Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 + 1483 word(s) 1483 2021-01-26 09:11:53 |
2 format correct Meta information modification 1483 2021-03-03 10:29:14 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Miyata, Y. Benign Prostatic Hyperplasia (BPH). Encyclopedia. Available online: (accessed on 20 April 2024).
Miyata Y. Benign Prostatic Hyperplasia (BPH). Encyclopedia. Available at: Accessed April 20, 2024.
Miyata, Yasuyoshi. "Benign Prostatic Hyperplasia (BPH)" Encyclopedia, (accessed April 20, 2024).
Miyata, Y. (2021, March 01). Benign Prostatic Hyperplasia (BPH). In Encyclopedia.
Miyata, Yasuyoshi. "Benign Prostatic Hyperplasia (BPH)." Encyclopedia. Web. 01 March, 2021.
Benign Prostatic Hyperplasia (BPH)

Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate and can cause obstructive and irritating lower urinary tract symptoms (LUTS); this proliferative change affects smooth muscle and epithelial cells within the transition zone of the prostate.

polyphenols flavonoids pharmacological effect benign prostatic hyperplasia

1. Introduction

Benign prostatic hyperplasia (BPH) is a health concern that is expected to increase with age, and its incidence increases with life expectancy [1]. BPH is a non-malignant enlargement of the prostate and can cause obstructive and irritating lower urinary tract symptoms (LUTS); this proliferative change affects smooth muscle and epithelial cells within the transition zone of the prostate [2]. Ultimately, these changes cause the compression of the urethra as a bladder outlet obstruction (BOO), manifested as LUTS [3]. Typical symptoms include pollakiuria, nocturia, urgency, decreased urinary dysfunction, dysuria, BOO, and residual urine [4]. BPH is observed in older men, and its incidence depends on age. BPH usually begins in men aged approximately 40–45 years and causes few symptoms in the early stages. Symptoms develop with age, and more than half of all men develop BPH [5]. These symptoms are known as LUTS [6].

The molecular and interstitial mechanisms associated with this etiology are not fully understood, but several factors, including inflammatory mediators, hormones, dietary factors, and environmental and oxidative stress, may be involved [7]. An increase in androgen dihydrotestosterone (DHT) is thought to stimulate prostate cell growth. Furthermore, the association between obesity, hypertension, hyperglycemia, dyslipidemia, and BPH has also been reported [8]. Insulin resistance induces hyperinsulinemia, which can lead to sympathetic hypertonia, increased prostatic smooth muscle proliferation and tone, and, finally, an appearance of LUTS [9]. According to a meta-analysis, people with metabolic syndrome display significantly larger prostate and transition area volumes of 1.8 and 3.67 mL, respectively, than those without any metabolic syndrome [10].

Prostate inflammation also plays an important role in hyperplasia [11][12]. A clinical study of 5α-reductase inhibitors reported that patients with inflammatory findings on prostate biopsy specimens had higher prostate volumes, had higher symptom scores [12], and were also at higher risk of urinary retention in inflamed cases [11]. Cytokines derived from inflammatory cells also induce growth factors. Among them, interleukin (IL)-1α induces fibroblast growth factor (FGF)-7, and the IL-1α-related system is involved in proliferation [13]. It is speculated that chronic inflammation and increased immune response brought about by bacterial infections or other foreign antigens cause the remodeling of the prostate structure, resulting in an enlargement of the prostate [14].

All things considered, the etiology of BPH is complex and has many uncertainties. As a result, treatment can often be multi-targeted. In this regard, phytotherapy, which is believed to have pharmacological properties, such as anti-androgens, anti-proliferation, antioxidant, and anti-inflammatory properties, may be useful. Isoflavonoids and lignans, which are abundant in vegetables, grains, and soybeans, are presumed to function as BPH suppressors. These exert some degree of estrogenic effects and are thought to inhibit prostatic cell growth [15]. These pharmacological products also exhibit 5α-reductase inhibitory activity and angiogenesis inhibitory activity [16]. Thus, phytotherapy may be therapeutic in the prevention of mild-to-moderate prostate disease. In recent years, phytochemicals found in fruits, vegetables, and tea have gained the interest of researchers because they are less toxic, more effective, and economical.

The structures and biological activities of polyphenols have already been discussed in numerous previous reports. Additionally, data regarding the clinical significance and pharmacological roles of polyphenols in BPH have also been discussed in previously published reviews [17][18]. However, few studies have focused on the molecular mechanisms of the pharmacological effects of polyphenols in BPH. The pathological characteristics and growth steps of BPH are strongly modulated by oxidative stress, inflammation, and angiogenesis, as discussed in followed sections. Importantly, these pathological activity-related molecules are also targets of the pharmacological effects of polyphenols in various pathological conditions, including BPH.

2. A Brief Overview of Inflammation and Oxidative Stress in BPH

2.1. Pathological Roles of Inflammation and Oxidative Stress

Inflammation is an important protective response against tissue damage or pathogens; however, uncontrolled chronic inflammatory reactions can cause various chronic diseases, including kidney disease, diabetes mellitus, and malignancies [19][20][21]. In addition, inflammation is associated with many diseases such as microbial and viral infections, exposure to allergens, radiation and toxic chemicals, autoimmune diseases, obesity, alcohol consumption, and tobacco use [22]. Inflammation is initiated by the synthesis and secretion of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), IL-1β, IL-6, IL-12, and interferon (IFN)-γ, and by macrophages in response to inflammatory injury [23]. It has also been reported that various inflammatory stimuli, such as excess reactive oxygen species (ROS) produced during oxidative metabolism, initiate the inflammatory process, leading to the synthesis and secretion of pro-inflammatory cytokines [22]. Inflammatory cytokines and their receptors promote mitogen-activated protein kinase activity, resulting in the activation of transcription factors NF-κB and activator protein (AP)-1 [24]. These transcription factors amplify the inflammatory response by activating the expression of various genes, such as cytokines, chemokines, adhesion molecules, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) [25]. The mechanism by which oxidative stress causes inflammation is unknown, but oxidative stress is clearly associated with many chronic inflammatory diseases and is especially important. Oxidative stress occurs when there is an imbalance between antioxidants and pro-oxidants, which in turn favors oxidation and can damage DNA, proteins, and lipids [26]. The imbalance between production and detoxification of ROS/free radicals can induce tissue damage [27]. Most chronic diseases that occur with increased ROS production cause oxidative stress and the oxidation of various proteins [28]. Protein oxidation induces the release of inflammatory signals [29]. Increased ROS production leads to inadequate antioxidant defense mechanisms; the disruption of proteins, lipids, and DNA; the disruption of cell function and cell death; and the induction of oxidative stress [30][31].

2.2. Benign Prostate Hyperplasia and Inflammation

Several investigators have suggested that inflammation plays important roles in the pathogenesis of prostate diseases, including BPH and prostate cancer [21][32]. Inflammation affects the balance between prostate cell proliferation and apoptosis by increasing factors such as cytokines, COX-2, and oxidative stress around the prostate [32]. These factors stimulate proliferation and minimize apoptosis [32]. In a study involving the etiology of BPH, the differential expression of cytokines and growth factors in BPH tissue suggested the role of inflammation in BPH development [33]. Various clinical trials have also suggested the role of inflammation in BPH. Previous studies have shown that the degree of BPH inflammation correlates with prostate size. A statistically significant correlation between chronic inflammation and International Prostate Symptom Score (IPSS) was observed, with severe inflammation associated with higher IPSS scores [12]. It has been reported that 57% of patients with prostatitis have a history of BPH and are at a significantly higher risk of developing hypertrophy and acute urinary retention [34]. Furthermore, it was shown that the use of COX-2 inhibitors in combination with 5α-reductase inhibitors could increase the apoptosis index in BPH tissues [34]. Pathological data were analyzed from 374 patients who underwent transurethral resection of the prostate (TURP) for BPH, and urinary retention with findings of acute and/or chronic prostatic inflammation were observed in 70% of the patients [11]. In another clinical study, the pathological data were analyzed from 3942 patients who underwent surgical treatment for BPH, and 43.1% primarily displayed chronic inflammation [35].

Inflammation distribution changed significantly with prostate volume, with a statistically significant correlation between chronic inflammation and prostate volume [35]. Inflammation is one of the factors that produces free radicals/ROS in the prostate and is associated with oxidative stress [32]. iNOS is induced and expressed in inflammatory cells, and it contributes to the pathogenesis of inflammation. iNOS is not detected in the normal prostate, but it is reported to be expressed in the prostate of all BPH patients [27]. COX-2 is associated with inflammation in BPH. Prostaglandins are synthesized from arachidonic acid via cyclooxygenase (COX-1 and COX-2) [36]. Prostaglandins, a group of inflammatory mediators, have been observed in the BPH tissues [37]. In addition, it has been reported that COX-2 is upregulated in the basal epithelial cells of BPH [36].

2.3. Benign Prostate Hyperplasia and Oxidative Stress

Oxidative stress is thought to be one of the mechanisms that triggers a series of reactions involved in the development and progression of BPH [31]. It has been reported that antioxidant levels are significantly reduced in prostate tissue during BPH [31]. In addition, human prostate tissue is susceptible to oxidative DNA damage due to the fast cell turnover and low levels of DNA repair enzymes. Therefore, BPH may be strongly associated with oxidative stress [27]. The antioxidant activities of glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase were all significantly reduced in the prostate of an untreated BPH rat model [38]. A significant increase in prostatic lipid peroxidation was also observed. After treatment with finasteride or kolaviron, the parameters of these antioxidants improved significantly [39].

Thus, inflammation and oxidative stress are among the major pathological mechanisms underlying the development of BPH. In addition, we should note the facts that there are cross-talks reported between inflammation and oxidative stress. A schema of pathological mechanisms leading to BPH development via the regulation of inflammation and oxidative stress is shown in Figure 1.

Figure 1. Pathological mechanisms of benign prostatic hyperplasia (BPH) development via inflammation and oxidative stress.


  1. Claus, G.R. Male lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH). Med Clin. North Am. 2011, 95, 87–100.
  2. Dragan, I.; Marie, M. Lycopene for the prevention and treatment of benign prostatic hyperplasia and prostate cancer: A sys-tematic review. Maturitas 2012, 72, 269–276.
  3. Bilal, C.; James, C.F.; Dominique, D.M.T.; Leanna, L.; Tania, H.; Henry, H.W.; Alexis. E. T.; Steven, A.K. Benign prostatic hy-perplasia. Nat. Rev. Dis. Primers 2016, 2, 16031.
  4. In, S.S.; Mee, Y.L.; Hye, K.H.; Chang, S.S.; Hyeun-Kyoo, S. Inhibitory effect of Yukmijihwang-tang, a traditional herbal for-mula against testosterone-induced benign prostatic hyperplasia in rats. BMC Complement Altern. Med. 2012, 2, 48.
  5. Ester, P.; Massimiliano, L.; Michele, G.; Raffaele, C. Phytotherapy of benign prostatic hyperplasia. A minireview. Phytother. Res. 2014, 28, 949–955.
  6. Jack, B. Benign prostatic hyperplasia and lower urinary tract symptoms: Evidence and approaches for best case manage-ment. Can. J. Urol. 2011, 18, 14–19.
  7. Aleksandra, R.; Iwona, R.; Tomasz, M.; Marcin, S.; Barbara, D.; Anna, L.; Maria, L. Metabolic syndrome and benign prostatic hyperplasia: Association or coincidence? Diabetol. Metab. Syndr. 2015, 7, 94.
  8. Ponholzer, A.; Temml, C.; Wehrberger, C.; Marszalek, M.; Madersbacher, S. The association between vascular risk factors and lower urinary tract symptoms in both sexes. Eur. Urol. 2006, 50, 581–586.
  9. McVary, K. Lower urinary tract symptoms and sexual dysfunction: Epidemiology and pathophysiology. BJU Int. 2006, 97, 23–28.
  10. Gacci, M.; Corona, G.; Vignozzi, L.; Salvi, M.; Serni, S.; De, N.C.; Tubaro, A.; Oelke, M.; Carini, M.; Maggi, M. Metabolic syndrome and benign prostatic enlargement: A systematic review and meta-analysis. BJU Int. 2015, 115, 24– 31.
  11. Vibhash, C.M.; Darrell, J.A.; Christophoros, N.; Haytham, S.; Charles, H.; Omer, M.A.K.; Hanif, G.M.; Marc, E.L. Does in-traprostatic inflammation have a role in the pathogenesis and progression of benign prostatic hyperplasia? BJU Int. 2007, 100, 327–331.
  12. Curtis, N.J.; Claus, G.R.; Michael, P.O.; David, G.B.; Matthew, C.S.; Roger, S.R. The relationship between prostate inflamma-tion and lower urinary tract symptoms: Examination of baseline data from the REDUCE trial. Eur. Urol. 2008, 54, 1379–1384.
  13. Dipak, G.; Michael, I. Interleukin-1alpha is a paracrine inducer of FGF7, a key epithelial growth factor in benign prostatic hyperplasia. Am. J. Pathol. 2000, 157, 249–255.
  14. Gero, K.; Dieter, M.; Michael, M. Is benign prostatic hyperplasia (BPH) an immune inflammatory disease? Eur. Urol. 2007, 51, 1202–1216.
  15. Denis, L.; Morton, M.S.; Griffiths, K. Diet and its preventive role in prostatic disease. Eur. Urol. 1999, 35, 377–387.
  16. Miyanaga, N.; Akaza, H.; Hinotsu, S.; Fujioka, T.; Naito, S.; Namiki, M.; Takahashi, S.; Hirao, Y.; Horie, S.; Tsukamoto, T.; et al. Prostate cancer chemoprevention study: An investigative randomized control study using purified isoflavones in men with rising prostate-specific antigen. Cancer Sci. 2012, 103, 125–130.
  17. Castelli, T.; Russo, G.I.; Reale, G.; Privitera, S.; Chisari, M.; Fragalà, E.; Favilla, V.; Cimino, S.; Morgia, G. Metabolic syn-drome and prostatic disease: Potentially role of polyphenols in preventive strategies. A review. Int. Braz. J. Urol. 2016, 42, 422–430.
  18. Cicero, A.F.G.; Allkanjari, O.; Busetto, G.M.; Cai, T.; Larganà, G.; Magri, V.; Perletti, G.; Robustelli, D.C.F.S.; Russo, G.I.; Stamatiou, K.; et al. Nutraceutical treatment and prevention of benign prostatic hyperplasia and prostate cancer. Arch. Ital. Urol. Androl. 2019, 91, 3.
  19. Kitamura, M.; Mochizuki, Y.; Miyata, Y.; Obata, Y.; Mitsunari, K.; Matsuo, T.; Ohba, K.; Mukae, H.; Yoshimura, A.; Nishino, T.; et al. Pathological Characteristics of Periodontal Disease in Patients with Chronic Kidney Disease and Kidney Trans-plantation. Int. J. Mol. Sci. 2019, 20, 3413.
  20. Kuryłowicz, A.; Koźniewski, K. Anti-Inflammatory Strategies Targeting Metaflammation in Type 2 Diabetes. Molecules 2020, 25, 2224.
  21. Olivas, A.; Price, R.S. Obesity, Inflammation, and Advanced Prostate Cancer. Nutr. Cancer 2020, 1–17, doi:10.1080/01635581.2020.1856889.
  22. Tarique, H.; Bie, T.; Yulong, Y.; Francois, B.; Myrlene, C.B.T.; Najma, R. Oxidative Stress and Inflammation: What Polyphe-nols Can Do for Us? Oxid. Med. Cell Longev. 2016, 2016, 7432797.
  23. Jean-Marc, C.; Djillali, A. Compartmentalization of the inflammatory response in sepsis and SIRS. J. Endotoxin Res. 2006, 12, 151–170.
  24. Nam, J.K.; Ki, W.L.; Dong, E.L.; Evgeny, A.R.; Ann, M.B.; Hyong, J.L.; Zigang, D. Cocoa procyanidins suppress transfor-mation by inhibiting mitogen-activated protein kinase kinase. J. Biol. Chem. 2008, 283, 20664–20673.
  25. Peter, J.B.; Michael, K. Nuclear factor-kappaB: A pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 1997, 336, 1066–1071.
  26. Kullisaar, T.; Türk, S.; Punab, M.; Mändar, R. Oxidative stress--cause or consequence of male genital tract disorders? Prostate 2012, 15, 977–983.
  27. Paola, L.M.; Antonino, I.; Michele, N.; Gioacchino, C.; Carlo, M.; Sebastiano, G. Oxidative stress in benign prostatic hyper-plasia: A systematic review. Urol. Int. 2015, 94, 249–254.
  28. Berlett, B.S.; Stadtman, E.R. Protein oxidation in aging, disease, and oxidative stress. J. Biol. Chem. 1997, 272, 20313–20316.
  29. Salzanoa, S.; Checconia, P.; Hanschmannc, E.M.; Lillig, C.H.; Bowler, L.D.; Chan. P.; Vaudry, D.; Mengozzi, M.; Coppo, L.; Sacre, S.; et al. Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal. Proc. Natl. Acad. Sci. USA 2014, 111, 12157–12162.
  30. Udensi, K.U.; Paul, B.T. Dual effect of oxidative stress on leukemia cancer induction and treatment. J. Exp. Clin. Cancer Res. 2014, 33, 106.
  31. Udensi, K.U.; Paul, B.T. Oxidative stress in prostate hyperplasia and Carcinogenesis. J. Exp. Clin. Cancer Res. 2016, 35, 139.
  32. Hamid, A.R.; Umbas, R.; Mochtar, C.A. Recent role of inflammation in prostate diseases:chemoprevention development opportunity. Acta. Med. Indones. 2011, 43, 59–65.
  33. Lee, K.L.; Peehl, D.M. Molecular and cellular pathogenesis of benign prostatic hyperplasia. J. Urol. 2004, 172, 1784–1791.
  34. Alessandro, S.; Gianna, M.; Stefano, S.; Ana, A.G.; Salvatore, M.; Vincenzo, T.; Franco, D.S. Prostate growth and inflamma-tion. J. Steroid Biochem. Mol. Biol. 2008, 108, 254–260.
  35. Di Silverio, F.; Gentile, V.; De-Matteis, A. Distribution of inflammation, pre-malignant lesions, incidental carcinoma in his-tologically confirmed benign prostatic hyperplasia: A retrospective analysis. Eur. Urol. 2003, 43, 164–175.
  36. Kirschenbaum, A.; Klausner, A.P.; Lee, R.; Unger, P.; Yao, S.; Liu, X.H. Expression of cyclooxygenase-1 and cyclooxygenase-2 in the human prostate. Urology 2000, 56, 671–676.
  37. Altavilla, D.; Minutoli, L.; Polito, F.; Irrera, N.; Arena, S.; Magno, C. Effects of flavocoxid, a dual inhibitor of COX and 5-lipoxygenase enzymes, on benign prostatic hyperplasia. Br. J. Pharmacol. 2012, 167, 95–108.
  38. Mbaka, G.; Ogbonnia, S.; Sulaiman, A.; Osiagwu, D. Histomorphological effects of the oil extract of Sphenocentrum jolly-anum seed on benign prostatic hyperplasia induced by exogenous testosterone and estradiol in adult Wistar rats. Avicenna J. Phytomed. 2019, 9, 21–33.
  39. Kalu, W.; Okafor, P.; Ijeh, I.; Eleazu, C. Effect of fractions of kolaviron on some indices of benign prostatic hyperplasia in rats: Identification of the constituents of the bioactive fraction using GC-MS. RSC Adv. 2016, 6, 94352–94360.
Subjects: Pathology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to :
View Times: 536
Revisions: 2 times (View History)
Update Date: 03 Mar 2021