum appeared in Proc Natl Acad Sci U S A 2007, 104:17240]): 12679-12684Crossref PubMed Scopus (163) Google Scholar generated conditional knockout AR mice that lack AR only in prostate epithelial cells (pes-ARKO) and found that the pes-ARKO mice developed larger but less differentiated prostate with increased cell death, compared with wild-type littermates. Further analyses of each individual cell type within the epithelium in pes-ARKO mice revealed that loss of epithelial AR increased the proportion of CK5+ basal epithelial cells but decreased the proportion of CK8+ luminal epithelial cells, suggesting that luminal epithelial AR may play survival roles and that basal epithelial AR may play suppressor roles in maintaining homeostasis of prostate epithelial cells.45Wu C.T. Altuwaijri S. Ricke W.A. Huang S.P. Yeh S. Zhang C. Niu Y. Tsai M.Y. Chang C. Increased prostate cell proliferation and loss of cell differentiation in mice lacking prostate epithelial androgen receptor.Proc Natl Acad Sci USA. 2007; 104 ([Erratum appeared in Proc Natl Acad Sci U S A 2007, 104:17240]): 12679-12684Crossref PubMed Scopus (163) Google Scholar It would be interesting to learn whether AR in epithelial cells of human BPH has roles similar to those in the normal prostate. Clinical studies showing better efficacy of dutasteride than finasteride in suppressing BPH33Shirakawa T. Okada H. Acharya B. Zhang Z. Hinata N. Wada Y. Uji T. Kamidono S. Gotoh A. Messenger RNA levels and enzyme activities of 5 alpha-reductase types 1 and 2 in human benign prostatic hyperplasia (BPH) tissue.Prostate. 2004; 58: 33-40Crossref PubMed Scopus (24) Google Scholar, 34Clark R.V. Hermann D.J. Cunningham G.R. Wilson T.H. Morrill B.B. Hobbs S. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor.J Clin Endocrinol Metab. 2004; 89: 2179-2184Crossref PubMed Scopus (374) Google Scholar suggest that prostate epithelial cells may play positive roles in promoting development of BPH. In two studies from the 1990s, epithelial cell content was significantly greater in the TZ than in the PZ,46Feneley M.R. Puddefoot J.R. Xia S. Sowter C. Slavin G. Kirby R.S. Vinson G.P. Zonal biochemical and morphological characteristics in BPH.Br J Urol. 1995; 75: 608-613Crossref PubMed Scopus (17) Google Scholar and epithelial cells were only 9.0% of BPH cells.47Svindland A. Eri L.M. Tveter K.J. Morphometry of benign prostatic hyperplasia during androgen suppressive therapy. Relationships among epithelial content, PSA density, and clinical outcome.Scand J Urol Nephrol Suppl. 1996; 179: 113-117PubMed Google Scholar However, epithelial cells may still play important roles in enhancing stromal cell growth via epithelial cell–stromal cell interaction. In coculture of primary human BPH stromal fibroblasts and epithelial cells, cell growth of cocultured cells was significantly increased, compared to separate culture,48Bayne C.W. Donnelly F. Chapman K. Bollina P. Buck C. Habib F. A novel coculture model for benign prostatic hyperplasia expressing both isoforms of 5 alpha-reductase.J Clin Endocrinol Metab. 1998; 83 ([Erratum appeared in J Clin Endocrinol Metab 1998, 83:910]): 206-213Crossref PubMed Scopus (55) Google Scholar suggesting that epithelial cells may have a supportive role in the growth of stromal cells in development of BPH. On the other hand, stromal androgen/AR signaling may be able to enhance the expression and/or release of growth factors that act on epithelial cells.49Peehl D.M. Rubin J.S. Keratinocyte growth factor: an androgen-regulated mediator of stromal-epithelial interactions in the prostate.World J Urol. 1995; 13: 312-317Crossref PubMed Scopus (58) Google Scholar, 50Nakano K. Fukabori Y. Itoh N. Lu W. Kan M. McKeehan W.L. Yamanaka H. Androgen-stimulated human prostate epithelial growth mediated by stromal-derived fibroblast growth factor-10.Endocr J. 1999; 46: 405-413Crossref PubMed Scopus (45) Google Scholar Thus, prostate epithelial and stromal cells may each support proliferation of the other cell type through growth factors in a paracrine manner. EMT is a physiological process in which epithelial cells acquire the motile characteristics of mesenchymal (stromal) cells.51Nisticò P. Bissell M.J. Radisky D.C. 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Epithelial-mesenchymal transition in cancer development and its clinical significance.Cancer Sci. 2010; 101: 293-299Crossref PubMed Scopus (632) Google Scholar Interestingly, Alonso-Magdalena et al12Alonso-Magdalena P. Brössner C. Reiner A. Cheng G. Sugiyama N. Warner M. Gustafsson J.A. A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasia.Proc Natl Acad Sci USA. 2009; 106: 2859-2863Crossref PubMed Scopus (123) Google Scholar found that EMT may also contribute to development of BPH. Although they found little evidence of proliferation in clinical human BPH stromal cells, they found that 0.7% of basal cells and 0.4% of luminal cells were positive for the proliferation markers Ki-67 and PCNA in the epithelium of some ducts.12Alonso-Magdalena P. Brössner C. Reiner A. Cheng G. Sugiyama N. Warner M. Gustafsson J.A. A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasia.Proc Natl Acad Sci USA. 2009; 106: 2859-2863Crossref PubMed Scopus (123) Google Scholar Importantly, they found that regions of the ductal epithelium had lost their polarization and expressed little E-cadherin.12Alonso-Magdalena P. Brössner C. Reiner A. Cheng G. Sugiyama N. Warner M. Gustafsson J.A. A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasia.Proc Natl Acad Sci USA. 2009; 106: 2859-2863Crossref PubMed Scopus (123) Google Scholar Others reported that Snail2/Slug is the important transcriptional factor for TGF-β1–induced EMT of prostate epithelial cells in BPH.54Slabáková E. Pernicová Z. Slavíčková E. Staršíchová A. Kozubík A. Souček K. TGF-beta1-induced EMT of non-transformed prostate hyperplasia cells is characterized by early induction of SNAI2/Slug.Prostate. 2011; 71: 1332-1343Crossref PubMed Scopus (81) Google Scholar These results suggest that EMT in epithelial cells may also promote development of BPH (Figure 2). Inflammation with infiltrating macrophages influences epithelial cells and may contribute to development of BPH. A study investigating the association between immune inflammation and AR expression in human BPH specimens from prostatectomy showed that the total prostate volume was significantly higher in specimens with infiltrated inflammatory cells including B or T lymphocytes than in those without infiltrated inflammatory cells, suggesting that the immune inflammatory process may also contribute to development of BPH.55Wu Z.L. Yuan Y. Geng H. Xia S.J. Influence of immune inflammation on androgen receptor expression in benign prostatic hyperplasia tissue.Asian J Androl. 2012; 14: 316-319Crossref PubMed Scopus (22) Google Scholar A recent study by Lu et al56Lu T. Lin W.J. Izumi K. Wang X. Xu D. Fang L.Y. Li L. Jiang Q. Jin J. Chang C. Targeting androgen receptor to sup
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