review article 5α-Reductase Inhibitors in the Treatment of Benign Prostatic Hyperplasia: A Review
Alok Nahata*
Ying Zhi Agricultural and Industries SdnBhd, Malaysia
*Corresponding author:Alok Nahata, Research and Development Manager, Ying Zhi Agricultural and Industries SdnBhd, Jitra 06000, Kedah Darulaman, Malaysia. Tel: +6049163846; Email: aloknahata@gmail.com
Received
Date: 18August, 2017; Accepted Date: 24 August, 2017; Published Date: 31 August, 2017
Citation:Nahata A (2017) 5α-Reductase Inhibitors in the Treatment of Benign Prostatic Hyperplasia: A Review. J Urol Ren Dis 2017: 153. DOI: 10.29011/2575-7903.000153
1. Abstract
Prostate Cancer and Prostatic diseases have become the major causes of concern to elderly men almost in every part of the world. One of the major problems faced by most of the aging men is Benign Prostatic Hyperplasia (BPH). There are varieties of treatments available but no of them have proved to be up to the mark. Most of the synthetic molecules suffer from the drawback of substantial side effects. The enzyme 5α-reductase has been found to be the major factor which plays an important role in the progression of the disease as it is the mediator in the conversion of testosterone to the more harmful dihydrotesterone. The inhibition of this conversion can help prevent BPH. Present review is an effort to list the studies undertaken on5α-reducatse inhibitors from synthetic and natural origin and the results obtained thereof. This could provide a substantial lead to further research in this area and help in the treatment of BPH.
2. Keywords:5α-reductase;Benign
Prostatic Hyperplasia; Finasteride; Ganoderma lucidum; Prostate disorders; Testosterone
1. Background
Benign Prostatic Hyperplasia (BPH) has the pathogenesis of an androgen dependent disorder and afflicts a large population of elderly men with chronobiologic progress. BPH does not occur in men castrated prior to puberty, and in a variety of medical conditions whereby testosterone production or function is inhibited, the prostate does not develop normally. In addition, hypogonadal men do not become bald, and hair loss can be induced by testosterone administration to these individuals.Androgens, particularly 5α-Dihydrotestosterone (DHT), are required to maintain the size and function of the prostate in men and are thought to play a major role in the pathogenesis of BPH, prostate cancer, acne and androgenetic alopecia. Because DHT is produced from Testosterone (T) by 5α-reductase (5α-R), this enzyme plays a key role in DHT- mediated effects of BPH and androgenetic alopecia. Androgens are believed to act on the hair follicle via the mesenchyme-derived dermal papilla situated in the middle of the hair follicle bulb. The individuals with autosomal recessive genetic disorder of 5α-R deficiencies do not exhibit androgenetic alopecia, suggesting that DHT is the active androgen in the development of hair loss. The normal growth and secretory activities of the prostate are controlled by androgens, especially by DHT. These observations lead to the development of 5α-R inhibitors like finasteride, which lowers DHT concentration in the prostate without increasing circulating testosterone levels.
1.1. Herbal Drugs as 5a-Reductase Inhibitors
Komoda (1989)[18] isolated the inhibitors of 5α-R from 50% ethanolic extract ofPopulusnigra. The compounds were identified as pinobanksin, 8, 7-dimethyl quercetin and pinocembrine. Pinocembrine showed most potent activity among them [18].Liao and Hiipakka (1995) [19]reported that green tea catechins, (-) epigallocatechin-3-gallate and (-) epicatechin-3-gallate are potent inhibitors of 5a-type 1 but not 5a-R type 2 [19].Lesuisse,et al. (1996) [20]evaluated the inhibition of 5a-R by the aqueous extract of Epilobiumparviflorum. The active compound was identified as macrocyclic tannin, oenothein B [20].Liang and Liao (1997)[21] reported that g-linolenic acid inhibits 5α-R activity in vitroand in vivo. The effect of g-linolenic acid was localized and did not affect the androgen dependent growth of testis and prostate, thus can only be useful for androgen dependent skin disorders [21].Palin et al. (1998) [22]showed the inhibitory action of Sereonarepenson prostate porcine microsomal 5α-R activities[22]. Sereonarepens(Permixon®) at a concentration of 10 mg/ml was shown to be an effective inhibitor of both 5a-R type 1 and 2 isozymes without influencing the secretion of PSA by the epithelial cells [23].Sundaram,et al. (1999) [24]evaluated the 5a-R inhibitory potential of Prostane, a polyherbal formulation consisting of Tribulusterrestsis, Areca catechu, Pedalium murex, Caesalpiniabonducella and Asparagus racemosususing rat prostate homogenate as an enzyme source [24]. Ishiguro et al. (2000) [25]investigated that the 35% ethanolic extract of aerial parts of Impatiensbalsamina has inhibitory activity for testosterone 5α-R [25].Shimizu et al. (2000) [26]reported the potent inhibitory activity of the methanolic extract of heartwood of Artocarpusincisusagainst 5α-R[26].Chlorophorin and artocarpin showed more potent inhibitory activity than α-linolenic acid. A geranylated chalcone was isolated from leaves of the plant which showed potent 5α-R inhibitory activity[27].
Shimizu,et al. (2000) [28] reported potent 5α-R inhibitory activity of the acetone extract of Boehmerianipononivea. The active components werea-linolenic, linolenic, palmitic, elaidic, oleic and stearic acid [28]. Matsuda,et al. (2001) [29]showed in vitrotestosterone 5α-R inhibitory activity of myricanone, myricanol and myricetin isolated from the aqueous ethanolic extract of Myricaecortex(bark of Myricarubra) [29]. Matsuda,et al. (2001) [30]reported the testosterone 5α-R inhibitory activity of the diethyl ether extract of rhizomes of Amenorrhenaasphodeloides [30].Liao,et al. (2001)[31] reported that certain unsaturated aliphatic fatty acids such as myristoleic acid and other natural compounds alizarin and curcumin are effective 5α-R inhibitors [31].Seoet al. (2002) [32]isolated a prenylated coumarin, osthenol and a sesquiterpene bisabolangelone from the root of Angelica koreanaand reported their 5α-R type 1 inhibitory effect in LNCaP cells [32].Hiipakkaet al. (2002) [33]reported that several polyphenolic compounds are potent inhibitors of type 1 and 2 5a-R. Myricetin, querectin, baicalein and fisetin were potent inhibitors type 1 5a-R. Biochanin A, diadzein, genistein and kaempferol were much better inhibitors of type 2 than the type 1 isozyme [33].Matsuda et al. (2002)[34] reported that the aqueous ethanolic extract of spores of Lygodiumjaponicumshowed in vitrotestosterone 5α-R inhibiting activity [34].Kim,et al. (2003) [35]evaluated the activity against 5α-R, of four diarylheptanoids from the acetone extract of the rhizomes of Alpiniaofficinarium [35].Park,et al. (2003) [36] reported that torilin isolated from the methanolic extract of the fruits of Torilis japonica, showed potent inhibition against 5a-reductase activity in vitroalong with demonstrated the inhibitory activity of Thujaeoccidentalissemen extract for 5α-R type 2 isozymes [36].
Liu,et al. (2006)[37]reported that triterpenoids isolated from ethanolic extract of Ganoderma luciduminhibited 5a-R activity. The presence of the C-3 carbonyl group and of the C-26 α, b-unsaturated carbonyl group was characteristic of almost all inhibitors isolated from G. lucidum [37].Ganoderma lucidumhas been reported to inhibit testosterone induced prostatic hyperplasia in rats and mechanism of action has been attributed to its activity to inhibit 5α-reductase enzyme [38-40]. Liu, et al. (2007) [41]identified the active principles in vivo as triterpenoids and hence suggested that the triterpenoid fraction of Ganoderma lucidum can be effective in the treatment of BPH [41]. Further varieties of herbs with proven antiandrogenic activity have been evaluated for their 5α-reductase inhibitory potential and Ganoderma lucidum was found to be the most potent among the eleven herbs included in the study [42]. Previously studies have been done on Benincasahispida[43], Echinopsechinatus[44], Urticadioica[45] and Sphaeranthusindicus[46] wherein all the tested herbs have been found to be potent inhibitors of 5α-reductase and had shown their effectiveness in the treatment and management of BPH in rat models. Furthermore, these herbs have shown their effectiveness on human prostate cancer cell lines (PC3 and DU145) proving their potential to be future candidates for cancer research, especially for prostate cancer [47, 48].
2. Conclusion
The main aim of this review was to shortlist all the
drugs useful in the treatment of Benign Prostatic hyperplasia which have 5α-reductase inhibitory activity. Targeting this enzyme
for the treatment of BPH is a very important strategy which has proved
successful in the research cited in this review and further research in this
area may lead to the discovery of some very potent combinations for the
treatment of BPH. Molecular level mechanistic studies are a need of the hour
for finding a sure remedy of this disease. It can be said that the findings in
this area should have a positive impact on the ongoing research on Prostate
Cancer too.
Figure 1: Chemical Structures of
Finasteride and Dutasteride.