Article

Structure-activity relationships for inhibition of human 5alpha-reductases by polyphenols

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Abstract

The enzyme steroid 5 alpha-reductase (EC 1.3.99.5) catalyzes the NADPH-dependent reduction of the double bond of a variety of 3-oxo-Delta(4) steroids including the conversion of testosterone to 5 alpha-dihydrotestosterone. In humans, 5 alpha-reductase activity is critical for certain aspects of male sexual differentiation, and may be involved in the development of benign prostatic hyperplasia, alopecia, hirsutism, and prostate cancer. Certain natural products contain components that are inhibitors of 5 alpha-reductase, such as the green tea catechin (-)-epigallocatechin gallate (EGCG). EGCG shows potent inhibition in cell-free but not in whole-cell assays of 5 alpha-reductase. Replacement of the gallate ester in EGCG with long-chain fatty acids produced potent 5 alpha-reductase inhibitors that were active in both cell-free and whole-cell assay systems. Other flavonoids that were potent inhibitors of the type 1 5alpha-reductase include myricetin, quercitin, baicalein, and fisetin. Biochanin A, daidzein, genistein, and kaempferol were much better inhibitors of the type 2 than the type 1 isozyme. Several other natural and synthetic polyphenolic compounds were more effective inhibitors of the type 1 than the type 2 isozyme, including alizarin, anthrarobin, gossypol, nordihydroguaiaretic acid, caffeic acid phenethyl ester, and octyl and dodecyl gallates. The presence of a catechol group was characteristic of almost all inhibitors that showed selectivity for the type 1 isozyme of 5 alpha-reductase. Since some of these compounds are consumed as part of the normal diet or in supplements, they have the potential to inhibit 5 alpha-reductase activity, which may be useful for the prevention or treatment of androgen-dependent disorders. However, these compounds also may adversely affect male sexual differentiation.

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... It is postulated that some types of CATs have binding affinity for ERβ, ERα, PR and/or AR and could exhibit similar effects to that of selective modulators of hormone receptors, such as ER modulators (SERMs) [66][67][68][69][70], selective estrogen down-regulators (SERDs) [71][72][73], selective progesterone receptors modulators (SPRMs) [72] and selective androgen receptor modulators (SARMs), even in androgen-independent PC [74,75]. Furthermore, it is suggested that CATs can inhibit different enzymes involved in estrogen and androgen synthesis such as aromatase (aromatase inhibitors (AIs)] [76][77][78][79]) and 5α-reductase [80,81]. Likewise, it seems that CATs exhibit a pleiotropic effect on several molecular targets (Figure 12A-C):  It is considered that the binding affinity of CATs to ERβ and ERα is likely conditioned by the structure and the dose as well as the cell type [66,68,69,72]. ...
... It was suggested that some CATs from green tea seed extract exert 5α-reductase inhibitory characteristics. On the other hand, it seems that natural compounds that act as inhibitors possessing a catechol group have selectivity for the type 1 isozyme [80]. Additionally, polymeric anthocyanins seem to be type 2 isozyme inhibitors [81]. ...
... Additionally, polymeric anthocyanins seem to be type 2 isozyme inhibitors [81]. Thereby, it was suggested that they are useful for the prevention as well as the treatment of androgen-dependent disorders [80]. According to the above mentioned, the effects of CAT and ProB2 would be expected to be greater in MCF-7 cells and DU145 cells compared to the remaining BC and PC cell lines used, as we observed. ...
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Prostate (PC) and breast cancer (BC) are heterogeneous hormonal cancers. Treatment resistance and adverse effects are the main limitations of conventional chemotherapy treatment. The use of sensitizing agents could improve the effectiveness of chemotherapeutic drugs as well as obviate these limitations. This study analyzes the effect of single catechin (CAT), procyanidin B2 (ProB2) treatment as well as the co-adjuvant treatment of each of these compounds with docetaxel (DOCE). We used PC- and BC-derived cell lines (PC3, DU-145, T47D, MCF-7 and MDA-MB-231). The short and long-term pro-apoptotic, anti-proliferative and anti-migratory effects were analyzed. RT-qPCR was used to discover molecular bases of the therapeutic efficacy of these compounds. ProB2 treatment induced a two- to five-fold increase in anti-proliferative and pro-apoptotic effects compared to single DOCE treatment, and also had a more sensitizing effect than DOCE on DU145 cells. Regarding BC cells, ProB2- and CAT-mediated sensitization to DOCE anti-proliferative and pro-apoptotic effects was cell-independent and cell-dependent, respectively. Combined treatment led to high-efficacy effects on MCF-7 cells, which were associated to the up-regulation of CDKN1A, BAX, caspase 9 and E-cadherin mRNA under combined treatment compared to single DOCE treatment. CAT and ProB2 can enhance the efficacy of DOCE therapy on PC and BC cells by the sensitizing mechanism.
... topical [32] Clinical and in vitro study androgenic in vivo 4 successive days EGCG stimulated hair growth / EGCG stimulates hair growth via its proliferative and antiapoptotic effects on DPCs, and may prolong the anagen stage [32], selective inhibition of 5α-reductase [31], antioxidant properties [29], and the stimulating effect on normal cell growth [ [41] androgenic 6 months stimulated hair growth, slowed down hair loss itching (in 1 out of 98 subjects) inhibition of 5α-reductase, germacrone acting anti-inflammatory [44] and antiandrogenic in vitro and in vivo [45], increases skin penetration of minoxidil [47] paradoxically promotes hair growth on male scalp and at the same time inhibits underarm (axillary) hair growth in females [42,46] Panax ginseng C.A. Meyer / Chinese red ginseng root extract topical traditionally [51] androgenic / prevented hair loss, improved hair growth. ...
... catechin, gallocatechin, epicatechin, epigalocatechin, epicatechin gallate, and epigallocatechin gallate (EGCG) [28]. Antioxidant properties [29] and the stimulating effect on normal cell growth in epidermal keratinocytes [30] have been reported, while Hiipakka et al. have also shown selective inhibition of 5α-reductase [31]. For this reason, Kwon et al. sought to examine the use of EGCG for the prevention or treatment of androgenic alopecia. ...
... Biohanin A, phytoestrogen flavonoid, and many other polyphenols have been shown to inhibit 5α-reductase activity in vitro [31]. Inhibition is said to be more potent than that of EGCG from green tea [34]. ...
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Though hair does not serve any crucial physiological function in modern humans, it plays an important role in our self-esteem. Androgenic baldness (androgenic alopecia) and circular/spot baldness (alopecia areata) are the most common forms of hair loss. Many active ingredients of synthetic origin are available for treatment; however, they have a number of limitations. Their effectiveness and safety are questionable and the amount of time needed to achieve the effect is both long and unclear. This has increased interest in finding an alternative approach against hair loss using preparations containing plants and/or their isolated active ingredients. A number of studies (mostly randomized, placebo-controlled) of plants and preparations made of plants have been performed to confirm their effectiveness in treating hair loss. The plants with the most evidence-based effect against alopecia are Curcuma aeruginosa (pink and blue ginger), Serenoa repens (palmetto), Cucurbita pepo (pumpkin), Trifolium pratense (red clover), and Panax ginseng (Chinese red ginseng). The assumed mechanism of action is predominately inhibition of 5α-reductase, with enhanced nutritional support and scalp blood circulation playing a role as well.
... Flavonoids function as inhibitors of type 2, 5-alpha reductase enzyme; thus, they may be potentially useful in AGA patients. 33 Green tea catechins inhibit conversion of testosterone. 33 Some examples of flavonoids are genistein, fistein, quercetin, daidzein, kaempferol, myricetin, baicalein, and biochanin A. 33 Probiotics have also been shown to have beneficial effect in AGA. ...
... 33 Green tea catechins inhibit conversion of testosterone. 33 Some examples of flavonoids are genistein, fistein, quercetin, daidzein, kaempferol, myricetin, baicalein, and biochanin A. 33 Probiotics have also been shown to have beneficial effect in AGA. 34 Soya bean drinks, which are a source of flavonoids, were found to have beneficial effect in AGA, with an optimal intake of 3 drinks per week. ...
... 33 Green tea catechins inhibit conversion of testosterone. 33 Some examples of flavonoids are genistein, fistein, quercetin, daidzein, kaempferol, myricetin, baicalein, and biochanin A. 33 Probiotics have also been shown to have beneficial effect in AGA. 34 Soya bean drinks, which are a source of flavonoids, were found to have beneficial effect in AGA, with an optimal intake of 3 drinks per week. ...
Article
Background While a plethora of literature continues to be published on the role of nutritional agents both in lay press and indexed journals, the data is not on a firm footing and leaves the dermatologist in a quandry and the patient confused. The various agents include vitamins, minerals, amino acids, antioxidants, diets & gluten. A proper knowledge of the role of nutritional supplements in dermatological diseases can be a useful tool in advising the patients and in certain cases ameliorating the disorder. Patients/Methods Literature review of last 15 years was made using the terms “diet in dermatology,” “nutrition and skin,” “nutritional supplements in dermatology,” “nutritional agents and acne,” “nutritional agents and alopecia,” and “nutritional agents and psoriasis.” Results While there are multiple publications on the use of nutritional supplements for amelioration of skin diseases, most of them are based on either associations or in vitro studies, but very few transcend the rigors of a clinical trial or the holey grail of a double-blinded randomized controlled trial. There seem to be some evidence in acne, psoriasis, telogen effluvium, urticaria & vitiligo. Coeliac disease and dermatitis herpetiformis have a strong link with diet. Rosacea has a strong link with certain foods, but the other disorders like melasma, aphthous stomatitis do not have any scientifically validated association with diet. Conclusions Our updated review examines the role of nutritional supplements and antioxidants in various dermatological disorders. We have found that there are varying levels of evidence with notable associations of low glycemic diet & acne, fish oil & weight loss with psoriasis, fish oils & probiotics with atopic dermatitis & vitamins & botanical extracts with vitiligo. The evidence for diet and nutrition in bullous disorders and photoageing is scarce. The role of low histamine diet in urticaria is useful in select cases of episodic urticaria. Rosacea is triggered by hot and spicy food . Apart from gluten and Dermatitis Herpetiformis, no diet can be considered disease modifying in our reveiw. The lack of comparison of nutritional or dietary modiffication with conventional validated agents, makes the data difficult to translate in real world patient management.
... Studies evaluated that Lawsonia inermis compounds can slow hair loss and help nourish the scalp (25). Epicatechin gallate (ECG) and Epigallactocatechin gallate (EGCG) are extracted from Camellia sinensis leaves (26)(27)(28). Other compounds are β-sitosterol and stigmasterol isolated from Serenoa repens. ...
... Furthermore, Hiipakka et al. determined that EGCG can affect 5AR in cell-free but not whole-cell assays. They suggested that EGCG with long-chain fatty acids is active in both cellfree and whole-cell assay systems (26,51). Koseki et al. suggested the potential of ECG to inhibit 5AR, which results in inhibiting the androgen-related pathogenesis of acne, testosterone conversion, and sebum synthesis. ...
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Background: Dihydrotestosterone (DHT), the most critical pathogenic androgen in hair loss, is identified as an etiologic factor of androgenetic alopecia (AGA). The AGA is a genetically common disorder among men and is characterized by the progressive conversion of hair follicles into small vellus hair. Steroid 5 alpha-reductase type 1 (5AR1) is a crucial target responsible for this gradual replacement. The 5AR1 function is determined by converting testosterone to DHT. The inhibitors of 5AR1 play their role by blocking the DHT production pathway. Objectives: This study focused on the potent inhibitors of the 5AR1 enzyme to suggest effective synthetic drugs for restoring hair loss with fewer side effects. Methods: The three-dimensional structure of 5AR1 was created using homology modeling methods. Then, the inhibitory effects of some significant compounds from natural sources were examined on the 5AR1 protein using molecular docking approaches. Results: The obtained results suggest that two natural compounds isolated from Serenoa repens, including beta-sitosterol and stigmasterol, could inhibit the regular activity of 5AR1 and can be recommended as safe and novel AGA medicines for hair restoration.
... While their work showed similar findings to those of finasteride (a type 2 5a-reductase inhibitor) and its use to treat benign prostate hyperplasia, these authors did not link green tea constituents to hair growth in this or their subsequent paper published 7 years later. 24 However, Kwon et al made that connection in 2007, being the first to report that EGCG-enhanced human hair growth using dermal papilla cells (DPCs) in vivo and in vitro. Kwon et al stated that "it was reported the EGCG may be useful in the prevention or treatment of androgenetic alopecia by selectively inhibiting 5a-reductase activity (44)." 25 However, no report yet had been published on the effect of EGCG on human hair growth. ...
... A careful consideration of the Hiipakka et al paper revealed that it provided no evidence or written statement indicating that EGCG prevents or reverses androgenic alopecia by any means, including 5a-reductase inhibitors. 24 It, therefore, appears that Kwon et al provided the first report that EGCG enhanced hair growth in experimental systems. 25 Using 3 concentrations (0.01, 0.1, and 0.5 mM), they reported a dose-dependent increase in DPC proliferation using the MTT assay along with similar increases in the phosphorylation of extracellular-signal-regulated kinase and protein kinase B (Akt). ...
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Green tea, and its principal constituent (–)-epigallocatechin-3-gallate (EGCG), are commonly shown to induce biphasic concentration/dose responses in a broad range of cell types, including non-tumor cells, and tumor cell lines. The most active area of research dealt with an assessment of neural cells with application to neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease cell models, often using preconditioning experimental protocols. The general findings demonstrate EGCGinduced hormetic effects resulting in an enhanced acquired resilience within an adaptive and temporally dependent homeodynamic framework. The biphasic dose responses displayed the typical quantitative features of the hormetic dose response with respect to the amplitude and width of the stimulatory response. These findings provide further evidence for the general occurrence of hormetic dose responses with such responses being independent of the biological model, end point, inducing agent, and mechanism. The biphasic nature of these responses has important implications since it suggests optimal dose ranges for endpoints of public health and therapeutic applications. These findings indicate the need to assess the entire dose-response continuum in order to better define the nature of the dose response, especially in the low-dose zone where such exposures are common in human populations. This is an open-access publication and can be downloaded for free at: https://doi.org/10.1177%2F1559325820936170
... Epilobium angustifolium, a native of the temperate northern hemisphere, could present some 5α-reductase inhibition as its ethanolic extract directly inhibits the proliferation of the PZ-HPV-7 cells that are sensitive to DHT [93]. Hiipakka et al. [94] identified the green tea (−)-epigallocatechin gallate as well as other natural flavonoids such as biochanin A, daidzein, genistein and kaempferol as potent inhibitors of the 5α-reductase type 2. Adina rubella, a shrub found in Korea, presents caffeic acid and grandifloroside from leaves that have potent inhibitory activity against 5α-reductase [95]. Cynomorium songaricum, a parasitic perennial flowering plant, contains polyphenolic constituents that significantly inhibit rat prostate enlargement, improved the pathological feature and reduced the thickness of the smooth muscle layer [96]. ...
... Melatonin [44] Naringin, apigenin, berberine, palmatine, bavachin, jatrorrhizine, bavachinin [80] Alangenes [82] Extracts of Brassaiopsis glomerulata [84] Bakuchiol [85] Extracts of Sarcococca saligna [86] Shu-Gan-Liang-Xue decoction [87,88] Aqueous extracts of white button mushrooms [90] Butein [89] Obacunone [91] 5α-reductase Finasteride [53] Dutasteride [54] Serenoa repens extracts [92] Ethanolic extracts of Epilobium angustifolium [93] (−)-epigallocatechin gallate, biochanin A, daidzein, genistein, kaempferol [94] caffeic acid, grandifloroside [95] polyphenols from Cynomorium songaricum [96] Androgen receptor (SARM) ...
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: The great majority of breast and prostate tumors are hormone-dependent cancers; hence, estrogens and androgens can, respectively, drive their developments, making it possible to use pharmacological therapies in their hormone-dependent phases by targeting the levels of steroid or modulating their physiological activity through their respective nuclear receptors when the tumors relapse. Unfortunately, at some stage, both breast and prostate cancers become resistant to pharmacological treatments that aim to block their receptors, estrogen (ER) or androgen (AR) receptors, respectively. So far, antiestrogens and antiandrogens used in clinics have been designed based on their structural analogies with natural hormones, 17-β estradiol and dihydrotestosterone. Plants are a potential source of drug discovery and the development of new pharmacological compounds. The aim of this review article is to highlight the recent advances in the pharmacological modulation of androgen or estrogen levels, and their activity through their cognate nuclear receptors in prostate or breast cancer and the effects of some plants extracts.
... p38 and JNK-MAPK pathways are essential for EGCG induction of p57 and caspase 14 in keratinocytes, reducing psoriasiform lesions in the flaky skin mouse model [89] (see Table 5). Recently, EGCG was proposed for the prevention or treatment of AGA by selectively inhibiting 5α-R activity [90]. It reveals as a potent inhibitor in cell-free environment but not in whole-cell assays of 5α-R. ...
... It reveals as a potent inhibitor in cell-free environment but not in whole-cell assays of 5α-R. Replacement of the gallate ester in EGCG with long-chain fatty acids produced potent 5α-R inhibitors that were active in both cell-free and whole-cell assay systems [90]. EGCG stimulates human HG via its proliferative and antiapoptotic effects on FDPC and may prolong anagen stage [91] Table 5. ...
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Abstract: Hair loss is a disorder in which the hair falls out from skin areas such as the scalp and the body. Several studies suggest the use of herbal medicine to treat related disorders, including alopecia. Dermal microcirculation is essential for hair maintenance, and an insu�cient blood supply can lead to hair follicles (HF) diseases. This work aims to provide an insight into the ethnohistorical records of some nutritional compounds containing flavonoids for their potential beneficial features in repairing or recovering from hair follicle disruption. We started from a query for “alopecia” OR “hair loss” AND “Panax ginseng C.A. Mey.“ (or other six botanicals) terms included in Pubmed and Web of Sciences articles. The activities of seven common botanicals introduced with diet (Panax ginseng C.A. Mey., Malus pumila Mill cultivar Annurca, Co�ea arabica, Allium sativum L., Camellia sinensis (L.) Kuntze, Rosmarinum o�cinalis L., Capsicum annum L.) are discussed, which are believed to reduce the rate of hair loss or stimulate new hair growth. In this review, we pay our attention on the molecular mechanisms underlying the bioactivity of the aforementioned nutritional compounds in vivo, ex vivo and in vitro studies. There is a need for systematic evaluation of the most commonly used plants to confirm their anti-hair loss power, identify possible mechanisms of action, and recommend their best adoption.
... Procyanidin, a polyphenol compound, promotes hair growth via release of nitric oxide from the vascular endothelium [33]. Polyphenols have also been shown to inhibit 5-AR activity [33]. ...
... Procyanidin, a polyphenol compound, promotes hair growth via release of nitric oxide from the vascular endothelium [33]. Polyphenols have also been shown to inhibit 5-AR activity [33]. Table 1 Complementary and alternative (CAM) and procedural and surgical options available in combination to pharmacotherapy for androgenic alopecia (AGA) ...
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Purpose of Review Androgenic alopecia (AGA) is the most common form of non-scarring alopecia, affecting millions of men and women in the United States (U.S.). This review highlights alternative and complementary treatment options for AGA. Recent Findings The treatment regimens for AGA have increased in pharmacotherapeutics, surgical, and complementary (CAM) categories. Each of the different treatment approaches can now be utilized by dermatologists to combat patient hair loss. Summary The U.S. Food and Drug Administration (FDA) has approved only two agents to treat AGA: prescription-only, oral finasteride and over-the-counter (OTC), topical minoxidil. Increased availability of therapies claiming hair regrowth properties, coupled with limited pharmacotherapeutic options for AGA, lead patients to seek alternative treatments. Increased awareness of the current evidence supporting complementary and alternative therapies among dermatologists will facilitate appropriate and timely education of AGA patients.
... The polyphenols from green tea are capable of altering lipids and cholesterol metabolism and have antioxidant, anti-inflammatory properties [20], cancer, cardiovascular disease prevention [11,21] and anabolic anti-obesity properties [22]. In addition, green tea polyphenols (mainly EGCG) have an anti-androgenic effect, whereby they modulate the metabolism of testosterone [23]. Based on these properties, green tea consumption may be indicated as prophylaxis or auxiliary therapy for several diseases, mainly CVD. ...
... The IGTG presented low serum testosterone values; however these values close to those of the control group. These data confirm the literature, demonstrating the anti-androgenic effects of the consumption of polyphenols extracted from green tea, either by the modulation of the 5alpha-reductase enzyme or other pathways [23,29]. ...
... This mixed agonist-antagonist may affect 5αreductase inhibitory properties or any phases of the hair growth cycle in chemically-induced alopecia in rats (Bhasin et al., 2012). These can be due to saturation of receptors, which include the 5αreductase enzymes found within hair follicles in bald areas during alopecia, by bioactive secondary metabolites present in the sample, such as flavonoids (Hiipakka et al., 2002). The advantage of these findings is based on achieving optimum therapeutic effects at lower concentrations without posing risks of adverse effects associated with higher concentrations. ...
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Context: The prevalence of alopecia around the world is high and awareness continuously increased due to social stigma. There are limited commercially-available medications for the management of different forms of baldness, most of which are prohibitively expensive and presents with various adverse effects. Aims: To evaluate the flavonoid-rich ethyl acetate extract of Equisetum hyemale stem for its hair-regenerative properties in chemically-induced alopecia in Sprague Dawley rats. Methods: Various concentrations of the flavonoid-rich extract of E. hyemale were applied in depilated areas in dorsal rat skin after chemical induction of alopecia. Evidence of hair growth was observed for 28 days in a weekly basis. Histopathological analysis of rat skin was performed to demonstrate evidence of follicular hair growth. Results: The abundance of flavonoids in the ethyl acetate extract was established by total flavonoid contents and LC-MS analyses. The 2.5% E. hyemale extract exhibited hair-regenerative properties with high tensile strengths, combined masses and follicular growth, which was comparable to the positive control, 5% minoxidil (p>0.05). The highest rate of hair follicular development was observed in the telogen phase in rat skin after 28 days of treatment. Conclusions: The flavonoid-rich ethyl acetate extract of E. hyemale exhibits in situ hair-regenerative properties in chemically-induced alopecia in rats at 2.5% w/v concentration.
... So far, there is no study about the effects of bioactive compounds on the transcriptional regulatory elements associated with SRD5A genes and AGA. Quercetin has been reported to possess anti-inflammatory activity and anti-androgen activity through the inhibition of steroid 5α-reductases and the downregulation of androgen receptors [37][38][39][40]. Quercetin-rich extracts including Ginkgo biloba, Camelia sinensis, and Cuscuta reflexa exhibited promising hair growth-promoting activities via the attenuation of steroid 5α-reductases [41]. ...
Article
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In Thai folklore wisdom, shallot (Allium ascalonicum L.) was applied as a traditional herbal medicine for hair growth promotion with no scientific evidence. Androgenetic alopecia (AGA) is a progressive hair loss caused by multiple factors, including androgen hormones, inflammation, and oxidative stress. Conventional medicines (finasteride, dutasteride, corticosteroids, and minoxidil) have been used with limited therapeutic efficacy and unpleasant side effects. In this study, we aimed to give the first estimation of bioactive compounds in shallot extract and evaluate the hair growth-promoting activities regarding anti-inflammatory and gene expression modulation involving androgen, Wnt/β-catenin, sonic hedgehog, and angiogenesis pathways. The results reveal that phenolic compounds (quercetin, rosmarinic, and p-coumaric acids) are the major constituents of the methanolic shallot extract. Compared with the lipopolysaccharide-stimulated control group (2.68 ± 0.13 µM), nitric oxide production was remarkably diminished by shallot extract (0.55 ± 0.06 µM). Shallot extract improves hair growth promotion activity, as reflected by the downregulation of the androgen gene expression (SRD5A1 and SRD5A2) and the upregulation of the genes associated with Wnt/β-catenin (CTNNB1), sonic hedgehog (SHH, SMO, and GIL1), and angiogenesis (VEGF) pathways. These findings disclose the new insights of shallot extract on hair growth promotions. Shallot extract could be further developed as nutraceutical, nutricosmetic, and cosmeceutical preparations for AGA treatment.
... Polyphenols can act on prostatic hyperplasia with different mechanisms: inhibition of 5α-reductase; decreased expression of growth factors (IGF-I and IGF-II); anti-inflammatory action (reduction of interleukin levels IL 1-β, IL 6, IL-I6 and tumor necrosis factor TNF-α, inhibition of COX-2 and 5-lipogenase, increased synthesis of nitric oxide and expression of nitric oxide synthase ); induction of apoptotic activity (increased expression of pro-apoptotic caspase-3 protein, up-regulation of peroxisomal proliferation receptors PPAR α and γ, increased expression of G protein estrogen receptor 1 coupled GPER); increased antioxidant activity (superoxide dismutase, glutathione peroxidase). Experimental evidences based on in vitro studies on homogenates of hyperplastic prostate cells or prostatic cell lines demonstrated prevalent inhibitory effect of 5αreductase type 2 of isoflavones (phytoestrogens), while flavonols and flavones show inhibitory effect of 5α-reductase type 1 but also anti-inflammatory ant antioxidant effects and induction of apoptosis (102,103). Phenolic acids and lignins also have a combined action on 5αreductase and induction of apoptosis (104). In experimental models of BPH in rats, the efficacy of cocoa extract, soy-derived isoflavones, quercitin, a mixture of baicalin and catechin (flavocoxid), equol, anthocyanins derived from black soy, flavonoids extracted from Garcinia kola (kolaviron), epigallocatechin-3-gallate, secoisolariciresinol and curcumin was demonstrated (105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115). ...
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During the last years, pharmaceutical innovations in primary care are dramatically less frequent and will be even more rare in the next future. In this context, preclinical and clinical research oriented their interest toward natural compounds efficacy and safety, supporting the development of a new “nutraceutical” science. Medicinal plants, in the form of plant parts or extracts of them, are commonly used for the treatment of prostate diseases such as benign hypertrophy, prostatitis and chronic pelvic pain syndrome. The pharmacological properties searched for the treatment of prostatic diseases are anti-androgenic, anti-estrogenic, antiproliferative, antioxidant and anti-inflammatory. The most studied and used medicinal plants are Serenoa repens, Pygeum africanum and Urtica dioica. Other promising plants are Cucurbita pepo, Epilobium spp, Lycopersum esculentum, Secale cereale, Roystonea regia, Vaccinium macrocarpon. In parallel, epidemiological studies demonstrated that diet may play an important role on incidence and development of prostatic diseases. The Mediterranean diet is rich of elements with anti-oxidant properties that act as a protective factor for prostatic cancer. Similarly, low intake of animal protein, high intake of fruits and vegetable, lycopene and zinc are a protective factor for benign prostatic hyperplasia (BPH). Serenoa repens in the treatment of symptoms of BPH has been tested either alone or, more frequently, in combination with other medicinal plants, alpha-blockers and inhibitors of 5- alpha reductase (5-ARI). Recent meta-analyses found the effectiveness of Serenoa repens similar or inferior of that of finasteride and tamsulosin but clearly higher than that of placebo in the treatment of mild and moderate low urinary tract symptoms (LUTS), nocturia and discomfort. Clinical trials showed potential synergistic effect of Serenoa repens with other medicinal plants and drugs. In addition to Serenoa repens, there are many other medicinal plants for which clinical evidence is still controversial. Urtica dioica, Pygeum africanum and Curcubita pepo can be considered as an adjunct to the common therapies and their use is supported by studies showing improvement of symptoms and flowmetric indices. Lycopene and selenium are natural products with antioxidant and anti-inflammatory action. The combination of lycopene and selenium with Serenoa repens was able to reduce inflammation in histological prostate sections and to further improve symptom scores and urinary flow in patients with BPH on tamsulosin treatment. Similar effects could be obtained with the use of other carotenoids, such as astaxanthin, and/or zinc. Efficacy on symptoms of patients with BPH of some polyphenols such as quercitin, equol and curcumin have been demonstrated by clinical studies. Pollen extract is a mixture of natural components able to inhibit several cytokines and prostaglandin and leukotriene synthesis resulting in a potent anti-inflammatory effect. Pollen extracts significantly improve symptoms, pain, and quality of life in patients affected by chronic pelvic pain syndrome and chronic prostatitis. Beta-sitosterol is a sterol able to improve urinary symptoms and flow measures, but not to reduce the size of the prostate gland. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide-signaling molecule with anti-inflammatory and neuroprotective effects that can have an interesting role in the management of chronic pelvic pain syndrome and chronic urological pain. Finally, several plant-based products have been subjected to preclinical, in vitro and in vivo, investigations for their potential pharmacological activity against prostate cancer. Some epidemiological studies or clinical trials evaluated the effects of beverages, extracts or food preparations on the risk of prostate cancer. Some plant species deserved more intense investigation, such as Camelia sinensis (green or black tea), Solanum lycopersicum (common tomato), Punica granatum (pomegranate), Glycine max (common soy) and Linum usitatissimum (linen).
... Procyanidin oligomers, and other polyphenols, most likely promote hair growth via nitric oxide, a gas produced in the lining of veins which promotes vasodilation and reduces cholesterol build-up. Polyphenols have also been shown to inhibit 5α-reductase activity which has been theorized to play a role in the pathogenesis of AGA [25]. ...
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Androgenetic alopecia (AGA) is characterized by non-scarring follicle miniaturization. Despite the success of approved therapies, commonly reported side effects and the need for continual use has led to the investigation of alternative therapies. The aim of this paper is to critically review the success of off-label, topical monotherapies for treatment of AGA in men. A literature search was conducted to obtain randomized, controlled and blinded studies that investigated off-label, topical, monotherapies in male patients. Hair density, hair diameter and hair growth were used to evaluate treatment success. Fourteen off-label topical therapies were investigated among the 16 studies that met inclusion criteria. Nine off-label therapies were reported to produce a significantly greater improvement in hair restoration parameters (e.g. mean change from hair count and hair diameter) as compared to placebo (p < 0.05 for all treatments). In two studies, procyanidin oligomers exhibited greater efficacy over vehicle with response to mean change in hair density (hairs/cm2) (ps < 0.0001 at Week 24). In conclusion, prostaglandin analogs and polyphenols, such as latanoprost and procyanidin oligomers, can improve hair restoration parameters in male AGA patients, possibly through targeting mechanisms proposed in the etiology of AGA. The current evidence suggests short-term (24 weeks) use may provide benefit for hair loss patients; however, long-term efficacy and safety data are required.
... The basis for this therapeutic effect might be the EGCG-induced inhibition of 5-α-reductase, given the key role that 5-α-reductase plays in the pathophysiology of androgenetic alopecia (Hiipakka, Zhang, Dai, Dai, & Liao, 2002). ...
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The purpose of this review is to examine epigallocatechin‐3‐gallate (EGCG) regarding its stability in different conditions (pH‐value, concentration, temperature), its interactions with common cosmetic ingredients, and its application in the dermatological field. The literature research considered published journal articles (clinical trials and scientific reviews). Studies were identified by searching electronic databases (MEDLINE and PubMed) and reference lists of respective articles. Higher concentrations of EGCG were reported to correlate with better stability and the same can be said for low temperatures and pH values. The interaction between EGCG and hyaluronic acid strengthens its antioxidant activities. Titanium dioxide coated with EGCG proved a suitable ingredient in sunscreens. The polyphenol possesses antioxidant properties, which proved effective in the prevention of UV‐induced skin damage and to alleviate the symptoms of Imiquimod‐induced psoriasis. The three endpoints of this review not only showed interesting results but also highlighted some limitations of EGCG. Studies show that the molecule is unstable, which may hinder its dermatological and cosmetic applications. The reported interactions with cosmetic ingredients were limited. As the health aspects of EGCG are well‐reported, ECGC has become a focus of interest for health professionals trying to treat common dermatological diseases.
... [16] The levels of heavy metals present in the extract were expressed as mean of heavy metal concentration (ppm) ± SD of three replicates. Calibration functions [23][24][25] for each element were determined. Concentrations of each heavy metal in the medicinal herb were calculated from the calibration functions. ...
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This study depicts a profile of existence of heavy metals (Cu, Cr, Cd, Hg, As, and Pb) in some important medicinal plants such as Hibiscus rosa-sinensis, Eclipta alba, and Solanum nigrum using atomic absorption spectroscopy. H. rosa-sinensis, E. alba, and S. nigrum these are indigenous plants having tremendous medicinal properties. Extracts of these plants are already reported to have many pharmacological activities. The purpose of this study is to determine heavy metal contents in these medicinal plants. The findings of this study were compared with prescribed limits of these metals in the WHO guidelines, and the content of all these heavy metals was found to be within safe limits. These findings indicate that the extract of H. rosa-sinensis, E. alba, and S. nigrum is safe from the point of view of heavy metal toxicity.
... This varied response might be due to a difference in the physiology of males and females or the pattern of hormones and adipocyte cells. Another explanation may be that green tea epigallocatechin inhibits the enzyme 5-alpha reductase which converts testosterone into dihydrotestosterone thereby increasing testosterone levels (Hiipakka, Zhang, Dai, Dai, & Liao, 2002;Liao & Hiipakka, 1995;Yu, Pu, Chen, Wang, & Wang, 2010). It appears that testosterone reduces hepatic lipogenesis and visceral adiposity in males while it increases peripheral insulin sensitivity and subsequent reducing pro-inflammatory cytokines such as TNF-α (Jaruvongvanich, Sanguankeo, Riangwiwat, & Upala, 2017, p. 18). ...
Article
The therapeutic potential of green tea as a rich source of antioxidants and anti‐inflammatory compounds has been investigated by several studies. The present study aimed to systematically review and analyze randomized clinical trials (RCTs) assessing the effects of green tea, catechin, and other forms of green tea supplementation on levels of liver enzymes. PubMed, SCOPUS, EMBASE, and Cochrane databases were searched until February 2019. All RCTs investigating the effect of green tea or its catechin on liver enzymes including alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and bilirubin were included. A total of 15 RCTs were included. The overall effect of green tea on liver enzymes was nonsignificant (ALT [Standardized mean difference (SMD)= −0.17, CI −0.42 to 0.08, p = .19], AST [SMD = −0.07, CI −0.43 to 0.29, p = .69], and ALP [SMD = −0.17, CI −0.45 to 0.1, p = .22]). However, subgroup analyses showed that green tea reduced the levels of liver enzymes in participants with nonalcoholic fatty liver disease (NAFLD) but in healthy subjects, a small significant increase in liver enzymes was observed. In conclusion, the results of this study suggest that the effect of green tea on liver enzymes is dependent on the health status of individuals. While a moderate reducing effect was observed in patients with NAFLD, in healthy subjects, a small increasing effect was found.
... Recently, it was found that green tea drinkers have no excess risk for epithelial ovarian cancer [75]. Furthermore, green tea has proved to have antiproliferative effects against human prostate cancer cells [76] and can lead to cell growth inhibition in some prostate cancer cells [77] showing potent inhibition of 5α-reductase enzyme, which may be involved in the development of benign prostatic hyperplasia, hirsutism, and prostate cancer [78,79]. GTPs also strongly inhibit the growth of renal cell carcinoma cell lines in a concentration-dependent manner [80]. ...
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Tea, Camellia sinensis, which belongs to the family Theaceae, is a shrub or evergreen tree up to 16 m in height. Green tea is very popular because of its marked health benefits comprising its anticancer, anti-oxidant, and antimicrobial activities, as well as its effectiveness in reducing body weight. Additionally, it was recognized by Chinese people as an effective traditional drink required for the prophylaxis against many health ailments. This is due to the complex chemical composition of green tea, which comprises different classes of chemical compounds, such as polyphenols, alkaloids, proteins, minerals, vitamins, amino acids, and others. The beneficial health effects of green tea ultimately led to its great consumption and increase its liability to be adulterated by either low-quality or non-green tea products with concomitant decrease in activity. Thus, in this review, green tea was selected to highlight its health benefits and phytoconstituents, as well as recent approaches for its quality-control monitoring that guarantee its incorporation in many pharmaceutical industries. More research is needed to find out other more biological activities, active constituents, and other simple and cheap techniques for its quality assurance that ascertain the prevention of its adulteration.
... oxygen to reach follicle cells without much hindrances. Research by [35,36] suggest that avonoids can also stimulate hair growth by inhibiting the activity of type II 5α reductase enzyme. ...
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Phytochemicals from Dicerocaryum senecioides were studied for hair rejuvenation activity using BalB/c mice. Solvent extractions and thin layer chromatography (TLC) were used to extract and isolate the phytochemicals respectively. Phytochemicals were identified by spraying with target-specific revealing reagents. In vivo hair growth stimulating activity for each extract was tested on denuded dorsal skin of 5-week old BalB/c mice against the controls and the standard drug minoxidil. The parameters used to evaluate hair growth were hair growth completion time, hair length, hair weight, hair follicle length, and relative hair follicle area. The identified phytochemicals from the active ethanol extract were steroidal glycosides, triterpenoid glycosides, and flavonoid glycosides. Flavonoid glycosides treatment had the uppermost hair rejuvenation capacity as measured by the shortest hair growth completion time (19 days) versus control (29 days) and longest hair length (11.04 mm and 11.86 mm for male and female mice respectively while the control group had 5.15 mm for male mice and 5.33 mm for female mice). Hair growth stimulation by flavonoid glycosides was also dependent on dose concentration. It can be concluded from this study that flavonoid glycosides extracted from the leaves of Dicerocaryum senecioides have remarkable hair rejuvenation capacity in BalB/c mice. The present results provides insights on the use of Dicerocaryum senecioides for hair rejuvenation in traditional practices and on the potential of the plant as a source of novel compounds that can be used as hair growth promoters.
... The study revealed significant improvement in hair growth (33% of animals) in comparison to control group [100]. One of the main catechins present in green tea extract-EGCG was proved to be strong 5α-reductase and aromatase inhibitor [101,102]. This fact may significantly explain the effectiveness of using green tea polyphenols to treat androgenic alopecia, which is mainly associated with increased activity of these both enzymes. ...
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Studies on the cosmetic applications of plant extracts are increasingly appearing in the scientific literature, which is due to the growing popularity of skincare products around the world. In the light of the observed changes, a return to natural treatment and skincare with cosmetics free of harmful substances or toxic preservatives is visible. Currently, tea extracts, due to their rich composition and various biological actions, play an important role among the dietary supplements and cosmetics. This review is intended to collect the reports on the properties of the tea plant, its extracts and preparations in cosmetology: for skin care products and for the treatment of selected dermatological diseases. Particular attention is paid to its antioxidant, anti-hyaluronidase, anti-inflammatory, slimming, hair-strengthening, photoprotective and sealing blood vessels properties.
... This mixed agonist-antagonist may affect 5αreductase inhibitory properties or any phases of the hair growth cycle in chemically-induced alopecia in rats (Bhasin et al., 2012). These can be due to saturation of receptors, which include the 5αreductase enzymes found within hair follicles in bald areas during alopecia, by bioactive secondary metabolites present in the sample, such as flavonoids (Hiipakka et al., 2002). The advantage of these findings is based on achieving optimum therapeutic effects at lower concentrations without posing risks of adverse effects associated with higher concentrations. ...
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Context: The prevalence of alopecia around the world is high and awareness continuously increased due to social stigma. There are limited commercially-available medications for the management of different forms of baldness, most of which are prohibitively expensive and presents with various adverse effects. Aims: To evaluate the flavonoid-rich ethyl acetate extract of Equisetum hyemale stem for its hair-regenerative properties in chemically-induced alopecia in Sprague Dawley rats. Methods: Various concentrations of the flavonoid-rich extract of E. hyemale were applied in depilated areas in dorsal rat skin after chemical induction of alopecia. Evidence of hair growth was observed for 28 days in a weekly basis. Histopathological analysis of rat skin was performed to demonstrate evidence of follicular hair growth. Results: The abundance of flavonoids in the ethyl acetate extract was established by total flavonoid contents and LC-MS analyses. The 2.5% E. hyemale extract exhibited hair-regenerative properties with high tensile strengths, combined masses and follicular growth, which was comparable to the positive control, 5% minoxidil (p>0.05). The highest rate of hair follicular development was observed in the telogen phase in rat skin after 28 days of treatment. Conclusions: The flavonoid-rich ethyl acetate extract of E. hyemale exhibits in situ hair-regenerative properties in chemically-induced alopecia in rats at 2.5% w/v concentration.
... The phenolic compounds, vitamins and trace elements we identified in the phytochemical analysis of our formulation, may also give more specific support to the maintenance of healthy hair. Myricetin, quercetin, kaempherol and copper keep the hair follicle longer in anagen phase by inhibiting 5α-R and preventing DHT formation (42,43). Vitamin C (ascorbic acid), improves blood vessel formation and increases blood flow in the scalp.by ...
Article
Background: Currently while, topical minoxidil and oral finasteride are the only medications approved in androgenetic alopecia (AGA), the cause oriented treatment and immunsupres-sive treatment are being performed in telogen effluvium (TE) and alopecia areata (AA) respectively. Considering the inflammatory factors in the pathogenesis of these three nonscarring al-opecia forms, we have formulated a mixture for topical usage composed of six different herbal extracts (HE) which have already known antiinflammatory and antioxidant features. Materials and Methods: In addition to performing the phytochemical analysis of HE, we detected the gene expression level of IL-1α, the crucial hair loss mediator, for the putative efficacy in non-scarring alopecia. Cell proliferation assay was performed by XTT reagent. After determination of non-cytotoxic concentration, HaCaT cells were treated with HE. RNA isolations were carried out from both non-treated and treated cell groups by using TRI-reagent. Gene expressions of IL-1α and as control GAPDH were determined by RT-qPCR analysis. Results: Results were represented as "IL-1α/GAPDH Fold Change". HE solution caused statistically significant downregulation of IL-1α gene expressions (p<0.0001), compared to untreated control cells. HE treatment ended up with 0.1900 fold change for IL-1α. Conclusion: IL-1α is a direct growth inhibitory agent in hair follicles and an important actor in the pathogenesis of AGA , TE, and AA. Considering together the vitamins, flavonoids, and trace elements identified in the phy-tochemical analyses and downregulation of IL-1α in HaCaT cells, our HE may be an auxiliary agent in the therapy of these three nonscarring alopecia forms.
... Acetylation of the five hydroxyl groups of EC was achieved using acetic anhydride in pyridine, followed by selective deacetylation using ammonium acetate in a methanol-water solution to afford 2a (Huo et al., 2008;Ramesh, Mahender, Ravindranath, & Das, 2003). Silylation of the four hydroxyl groups of 2a and subsequent deacetylation of 3a yielded compound 4a (Hiipakka, Zhang, Dai, Dai, & Liao, 2002;Wang et al., 2016). The two hydroxyl groups of caffeic acid were acetylated using acetic anhydride in pyridine, and then chlorinated using thionyl chloride to afford 5a (Akita, Nozawa, Mitsuda, & Ohsawa, 2000; Frank, Zehentbauer, & Hofmann, 2006). ...
Article
The contents of hydroxycinnamoylated catechins (HCCs) in tea leaves have yet to be thoroughly investigated. Herein, four HCCs, (–)-epicatechin 3-O-p-coumaroate (EC-pC), (–)-epicatechin 3-O-caffeoate (EC-C), (–)-epigallocatechin 3-O-p-coumaroate (EGC-pC), and (–)-epigallocatechin 3-O-caffeoate (EGC-C) were synthesized as standards through an improved route and then identified in leaves of 40 and quantified in 20 tea cultivars using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS). ECC and EC-pC were synthesized for the first time. This study found that HCCs were widely present in the two varieties of tea, Camellia sinensis var. sinensis (CSS) and var. assamica (CSA). The contents of total four HCCs and EGC-pC were higher in CSS (729–1398 mg/kg for total HCCs, 483–1052 mg/kg for EGC-pC), while EC-C was higher in CSA (65–176 mg/kg) cultivars, suggesting that EC-C and EGC-pC could be used as biochemical markers to differentiate CSS from CSA tea cultivars. Changes in HCCs contents were detected from the tea leaves collected from April to October, indicating that tea leaves harvested in August would have the highest HCCs content.
... Anthrarobin (anthracene-1,2,10-triol) is also found to have xanthine oxidase inhibitory activity at 68.35 μM concentration (Sheu and Chiang, 1997). Any minute change in the existing structure of anthrarobin may reveal different biological activities and various pharmacological effects (Giacobini 2001;Hiipakka et al., 2002). Due to the potent and diverse activities of anthrarobin derivatives, this study was planned to synthesize and determine the BuChE inhibition activity of new anthrarobin derivatives. ...
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To treat Alzheimer's disease (AD), the available candidates are effective only against mild AD or have side effects. So, a study was planned to synthesis new candidates that may have good potential to treat AD. A series of new anthrarobin acyl derivatives (2-8) were synthesized by the reaction of anthrarobin (1) and acetic anhydride/acyl chlorides. The product were characterized by 1 H NMR and EI-MS, and evaluated for butyrylcholinesterase (BuChE) inhibition activity. Compounds 5 and 4 showed notable BuChE inhibitory potential with IC 50 5.3 ± 1.23 and 17.2 ± 0.47 μM, respectively when compared with the standard eserine (IC 50 7.8 ± 0.27 μM), compound 5 showed potent BuChE inhibition potential than
... Both mechanisms are critical to reverse or abolish androgen dependent alopecia via inhibition of conversion of testosterone to DHT. Thujae occidentalis extract and linolenic acid [63] , Panax ginseng extracts and ginsenoside Ro [64] , Cuscuta reflexa extract [65] , natural flavonoids (myricetin, quercitin, baicalein, fisetin, biochanin A, daidzein, genistein, kaempferol) and polyphenolic compounds (alizarin, anthrarobin, gossypol, nordihydroguaiaretic acid, caffeic acid phenethyl ester, octyl and dodecyl gallates) [66] have efficacious effects of inhibition of 5α-reductase activity and inhibition of conversion of testosterone to DHT in androgen dependent alopecia. Scutellaria baicalensis extract and its main component baicalin [67] , Rosmarinus officinalis extract and 12-methoxycarnosic acid [68] and forsythiaside A derived from Forsythia suspensa [69] inhibit the binding of DHT to androgen receptors. ...
... [26][27][28][29][30] The improvements in AGA in the patients who received the herbal extract combination in our study could be the result of multiple mechanisms based on previously published study data, including the inhibition of 5α-reductase, increase of hair anchoring, and hair diameter via the stimulation of extracellular matrix (ECM) production of dermal papilla, and decrease of micro-inflammation in the pathogenesis of both male and female pattern hair loss. 9,13,16,32,33,34 ...
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OBJECTIVE: We sought to evaluate the efficacy and safety profile of an herbal extract combination comprising biochanin A, acetyl tetrapeptide-3, and ginseng extracts, and compare this to 3% minoxidil solution for the treatment of andogenetic alopecia (AGA). METHODS: A 24-week, triple-blinded, randomized controlled study was conducted in male and female subjects (N=32) with mild to moderate AGA. All were randomized to receive twice-daily, 1mL applications of the herbal extract combination or 3% minoxidil solution. Clinical efficacy from photographic assessment and adverse reactions were evaluated. RESULTS: There were thirty-two subjects (16 male, mean age 41.3±13.8 years), with AGA onset and duration of 35.5±13.6 and 6.5±5.1 years, respectively. The herbal extract combination demonstrated a comparable efficacy to 3% minoxidil solution. Expert panel photographic assessment observed a response to both treatments in most patients at 24 weeks, with no statistically significant difference in an increase of terminal hair counts (8.3% [P=0.009] and 8.7% [P=0.002] at 24 weeks in the herbal extract combinations and the 3% minoxidil solution groups, respectively). No local adverse reactions from the herbal extract combination were observed, but one subject developed scalp eczema after using the 3% minoxidil solution. CONCLUSION: The non-significant difference in clinical efficacy and safety to 3% minoxidil solution suggests that the herbal extract combination evaluated here could potentially be an alternative treatment with for AGA. Further studies with larger groups and longer follow-up periods are recommended to verify our results.
... Hiipakka et al. reported that treatment with polyphenols isolated from green tea decreased the DHT production, and inhibited prostate cells proliferation. Because N. sativa contains polyphenolic compounds [31], it can be argued that, at least, inhibition of 5a-reductase contributes to the beneficial effect of this plant. The high amount of fatty acids of N. sativa oil has essential unsaturated fatty acids (about 1% omega-3, 25% omega-9 and 58% omega-6) in abundance [10,12]. ...
Article
Background: Benign prostatic hyperplasia (BPH) is the most prevalent disease of the prostate in elderly men. Since Nigella sativa has been reported to show various pharmacological effects, this study was conducted to examine the effect of N. sativa seed oil on experimental BPH. Methods: The oil was extracted using the cold-pressing method. Fifty rats were divided into five groups of 10 each as follows: Group 1 orally (p.o.) received normal saline; groups 2-5 were castrated and subcutaneously received 5 mg/kg testosterone propionate for four weeks. Group 2, namely, BPH model, underwent no further treatment, Groups 3 and 4 were treated with 400 mg/kg and 800 mg/kg N. sativa seed oil, Group 5 received finasteride (0.5 mg/kg, p.o.) for 28 days. All groups received repeated testosterone injections for the following four weeks after BPH induction. After the treatments, rats were sacrificed and the prostate tissues removed. Wet weight, prostatic volume (PV) and prostatic index (PI) were determined. Serum prostate-specific antigen (PSA), dihydrotestosterone (DHT), malondialdehyde (MDA) and antioxidant levels were determined. Results: Our results showed that oral treatment with 400 and 800 mg/kg N. sativa oil led to a significant decrease in PI, PV, DHT concentration, PSA, and serum MDA level, and also significantly increased serum antioxidant capacity. Conclusions: The study demonstrated that the oil seed exerted anti-BPH effects which may be associated with its antioxidant properties in vivo.
... It must be referred to that, gallated catechins have additionally been inhibited other steroid-related enzymes consisting of eleven-beta-hydroxysteroid dehydrogenase [109], 5-alpha-reductase [110] and aromatase [111]. Reduced five-alpha-reductase hobby may be related to weight loss of androgen-dependent organs including prostates and seminal vesicles, found in catechins treated male rat [54]. ...
... Antiandrogen activity via inhibition of 5α-reductase is critical for male sexual differentiation and its deficiency may be involved in the development of prostate cancer. 45 From the heartwood of A. incisus, artocarpin inhibited 5α-reductase (IC 50 = 85 μM). 46 Structure-activity investigations of the isolated compounds suggested that the presence of an isoprene substituent (prenyl and geranyl) would enhance 5α-reductase inhibitory effects. ...
... Pharmacological treatments used for BPH, such as α-blockers and Type I/II 5α-reductase inhibitors, do not cause long-term regression and have side effects such as orthostatic hypotension, diarrhea, headache, nasal congestion and sexual dysfunction [2,15]. However, it has been reported that many natural and synthetic polyphenol compounds, containing catechin group as their main characteristics, potentially show an anti-androgen effect by inhibiting 5α-reductase activity [16][17]. Therefore, there is an increasing tendency towards phytotherapy in the treatment of BPH in recent years [2,5]. ...
... Ginkgo biloba bitkisinin antiödem ve vazodilatör etkileri dolayısıyla alopesi tedavisinde kullanımı desteklenmiştir.35 Camellia sinensis bitkisi antioksidan, saç uzamasını artırıcı, saç kepeklenmesini önleyici, alopesiyi tedavi edici özellikler göstermektedir.[36][37][38][39] Aloe vera bitkisinin antiinflamatuar ve antimikrobiyal etkileri ortaya konarak saç gelişimini artırıcı ve seboreik dermatit tedavisinde kullanımını destekleyici sonuçları bulunmaktadır.40,41 ...
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Objective: Hair cosmetics are widely used by the public for various purposes. In order to avoid the possible damages and side effects when using products, the trend towards herbal products is increasing. The main purpose of this study is to determine the most common plants, which are existed in the hair products, and their using purposes by investigation of shampoos, hair care products and hair dyes contain plant parts. Material and Methods: 259 hair cosmetics products of 45 brands in pharmacies and personal care markets were searched, the plants in their content, parts of the plants used and their usage purposes were investigated. The data obtained are presented in tables and the plants and their families which are the most common in the hair products are given in graphics based on the number of plants' participation in the products. Results: As a result of research, 182 plants belonging to 70 families were determined in the hair products and the total number of participation of plants to products was found as 852. The 5 most widely used species in shampoos, hair care products and hair dyes are defined as; Rosmarinus officinalis L., Lawsonia inermis L., Olea europaea L., Urtica dioica L. and Matricaria chamomilla L. Conclusion: It is thought that this study will be a reference to the future scientific studies by detecting the most common plants in hair cosmetic products and will be a resource for health care workers to offer the appropriate product for the treatment of the patient.
... Consuming a diet rich in phenolic acids, such as fruits and vegetables, is related to a reduced risk of prostate cancer progression. For example, phenolic acids and flavonoids induce apoptosis by increased expression of pro-apoptotic proteins and suppressed expression of anti-apoptotic proteins in in vitro study [13,14]. Some dietary compounds show anti-cancer properties against prostate cancers through inhibition of proliferation and metastasis [15]. ...
Article
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Houttuynia cordata Thunb. (HCT) is a well-known Asian medicinal plant with biological activities used in the treatment of many diseases including cancer. This study investigated the effects of HCT extract and its ethyl acetate fraction (EA) on prostate carcinogenesis and castration-resistant prostate cancer (CRPC). HCT and EA induced apoptosis in androgen-sensitive prostate cancer cells (LNCaP) and CRPC cells (PCai1) through activation of caspases, down-regulation of androgen receptor, and inactivation of AKT/ERK/MAPK signaling. Rutin was found to be a major component in HCT (44.00 ± 5.61 mg/g) and EA (81.34 ± 5.21 mg/g) in a previous study. Rutin had similar effects to HCT/EA on LNCaP cells and was considered to be one of the active compounds. Moreover, HCT/EA inhibited cell migration and epithelial-mesenchymal transition phenotypes via STAT3/Snail/Twist pathways in LNCaP cells. The consumption of 1% HCT-mixed diet significantly decreased the incidence of adenocarcinoma in the lateral prostate lobe of the Transgenic rat for adenocarcinoma of prostate model. Similarly, tumor growth of PCai1 xenografts was significantly suppressed by 1% HCT treatment. HCT also induced caspase-dependent apoptosis via AKT inactivation in both in vivo models. Together, the results of in vitro and in vivo studies indicate that HCT has inhibitory effects against prostate carcinogenesis and CRPC. This plant therefore should receive more attention as a source for the future development of non-toxic chemopreventive agents against various cancers.
... It was reported that kaempferol exhibited its androgeniclike activity and served as a selective androgen receptor modulator that contributed to androgen-related BPH development [29]. Kaempferol was revealed to be much better inhibitor of the type 2 than type 1 isozyme, quercetin was proved to be a potent inhibitor of the type 1 5α-reductase [30]. Moreover, kaempferol and its glycosides (kaempferol3-(3-E-p-coumaroylα-L-rhamnopyranoside), kaempferol 3-(2,3-di-E-pcoumaroyl-α-L-rhamnopyranoside)) from the pollen of Brassica napus L. were found to exhibit down-regulation of prostate specific antigen in LNCaP cells [31]. ...
Article
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Background: The Prinsepia utilis Royle leaves (P. utilis) is a folk herb used for benign prostatic hyperplasia (BPH) control by ethnic minorities for centuries in China with rich in resources. Our previous studies have confirmed the anti-BPH effect of its water extract (QCJ) and the active fraction (Fr. B) separated from the QCJ by animal test. The Fr. B from P. utilis should be a potential candidate for BPH control. Methods: In this study, the chemical ingredients of Fr. B were identified by UPLC-QTOF-MS, and quantified by HPLC. Murine animal models were divided into 8 groups, Sham rats, BPH rats, BPH rats administered with finasteride (1 mg/kg), BPH rats administered with Pule'an (460 mg/kg), BPH rats administered with low, high dosage of QCJ (860 mg/kg, 2580 mg/kg respectively), BPH rats administered with low, high dosage of Fr. B (160 mg/kg, 480 mg/kg respectively). The expression of vascular endothelial growth factor (VEGF) in the prostate tissue of rats was tested, and serum levels of dihydrotestosterone (DHT), testosterone (T), estradiol (E2), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and total superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), malondialdehyde (MDA) in prostate homogenate were measured. One-way ANOVA followed by LSD was used for statistical analysis. Results: The BPH rats treated by Fr. B exhibited significant reductions of VEGF and MDA levels, as well as significant increases of SOD, GSH-Px and CAT in the prostate tissue after 28 day administration (P < 0.05). Moreover, Fr. B significantly reduced DHT, DHT/E2 ratio, TNF-α, while increased T levels in serum of BPH rats (P < 0.05). UPLC-QTOF-MS analysis revealed 10 flavonoids as the key constituents of this fraction, which accounted for 54.96% of all substance of Fr. B. The relative contents of compound 1, 2 are 11.1%, 13% in Fr. B respectively. Conclusions: These results indicated that the Fr. B obtained from P. utilis alleviated the symptoms of BPH rats through multiple mechanisms including reduction of DHT/E2 ratio, inhibition of growth factor, anti-inflammation and anti-oxidation, in which flavonoids might be the key constituents. It supported the hypothesis that the Fr. B should be further explored as a candidate for BPH patients.
... Cactus containing the higher amount of flavonoids and it helps to prevent the hair loss and reuce the 5--α-reductase. [10,12,13]. Similarly the cactus containing the higher amount of anti-oxidant potential and it helps the healthy sebum in the scalp. ...
... There is controversy regarding whether phenolic compounds affect the downregulation of the SRD5A1 gene [61]. Additionally, the study reported that the activity of 5α-reductase type 1 was attenuated by natural phenolic compounds, such as green tea EGCG, myricetin, quercetin, baicalein, and fisetin, whereas type 2 was favorably inhibited by other flavonoids, including biochanin A, daidzein, genistein, and kaempferol [65]. The bioactive compounds of BB3CMU-H were mainly phenolic and flavonoid components, which did not influence SRD5A gene expression, but might affect the 5α-reductase enzyme [56]. ...
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Androgenetic alopecia (AGA), a hair loss disorder, is a genetic predisposition to sensitive androgens, inflammation, and oxidative stress. Unfortunately, current treatments with synthetic medicines contain a restricted mechanism along with side effects, whereas the bioactive constituents of plant extracts are multifunctional, with fewer side effects. The massive amounts of rice husk and bran are agricultural wastes that may cause pollution and environmental problems. Owing to these rationales, the local rice variety, Bue Bang 3 CMU (BB3CMU), which is grown in northern Thailand, was evaluated for the valuable utilization of rice by-products, husk (BB3CMU-H) and bran (BB3CMU-RB) extracts, for AGA treatment regarding antioxidant, anti-inflammatory, anti-andro-genic activities, and the characterization of bioactive compounds. Our study verified that BB3CMU-H had the highest level of polyphenols, contributing to its greater antioxidant activity. Conversely, BB3CMU-RB was the predominant source of tocopherols, resulting in better anti-androgenic activities regarding the downregulation of steroid 5α-reductase genes (SRD5A). Notably, anti-inflammation via the attenuation of nitric oxide productions was observed in BB3CMU-H (0.06 ± 0.13 μM) and BB3CMU-RB (0.13 ± 0.01 μM), which were significantly comparable to diclofenac sodium salt (0.13 ± 0.19 μM). Therefore, the combination of BB3CMU-H and BB3CMU-RB could be utilized in cosmeceutical and pharmaceutical applications for AGA patients.
... Flavonoids were reported to inhibit 5aR1 enzymes such as myricetin, quercetin, baicalein, and fisetin. Biochanin A, kaempferol, genistein, and daidzein can also inhibit 5aR activity [4]. ...
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Momordica charantia (M. charantia) is rich in flavonoids, which possess a strong antioxidant capacity andmay help prevent hair loss. This study aims to develop the microemulsion of M. charantia with antioxidant activity and 5 alpha-reductase (5aR) inhibitory activity. The total phenolic content (TPC), antioxidant activity, and 5aR inhibitory activity of ethanolic and aqueous extracts of the fruit were investigated. The preparation of M. charantia extract-loaded microemulsion (MELM) was optimized and characterized the MELM. The aqueous extract of M. charantia fruit flesh displayed a TPC of 780.75 � 24.82 mg Gallic acid equivalence/g of extract. ABTS (2,20-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid), DPPH (2,2-diphenyl-1-picrylhydrazyl), and nitric oxide (NO) radical scavenging activities were observed in all the extracts. About 0.461 � 0.003 mg finasteride equivalence/g of extract of 5aR inhibitory activity was detected in the aqueous extract of the inner tissue of M. charantia fruit. Based on NO radical scavenging and 5aR inhibitory activity, an aqueous extract of the inner tissue (pericarp with seed) of M. charantia fruit was used to prepare the MELM. The MELM was prepared using a different ratio of tween 80 and ethanol as Smix. The results showed that the 1:1 ratio of tween 80: ethanol produced microemulsion of an optimum size, zeta potential, and polydispersity index. The MELM samples were stored at 5, 30, and 40 �C for 12 weeks, and the stability was assessed. The results revealed that the size, zeta potential, and polydispersity index of the formulated MELM remained unchanged during the investigated time. This study primarily reports the 5aR inhibitory activity of M. charantia extract and the development of microemulsion. The prepared MELM could be further developed into cosmetic or pharmacological preparations to manage hair loss.
... Kao reported that plasma T concentrations decreased by 70% in EGCG treated mice [156]. Hipaka showed in 2002 that EGCG and ECG inhibit 5αR activity in rats [157]. In guinea pigs receiving catechin, quercetin, and resveratrol, aortic fat reduction of 84%, 80%, and 76%, respectively, was found compared with the control group [158]. ...
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Prostate cancer (CaP) is one of the leading causes of death in men worldwide. Much attention has been given on its prevention and treatment strategies, including targeting the regulation of 5-alpha-Reductase (5αR) enzyme activity, aimed to limit the progression of CaP by inhibiting the conversion of potent androgen dihydrotestosterone from testosterone that is thought to play a role in pathogenesis of CaP, by using the 5-alpha-Reductase inhibitors (5αRis) such as finasteride and dutasteride. However, 5αRis are reported to exhibit numerous adverse side effects, for instance erectile dysfunction, ejaculatory dysfunction and loss of libido. This has led to a surge of interest on plant-derived alternatives that might offer favourable side effects and less toxic profiles. Phytochemicals from plants are shown to exhibit numerous medicinal properties in various studies targeting many major illnesses including CaP. Therefore, in this review, we aim to discuss the use of phytochemicals namely phytosterols, polyphenols and fatty acids, found in various plants with proven anti-CaP properties, as an alternative herbal CaP medicines as well as to outline their inhibitory activities on 5αRs isozymes based on their structural similarities with current 5αRis as part of CaP treatment approaches.
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Dihydrotestosterone has been shown to be a major metabolite of testoterone. Human skin has been shown to actively convert testosterone to dihydrotestoterone. Since the levels of circulating testoterone in normals and in individuals with acne are the same, “end organ sensitivity” has been postulated. To evaluated the possibility that this may be a function of the rate of conversion of testosterone to dihydrotestoterone, a total of 62 biopsies were studied from 32 subjects without and with acne from effected and unaffected areas. Labeled testosterone metabolites were identified by TLC, GLC, and GFP. Acne bearing skin produced from 2 to 20 times more dihydrotestosterone than normal back skin. It thus appears that the previously postulated end organ sensitivity, thought to account in, part for the occurrence and distribution of acne, may indeed exist and may be mediated by differential rats of conversion of testosterone to dihydrotestosterone in the skin.
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In the 20 yr since it was established that impairment of dihydrotestosterone formation is the cause of a rare form of human intersex, a wealth of information has accumulated about the genetics, endocrinology, and variable phenotypic manifestations, culminating in the cloning of cDNAs encoding two 5 alpha-reductase genes and documentation that mutations in the steroid 5 alpha-reductase 2 gene are the cause of 5 alpha-reductase deficiency. Perplexing and difficult problems remain unresolved, e.g. whether the variability in manifestations is due to variable expressions of steroid 5 alpha-reductase 1 or to effects of testosterone itself. It is also imperative to establish whether defects in steroid 5 alpha-reductase 2, perhaps in the heterozygous state, are responsible for a portion of cases of sporadic hypospadias, to determine whether 5 alpha-reductase plays a role in progesterone action in women, and to elucidate the relation between androgen action and gender role behavior.
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Background: Androgenetic alopecia (male pattern hair loss) is caused by androgen-dependent miniaturization of scalp hair follicles, with scalp dihydrotestosterone (DHT) implicated as a contributing cause. Finasteride, an inhibitor of type II 5α-reductase, decreases serum and scalp DHT by inhibiting conversion of testosterone to DHT. Objective: Our purpose was to determine whether finasteride treatment leads to clinical improvement in men with male pattern hair loss. Methods: In two 1-year trials, 1553 men (18 to 41 years of age) with male pattern hair loss received oral finasteride 1 mg/d or placebo, and 1215 men continued in blinded extension studies for a second year. Efficacy was evaluated by scalp hair counts, patient and investigator assessments, and review of photographs by an expert panel. Results: Finasteride treatment improved scalp hair by all evaluation techniques at 1 and 2 years (P < .001 vs placebo, all comparisons). Clinically significant increases in hair count (baseline = 876 hairs), measured in a 1-inch diameter circular area (5.1 cm2 ) of balding vertex scalp, were observed with finasteride treatment (107 and 138 hairs vs placebo at 1 and 2 years, respectively; P < .001). Treatment with placebo resulted in progressive hair loss. Patients’ self-assessment demonstrated that finasteride treatment slowed hair loss, increased hair growth, and improved appearance of hair. These improvements were corroborated by investigator assessments and assessments of photographs. Adverse effects were minimal. Conclusion: In men with male pattern hair loss, finasteride 1 mg/d slowed the progression of hair loss and increased hair growth in clinical trials over 2 years. (J Am Acad Dermatol 1998;39:578-89.)
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To investigate the relation between androgens and hair growth, testosterone-1,2-³H metabolism was assessed under standardized conditions in growing (anagen) and resting (telogen) hair roots from 10 anatomical sites from 4 women and 14 men, 6 of whom had varying degrees of male pattern baldness. A micromethod was developed to quantitate androgen metabolism in only a few hair roots. In all hairs examined, 5α-reduced and 17-ketosteroids were the major metabolites of testosterone. No significant relation was found between androgen-mediated growth of hair and the capacity to form 5α-metabolites, e.g., scalp hair of women performed 5α-reduction to approximately the same degree as beard hair from men. The formation of 17-ketometabolites was decreased in telogen hairs from all body sites, whereas the formation of dihydrotestosterone was decreased in telogen hairs only from the scalp. In general a higher formation of 5α-reduced metabolites and 17-ketosteroid metabolites was observed at all sites of the scalp of bald men as compared to hair obtained from the corresponding sites of women and nonbalding men, and a significantly higher rate of metabolism was found at the frontal area of the bald men. It is not clear at present whether these changes are secondary to the balding process or are related causally to the hair loss. On the basis of these studies it is concluded that regional differences in androgen-mediated hair growth cannot be the result of variations in testosterone metabolism in the hair follicles.
Article
Objective To investigate the possible role of the maternal diet, particularly vegetarianism and consumption of phytoestrogens, in the origin of hypospadias, which is reported to be increasing in prevalence. Subjects and methods Detailed information was obtained prospectively from mothers, including previous ob-stetric history, lifestyle and dietary practices, using structured self-completed questionnaires during pregnancy. Previously recognized associations with en-vironmental and parental factors were examined, focusing particularly on the hypothesized hormonal link. Multivariate logistic regression was used to identify independent associations. Results Of 7928 boys born to mothers taking part in the Avon Longitudinal Study of Pregnancy and Childhood, 51 hypospadias cases were identified. There were no significant differences in the proportion of hypospadias cases among mothers who smoked, consumed alcohol or for any aspect of their previous reproductive history (including the number of previous pregnancies, number of miscarriages, use of the contraceptive pill, time to conception and age at menarche). Significant differences were detected for some aspects of the maternal diet, i.e. vegetarianism and iron supplementation in the first half of pregnancy. Mothers who were vegetarian in pregnancy had an adjusted odds ratio (OR) of 4.99 (95% confidence interval, CI, 2.10–11.88) of giving birth to a boy with hypospadias, compared with omnivores who did not supplement their diet with iron. Omnivores who supplemented their diet with iron had an adjusted OR of 2.07 (95% CI, 1.00–4.32). The only other statistically significant association for hypospadias was with influenza in the first 3 months of pregnancy (adjusted OR 3.19, 95% CI 1.50–6.78). Conclusion As vegetarians have a greater exposure to phytoestrogens than do omnivores, these results support the possibility that phytoestrogens have a deleterious effect on the developing male reproductive system.
Article
Female mice deficient in steroid 5 alpha-reductase type 1 have a decreased litter size. The average litter in homozygous deficient females is 2.7 pups vs. 8.0 pups in wild type controls. Oogenesis, fertilization, implantation, and placental morphology appear normal in the mutant animals. Fetal loss occurs between gestation days 10.75 and 11.0 commensurate with a midpregnancy surge in placental androgen production and an induction of 5 alpha-reductase type 1 expression in the decidua of wild type mice. Plasma levels of androstenedione and testosterone are 2- to 3-fold higher on gestation day 9, and estradiol levels are chronically elevated by 2- to 3-fold throughout early and midgestation in the knockout mice. Administration of an estrogen receptor antagonist or inhibitors of aromatase reverse the high rate of fetal death in the mutant mice, and estradiol treatment of wild type pregnant mice causes fetal wastage. The results suggest that in the deficient mice, a failure to 5 alpha-reduce androgens leads to their conversion to estrogens, which in turn causes fetal death in midgestation. These findings indicate that the 5 alpha-reduction of androgens in female animals plays a crucial role in guarding against estrogen toxicity during pregnancy.
Article
We determined whether 5a-reductase type 2 mutations are present in boys with isolated hypospadias. Penile skin tissues obtained at surgery during hypospadias repair were examined for 5alpha-reductase type 2 mutations by single strand conformational polymorphism and deoxyribonucleic acid sequence analysis. Clinical data, including family history of hypospadias and preoperative position of the urethral meatus, were correlated with the genetic findings. Of the 81 specimens examined 7 (8.6%) involved a mutation in at least 1, 5alpha-reductase type 2 gene, while 2 patients had mutations in both alleles. The mutations identified were A49T, L113V and H231R. The A49T mutation in 5 patients was the most common (71%) and it was generally present in less severe forms of hypospadias. To our knowledge neither the A49T nor the L113V mutation has been previously reported in association with 5alpha-reductase type 2 deficiency and to date they have only been identified in cases of isolated hypospadias. Family history was negative in the 7 patients with 5a-reductase type 2 mutations but positive in 5 without mutations. Some boys with isolated hypospadias have a mutation in at least 1 gene for 5alpha-reductase type 2. This finding suggests that a partial deficiency of 5alpha-reductase activity and inadequate levels of dihydrotestosterone in the fetal urethra may be sufficient to cause the phenotype of hypospadias without other clinical features of 5alpha-reductase deficiency. Family history may not be reliable for determining which boys with hypospadias are likely to have such mutations.
Article
The conversion of testosterone into dihydrotestosterone by steroid 5 alpha-reductase is a key reaction in androgen action, and is essential both for the formation of the male phenotype during embryogenesis and for androgen-mediated growth of tissues such as the prostate. Single gene defects that impair this conversion lead to pseudohermaphroditism in which 46X,Y males have male internal urogenital tracts, but female external genitalia. We have described the isolation of a human 5 alpha-reductase complementary DNA from prostate. Subsequent cloning and genetic studies showed that this gene (designated 5 alpha-reductase 1) was normal in patients with 5 alpha-reductase deficiency. We report here the isolation of a second 5 alpha-reductase cDNA by expression cloning and the polymerase chain reaction. The biochemical and pharmacological properties of this cDNA-encoded enzyme (designated 5 alpha-reductase 2) are consistent with it being the major isozyme in genital tissue. A deletion in this gene is present in two related individuals with male pseudohermaphroditism caused by 5 alpha-reductase deficiency. These results verify the existence of at least two 5 alpha-reductases in man and provide insight into a fundamental hormone-mediated event in male sexual differentiation.
Article
We have previously shown that [2'-P-32]-2-azido-NADP(+) is an effective probe of the NADP-(H) binding site of rat liver microsomal 5 alpha-reductase (5 alpha R-1) [Bhattacharyya et al. (1994) Steroids 59, 634-641]. PEG-fractionated (6.5%) detergent-solubilized preparations (40 mg) containing 5 alpha R-1 activity were W-photolyzed with [P-32]-2-azido-NADP(+) and subjected to preparative gel electrophoresis on 8% SDS-PAGE. Fractions corresponding to the second major [P-32]-labeled peak following the dye-front were analyzed by 10% SDS-PAGE and showed a single [P-32]-labeled species with an apparent molecular mass of similar to 26 kDa (5 alpha R-1). TCA precipitation (13.6%) of the labeled fractions resulted in recovery of >70% of the total radioactivity in the protein pellet. Trypsin digestion of the resuspended pellet followed by immobilized-Al3+ affinity chromatography indicated that >90% of the radioactivity remained bound to the affinity column. The [P-32]-2N(3)-NADP(+)-labeled peptide was eluted with potassium phosphate, concentrated, and further purified by reverse-phase (C-8) HPLC. Sequence analysis of the purified peptide indicated that it consisted of 11 amino acids with the sequence N-L-R-K-P-G-E-T-G-Y-K, corresponding to residues 170-180 of the rat 5 alpha R-1 sequence
Article
The enzyme steroid 5 alpha-reductase utilizes NADPH to reduce the double bonds of a variety of steroid substrates with generalized 3-oxo, Delta(4,5) structures. One substrate for this membrane-bound enzyme is testosterone, whose reduction to dihydrotestosterone is required for the embryonic differentiation of the external male genitalia and prostate. There are two 5 alpha-reductase isozymes, designated types 1 and 2, which have different biochemical and pharmacological properties. Inherited deficiencies of 5 alpha-reductase type 2 result in a form of male pseudohermaphroditism in which the external genitalia fail to develop normally. Here, nine additional mutations in the 5 alpha-reductase 2 gene in subjects with 5 alpha-reductase deficiency are described. The biochemical consequences of these mutations, as well as 13 previously identified missense mutations, were characterized by recreating the mutations in an expressible cDNA and transfecting into mammalian cells. Twelve of the 22 mutations inactivated the enzyme. The remaining 10 mutations impaired enzyme function by affecting either substrate or cofactor binding. Almost all mutations decreased the half-life of the protein, and all but one of the impaired enzymes had an altered pH optimum. The mutations provide insight into functional domains in the protein as well as an unusual acidic pH optimum characteristic of the 5 alpha-reductase type 2 isozyme.
Article
Green tea catechins (GTCs), which include (−)-epicatechin (EC), (−)-epicatechin gallate (ECG), (−)-epigallocatechin (EGC) and (−)-epigallocatechin gallate (EGCG), possess a variety of biological activities. We have previously studied the effect of dietary GTCs as a mixture on membrane oxidation of red blood cells and found that GTCs were partially absorbed and detected in the blood of rats given an oral ingestion of 100 mg of GTCs. To explain the partial absorption of GTCs and their varying free-radical scavenging capacity at different pH, the present paper was to study further the pH stability of these GTC isomers because there is a sharp increase in pH from the acidic stomach to the slightly alkaline intestine. Longjing GTCs as a mixture in alkaline solutions (pH > 8) were extremely unstable and degraded almost completely in a few minutes, whereas in acidic solutions (pH < 4) they were very stable. For the pH between 4 and 8, the stability of GTCs was pH-dependent, i.e., the lower the pH, the greater the stability. Four epicatechin isomers examined demonstrated varying stability in alkaline solutions with EGCG and EGC being equally instable, and EC and ECG being relatively stable. The present results suggest that part of the mechanism by which GTCs were partially absorbed may be attributed to instability of EGCG and EGC in the intestine where the pH is neutral or alkaline. Keywords: Epicatechin; epicatechin gallate; epigallocatechin gallate; epigallocatechin; longjing tea
Article
The degradation kinetics of (−)-epigallocatechin gallate (EGCG) as a function of pH (4 to 7) and dissolved oxygen concentration (0 to 7.59 mg/L) in citrate buffer solutions were determined. EGCG degradation followed a pseudofirst order kinetic model, regardless of the conditions when the fractional conversion technique was applied for data reductions. The rate constant increased log-linearly with respect to both pH and dissolved oxygen concentration. The temperature dependence of the rate constant was adequately modeled by the Arrhenius equation with an average activation energy of 18.7 ± 1 kcal/mol. A mathematical model that relates the rate constant to temperature, pH, and dissolved oxygen concentration was developed and validated. These results can help predict losses of EGCG during processing and/or storage.
Article
Inhibitors of 5 α-reductase may be effective in the treatment of 5 α-dihydrotestosterone-dependent abnormalities, such as benign prostate hyperplasia, prostate cancer and certain skin diseases. The green tea catechins, (−)epigallocatechin-3-gallate and (−)epicatechin-3-gallate, but not (−)epicatechin and (−)epigallocatechin, are potent inhibitors of type 1 but not type 2 5α-reductase. (−)Epigallocatechin-3-gallate also inhibits accessory sex gland growth in the rat. These results suggest that certain tea gallates can regulate androgen action in target organs.
Article
A rat cell line has been isolated which is (a) highly transfectable by exogenous DNA, (b) lacking in appreciable levels of nuclear thymidine kinase, and (c) phenotypically “normal” by all criteria tested. This cell line should prove useful for nonselective transfection of genetic information, particularly potentially transforming viral or cellular sequences, through cotransfection with a thymidine kinase gene.
Article
The hydrogen peroxide (H2O2)-generating effects of 14 flavonoids were investigated. Seven out of 14 flavonoids tested were found to generate H2O2 in an acetate buffer of pH 7.4. The H2O2-generating abilities of flavonoids decrease in the order of myricetin > baicalein > quercetin > (-)-epicatechin > (+)-catechin > fisetin = 7,8-dihydroxy flavone. This ability was observed in flavonoids with either a pyrogallol or catechol structure, and the pyrogallol-type flavonoids generated more H2O2 than the catechol-types. The amount of H2O2 generated by myricetin (pyrogallol-type flavonoid) was proportional to its concentration and to the reaction time until about 4 h. In addition, H2O2 generation by myricetin was dependent on the amount of dissolved oxygen in the buffer, and it was inhibited by the addition of superoxide dismutase. These results suggest that the flavonoids generate H2O2 by donating a hydrogen from their pyrogallol or catechol structure to oxygen, through a superoxide anion radical. It was also found that flavonoids which generated more H2O2 were more powerful antioxidants in the NADPH-dependent lipid peroxidation of rat microsomes.
Article
The concentrations of testosterone, androstenedione and dihydrotestosterone (DHT) in the plasma and 5α-androstane-3α,17β-diol (androstanediol) in the urine were measured in 40 women with hirsutism of ovarian, adrenal and idiopathic origin. Conversion of [ ³ H]testosterone to DHT, 3α- and 3β-androstanediols was also studied in homogenates of pubic skin obtained from 15 of the patients. Results were compared with values obtained from normal men and women. Values for the levels of testosterone, DHT and androstenedione in the plasma and androstanediol in the urine of hirsute women were all above control levels, especially for plasma androstenedione and urinary androstanediol ( P < 0·001). This finding was particularly marked in patients with hirsutism of ovarian origin. Conversion of [ ³ H]testosterone to 5α-reduced metabolites by homogenates of skin obtained from hirsute women was significantly greater than by homogenates of skin from normal women ( P < 0·001) but was the same as the value for normal men. The highest values for conversion were obtained from the patients with idiopathic hirsutism. These results indicate that androstenedione is the principal androgen secreted in hirsutism. In sexual skin this steroid may be converted to DHT and 3α-, and 3β-androstanediols and the increased activity of testosterone 5α-reductase may result in an exaggerated 'utilization' of androstenedione in this tissue. The high rate of excretion of androstanediol in the urine of patients with idiopathic hirsutism may be explained by the fact that this steroid is an end-product of testosterone metabolism.
Article
The incidence of prostate cancer varies widely between countries and ethnic groups. Black-Americans have the highest incidence rates world wide, whereas native Japanese have among the lowest. The reasons for this risk differential are unknown, although we have previously shown that higher circulating testosterone concentrations in young adult black men compared with young adult white men may explain the underlying differences in subsequent prostate cancer incidence between these two populations. We have now compared serum testosterone concentrations in young adult Japanese men with those of young adult whites and blacks, but found no significant differences. However, these white and black men had significantly higher values of 3 alpha, 17 beta androstanediol glucuronide (31% and 25% higher, respectively) and androsterone glucuronide (50% and 41% higher, respectively) than Japanese subjects. These two androgens are indices of 5 alpha-reductase activity. Our results raise the possibility that reduced 5 alpha-reductase activity has a role in producing the low prostate cancer incidence rates among Japanese. This finding may have important implications for prostate cancer prevention.
Article
Finasteride (Proscar--an orally active 5 alpha-reductase enzyme inhibitor) blocks the conversion of testosterone to dihydrotestosterone. The effects of finasteride in patients with benign prostatic hyperplasia were investigated in 2 double-blind, placebo-controlled studies. In study 1, 86 patients were treated with placebo or finasteride (5 to 80 mg. per day) for 12 weeks, followed by a 12-week drug-free period. After 12 weeks of treatment all doses of finasteride showed significant decreases in prostate volume. However, 12 weeks after discontinuation of finasteride prostate volume returned to near baseline values. In study 2, 104 patients were treated with placebo or finasteride (0.2 to 40 mg. per day) for 24 weeks. After 24 weeks of finasteride treatment prostate volume showed a mean decrease of 24% and 28% (p less than 0.01) in the 1 and 5 mg. groups, respectively. Lower doses had a lesser effect on prostate shrinkage. Maximum urinary flow showed a mean increase of 3.7 cc per second when the 1 and 5 mg. groups were combined. Symptom improvement was observed in the 1 and 5 mg. groups, although this was not statistically different from the placebo group due to the small sample size.