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A scientific basis for therapeutic effects of Pygeum africanum and Serenoa repens
Abstract
In Europe, phytotherapeutic preparations have been prescribed for the treatment of symptomatic benign prostatic hyperplasia (BPH) for over 20 years [l–4]. In these countries, phytotherapeutic preparations represent approximately l/3 of total sales of all therapeutic agents sold for the treatment of BPH. In France, and other countries, phytotherapeutic preparations are the most widely used drugs for the treatment of BPH. In Asia, Africa, and India, phytotherapy is considered a first-line treatment for BPH and has been utilized effectively for centuries. In the United States, the multi-million dollar sales of phytotherapeutic preparations for “the health of the prostate and bladder” attests to the widespread utilization of these agents [3, 4].
Two of the most popular phytotherapeutic agents that have undergone both clinical studies to determine their efficacy, and have been the subject of basic science studies to identify the mechanism(s) of action are Pygeum africanum (Tadenan), an extract from the bark of the African plum tree, and Serenoa repens (Permixon), a lipido-sterol extract of dwarf palm. Tadenan and Permixon are registered therapeutic agents of Debat Pharmaceuticals, and Pierre Fabre Medicament, respectively. Manufacture of both preparations are tightly controlled and subjected to strict quality control for stability of component composition. In regard to phytotherapeutic agents, each individual preparation (even from the same plant source) must be considered individually because of differences in the extraction techniques, preparation of products, composition, and biological activities. Thus, the clinical and biological activities of one preparation cannot be extrapolated to other preparations of the same plant source. Thus, studies described in this review which utilize the preparations that are manufactured by DEBAT (Pygeum africanum) or Pierre Fabre Medicament (Serenoa repens) are referred to by their trade names, Tadenan and Permixon, to differentiate them from other nonstandardized preparations of the same plants.
... La somiglianza dei sintomi del tratto urinario inferiore associati alla prostatite cronica con quelli causati dall'iperplasia (o ipertrofia) prostatica benigna (IPB) e la relativa efficacia dei fitoterapici nel migliorare la sintomatologia legata a quest'ultima giustificano il loro uso nella terapia delle CP/CPPS. Benché si ritenga che alcuni fitoterapici siano attivi a livello ormonale, sembra in realtà che molti di questi preparati esercitino un'azione prevalentemente antinfiammatoria il cui preciso meccanismo cellulare e molecolare non è sempre ben caratterizzato 349 . I dati di letteratura sulla loro efficacia non sono numerosi e il quadro derivante degli studi clinici non è sempre chiaro. ...
... es., licopene, selenio, zinco, ecc.). La SR è stata oggetto di intense ricerche per il trattamento dei sintomi dell'ipertrofia prostatica benigna e, più recentemente, delle CP/CPPS e delle infezioni del tratto urinario, in monoterapia o in associazione, in studi comparativi con altri fitoterapici, antibiotici, α-bloccanti, antinfiammatori o inibitori della 5α reduttasi 349,350 . ...
... Il meccanismo d'azione della SR a livello molecolare non è certo. I meccanismi generalmente proposti includono l'inibizione dei recettori degli androgeni (effetto antiandrogeno), l'inibizione dell'attività dei fattori di crescita (effetto antiproliferativo) e la riduzione dei prodotti generati dalla arachidonato 5-lipossigenasi (effetto antinfiammatorio) 349,350,352,353 . Le prove esistenti sull'attività antiandrogena ed antiproliferativa della SR attraverso l'inibizione della 5-α reduttasi sembrano essere piuttosto contrastanti 354,355 . ...
... For centuries phytotherapy is considered a first line treatment for BPH in Asia, Africa and India. Also in Europe and in the United States medicinal plants have been used even more extensively the last decades [21]. ...
... In this study we wanted to gain some insights into the action of AA. The data reveal that the novel F o r P e e r R e v i e w 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 ...
... The cells were trypsinized and counted using a counting cell chamber (Double Neubauer, Brand, Germany) at the indicated times. 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 F o r P e e r R e v i e w Nuclear extract preparation LNCaP cells reaching 50 % confluency were washed three times in PBS and RPMImedium supplemented with 2 % (v/v) charcoal-dextran-stripped fetal bovine serum was added. After 3 days of cultivation the cells were treated with the indicated hormones for 1 hr. ...
Extracts from Pygeum africanum are used in the treatment of prostatitis, benign prostatic hyperplasia and prostate cancer (Pca), major health problems of men in Western countries. The ligand-activated human androgen receptor (AR) supports the growth of the prostate gland. Inhibition of human AR by androgen ablation therapy and by applying synthetic anti-androgens is therefore the primary goal in treatment of patients. Here, we show that atraric acid (AA) isolated from bark material of Pygeum africanum has anti-androgenic activity, inhibiting the transactivation mediated by the ligand-activated human AR. This androgen antagonistic activity is receptor specific and does not inhibit the closely related glucocorticoid or progesterone receptors. Mechanistically, AA inhibits nuclear transport of AR. Importantly, AA is able to efficiently repress the growth of both the androgen-dependent LNCaP and also the androgen-independent C4-2 Pca cells but not that of PC3 or CV1 cells lacking AR. In line with this, AA inhibits the expression of the endogenous prostate specific antigen gene in both LNCaP und C4-2 cells. Analyses of cell invasion revealed that AA inhibits the invasiveness of LNCaP cells through extracellular matrix. Thus, this study provides a molecular insight for AA as a natural anti-androgenic compound and may serve as a basis for AA derivatives as a new chemical lead structure for novel therapeutic compounds as AR antagonists, that can be used for prophylaxis or treatment of prostatic diseases.
... PCa as well as BPH are also treated with inhibitors (e.g. finasteride) of the 5α-reductase, the enzyme that converts testosterone into its more active metabolite DHT (Levin and Das, 2000). A decrease of the total level of androgens and a shrinkage of the prostate are the consequence (Levin and Das 2000). ...
... finasteride) of the 5α-reductase, the enzyme that converts testosterone into its more active metabolite DHT (Levin and Das, 2000). A decrease of the total level of androgens and a shrinkage of the prostate are the consequence (Levin and Das 2000). Finasteride only targets one of the two isoforms of the 5α-reductase and therefore is not sufficient to block androgens levels, especially in advanced PCa (Vis and Schröder, 2009). ...
... Since the late 1960´s bark extracts of Pygeum africanum are used in Europe to treat BPH (Isaacs, 1990). In France Pygeum africanum is the most commonly used medicine for BPH (Ishani et al., 2000;Levin and Das, 2000). Herby, the pulverized bark is incorporated into capsules and commercially available as the remedy Tadenan ® and in other European countries under various different trade names (Ishani et al., 2000). ...
Extracts from the plant Pygeum africanum are widely used in the therapy of benign prostate hyperplasia (BPH) and in combinational therapy for prostate cancer, the second leading cause of cancer death and the mostly diagnosed form of cancer in men. The androgen receptor (AR) plays a crucial role in the development of the prostate as well as in prostate diseases. Even though the extracts from P. africanum are considered as beneficial for prostate diseases in clinical trials, and some active compounds for treatment of BPH could be identified, compounds responsible for AR inhibition and the molecular mechanism for inhibition of prostatitis need to be identified. Recently, atraric acid and N-butylbenzene-sulfonamide were isolated from a selective dichlormethane extract of P. africanum as two novel AR antagonistic compounds. The molecular mechanisms of AR inhibition were analyzed and are summarized here. Both compounds are the first known natural, complete and specific AR antagonist.
... Among the therapeutical alternatives for the treatment of BPH, the lipidosterolic extract from the dwarf palm S. repens (Permixon®) has been studied thoroughly for many years and has been prescribed for treatment of LUTS associated with BPH in Europe [17][18][19][20]. It is known that S. repens acts in prostaglandin metabolism in cultured prostatic cells, has anti-inflammatory activity in prostate tissue by inhibiting cyclooxygenases [21], modulates activity of human 5α-reductase [21,22], has anti-proliferative activity by modulating FGF-2 and VEFG, exerts anti-edema effects in animals [23,24], and has anti-estrogenic activity [25]. Moreover, a double-blind multicenter trial in 1,098 patients showed that compared with finasteride, the extract of S. repens has similar efficacy with less adverse effects [26]. ...
... Among the therapeutical alternatives for the treatment of BPH, the lipidosterolic extract from the dwarf palm S. repens (Permixon®) has been studied thoroughly for many years and has been prescribed for treatment of LUTS associated with BPH in Europe [17][18][19][20]. It is known that S. repens acts in prostaglandin metabolism in cultured prostatic cells, has anti-inflammatory activity in prostate tissue by inhibiting cyclooxygenases [21], modulates activity of human 5α-reductase [21,22], has anti-proliferative activity by modulating FGF-2 and VEFG, exerts anti-edema effects in animals [23,24], and has anti-estrogenic activity [25]. Moreover, a double-blind multicenter trial in 1,098 patients showed that compared with finasteride, the extract of S. repens has similar efficacy with less adverse effects [26]. ...
PurposeTomato is an important source of lycopene, a carotenoid that has been emerging as a natural preventive agent for prostate disease. Moreover, tomato contains other components with a wide range of physiological properties, but their potential beneficial effects on prostatic hyperplasia (PH) during obesity have not been completely established. In this study, we compared the effect of a lipidic extract of tomato saladette (STE) with Serenoa repens (SR) on obese rats with PH.Methods
Forty-eight Wistar rats were divided in Control (C) and Obese (Ob) treated without (n = 12) and with (n = 36) testosterone enanthate (TE), once a week for 8 weeks to induce PH. After 4 weeks, SR and STE were administered. Biochemical parameters, oxidative stress markers and inflammatory cytokines production were determined.ResultsTE increased prostate weight and caused prostatic hyperplasia in C group, and these effects were exacerbated by obesity. SR and STE reverted the increase in prostate weight and hyperplasia caused by TE in C and Ob groups. Obesity increased LDL, TGs, NOx and MAD, but decreased HDLc, GSx, SOD and CAT. SR reverted the effects of obesity, but these were significantly reduced and HDLc increased with STE. Obesity and TE increased TNFα, IL-1β and IL-6 levels, but these were partially reverted by STE compared with SR.Conclusions
Excess of fat tissue increases the alterations by PH. STE diminishes these alterations compared with SR, suggesting its beneficial effect to improve prostate function. Whole tomato lipid extract could serve as sole therapy or as an adjunct to pharmacological treatment for PH.
... Среди ненасыщенных жирных кислот преобладает олеиновая кислота (28%), в значительно меньшем количестве содержится линолевая кислота (4,6%) и в минимальном -линоленовая кислота (0,6%). В минимальных количествах SRE также содержат: жирные спирты (гексакозаноловый, октакозаноловый, тетракозаноловый и триконтаноловый -0,146 -0,003%) и стеролы (кампрестерол, стигмастерол и β-стигмастерол -0,22 -0,03%) [9,10]. ...
... По данным этих авторов, содержание свободных жирных кислот варьировало от 40,7% до 80,7%, метиловых и этиловых эфиров этих кислот -от 1,5% до 16,7%, а их глицеридных форм -от 6,8% до 52,2% [10]. Такие различия могут быть связаны с источниками сырья, видом их обработки, методом экстракции и могут влиять на биологическую эффективность препаратов [9]. ...
Introduction. The review analyzes the clinical efficacy and mechanism of action of lipidsterol extracts of the American dwarf palm fruit Serenoa repens (SRE), including the drug Permixon (Pierre Fabre), used for the treatment of urination disorders in men with benign prostatic hyperplasia (BPH). Material and methods. When writing the review, data from the PubMed database was used (https://www.ncbi.nlm.nih.gov/pubmed/) and scientific electronic library Elibrary.ru (https://elibrary.ru/). Search keywords for articles on the review topic were «BPH», «therapy of urinary dysfunction», «Serenoa repens», «Permixon», «mechanism of action», «bladder receptors». As a result, 48 publications were selected in peerreviewed foreign and domestic journals. Results. It is noted that the composition of extracts from different manufacturers and for different types of extraction (supercritical fluid extraction with carbon dioxide under high pressure, extraction with hexane, ethanol or diethyl ether) differs significantly, which may affect the effectiveness of therapy. At the same time, according to the authors, the greatest effect is observed when using preparations with hexane extraction of SRE components, which include Permixon. The main ingredients that provide antiandrogenic, adreno- and cholinolytic and antiinflammatory effects of SRE drugs were determined. Analysis of the effectiveness of the Permixon in the form of monotherapy, in comparison with the traditionally used α-blockers and in combination with them, showed a significant improvement in the quality of urination in patients with BPH during treatment with this drug, comparable to the effect of α-blockers. Data are discussed indicating that the mechanism of action of SRE can be associated not only with the effect on the prostate gland, but also on the bladder, improving the contractile function of detrusor due to α-adrenolytic, M-cholinolytic and antiinflammatory actions, which helps to reduce the dysfunction of urine accumulation in the spectrum of lower urinary tract symptoms. Conclusion. The mechanisms of action of SRE in LUTS/BPH should be considered more broadly and comprehensively, including the possible effect of drugs not only on the prostate, but also on the obstructive bladder. However, there are few objective data on this issue, which requires new special studies.
... The first one is a lipidosterolic extract of Serenoa repens (SR), while the second one consists of a combined formulation containing a fruit extract of Serenoa repens and a root extract of Urtica dioica (SR/UD). Particularly, the fruit extract of Serenoa repens has been indicated by several studies as a potential treatment for BPH [15][16][17][18]. The positive effect of this plant extract is due both to the direct inhibition of 5α-reductase and to the prevention of inflammation [19,20]. ...
... Furthermore, we compared it with another approved drug for BPH treatment, consisting of an esanic fruit extract of Serenoa repens (SR). Previous studies on Serenoa repens proved its ability to ameliorate inflammation and to prevent ROS production in the BPH scenario [15][16][17][18]. Urtica dioica was indicated to possess anti-inflammatory activity as well [40]. ...
Benign prostatic hyperplasia (BPH) is an age-related chronic disorder, characterized by the hyperproliferation of prostatic epithelial and stromal cells, which drives prostate enlargement. Since BPH aetiology and progression have been associated with the persistence of an inflammatory stimulus, induced both by Nuclear Factor-kappa B (NF-κB) activation and reactive oxygen species (ROS) production, the inhibition of these pathways could result in a good tool for its clinical treatment. This study aimed to evaluate the antioxidant and anti-inflammatory activity of a combined formulation of Serenoa repens and Urtica dioica (SR/UD) in an in vitro human model of BPH. The results confirmed both the antioxidant and the anti-inflammatory effects of SR/UD. In fact, SR/UD simultaneously reduced ROS production, NF-κB translocation inside the nucleus, and, consequently, interleukin 6 (IL-6) and interleukin 8 (IL-8) production. Furthermore, the effect of SR/UD was also tested in a human androgen-independent prostate cell model, PC3. SR/UD did not show any significant antioxidant and anti-inflammatory effect, but was able to reduce NF-κB translocation. Taken together, these results suggested a promising role of SR/UD in BPH and BPH-linked disorder prevention.
... απόφραξη όσο και στην δευτεροπαθή φλεγµονή. Η αποτελεσµατικότητα των φυτοθεραπευτικών στα συµπτώ µατα που συνδέονται µε την καλοήθη υπερτροφία του προστάτη δικαιολογεί την τη χρήση τους στη θεραπεία της χρόνιας προστατίτιδας 6 . Το πιο γνωστό φυτοθεραπευτικό είναι το serenoa repens, συστατικό του οξύφυλλου φυτού saw palmetto. ...
... Το πιο γνωστό φυτοθεραπευτικό είναι το serenoa repens, συστατικό του οξύφυλλου φυτού saw palmetto. Περιέχει λιπαρά οξέα φυτοστερόλες και βιταµίνες Δεν είναι απόλυτα εξακριβωµένος ο ακριβής µηχανισµός του ωστόσο ωφείλεται σε ορµονικά και µη ορµονικά διαµεσο λαβούµενη αντιφλεγµονώδη δράση 6 . Η πρώτη σχετίζεται µε την αναστολή της µετατροπής της τεστοστε ρόνης στο ισχυρότερο ανδρογόνο την DHT στο επίπεδο των ανδρογονικών υποδοχέων. ...
Introduction. Chronic prostatitis displays a variety of symptoms (mainly local pain xhibiting variability in origin and intensity). The purpose of this article is to briefly present the liminary results of our study examining the role of phytotherapeutic agents in the treatment of hronic prostatitis patients. Patients and Methods. The study was designed as a prospective, mized, single blind and included in total fifty-six patients who visited the outpatient department. Subjects were randomized in two groups. Subjects of the first group (29 patients) received prulifloxacin 600mg for 15 days, while subjects of the second group (27 patients) received prulifloxacin 600mg for 15 days and serenoa repens extract for 8 weeks. The response was tested with laboratory and clinicalcriteria. Results. We found statistically significant differences between the two groups regarding pain and discomfortin urination but no differences were found regarding erectile or sexual sfunction. Conclusions. Serenoarepens extract for 8 weeks seems to improve pain and prostatitis related difficulty in urination. Further random
... Similar symptoms are also encountered in benign prostatic hypertrophy and are attributed to both obstruction and secondary inflammation. The effectiveness of phytotherapeutic agents used for symptoms related to benign prostatic hypertrophy justifies their use in the treatment of chronic prostatitis (6). The best known phytotherapeutic is Serenoa repens, a constituent of the acid-loving plant saw palmetto. ...
... It contains fatty acids, phytosterols and vitamins. Its mechanism of action has not been fully elucidated, however is attributed to hormonally and non-hormonally mediated anti-inflammatory activity (6). The former is related to the inhibition of conversion of testosterone to the more potent antiandrogen dihydrotestosterone at the level of androgen receptors. ...
Introduction:
Chronic prostatitis displays a variety of symptoms (mainly local pain exhibiting variability in origin and intensity). The purpose of this article is to briefly present the preliminary results of our study examining the role of phytotherapeutic agents in the treatment of chronic prostatitis patients.
Materials and methods:
The study included in total fifty-six consecutive patients who visited the outpatient department. Subjects were randomized into two groups. Subjects in the first group (28 patients) received prulifloxacin 600 mg for 15 days, while subjects in the second group (28 patients) received prulifloxacin 600 mg for 15 days and Serenoa repens extract for 8 weeks. The response was tested using laboratory and clinical criteria.
Results:
We found statistically significant differences between the two groups regarding pain regression and no statistically significant regarding bacterial eradication. Moreover however while sexual dysfunction improvement was equally achieved in both groups, improvement of urinary symptoms was more evident in the 2nd group especially after the completion of the antibiotic treatment.
Conclusions:
Serenoa repens extract for 8 weeks seems to improve prostatitis related pain. Further randomized, placebo-controlled studies are needed to substantiate safer conclusions.
... В минимальных количествах присутствуют: жирные спирты (гексакозаноловый, октакозаноловый, тетракозаноловый и триконтаноловый) и фитостеролы. Фитостеролы представлены в основном бетта-ситостеролом (более 80% от фитостеролов), а также кампестеролом и стигмастеролом и β-стигмастерол [30,[32][33][34][35]. ...
Introduction. Among the existing methods of surgical treatment of patients with benign prostatic hyperplasia (BPH) transurethral resection (TUR) of the prostate is the most widely used. Due to the long-term improvement of the technique, non-lethal complications are now more characteristic of this operation. These include postoperative urinary incontinence, which dramatically reduces the quality of life of patients and casts doubt on the effectiveness of the operation performed. Stress urinary incontinence, the most common type of disorder, basically has sphincter insufficiency associated with iatrogenic damage to the external closure apparatus of the bladder when it goes beyond the distal border of resection in TUR BPH. However, an equally important role in the genesis of sphincter insufficiency belongs to the inflammatory process, which always accompanies trauma to muscle structures during surgery. The aim of this prospective study was to improve outcomes in patients with urinary incontinence after TUR BPH. Materials and methods. The study involved 86 patients who underwent TUR BPH, with the leading complaint of urinary incontinence. Patients were divided into 2 groups, initially comparable in terms of the main evaluated criteria. Patients of the first (control) group (n=30) received complex antibacterial and anti-inflammatory therapy, according to indications - alpha-blockers, prostatotropic regulatory biopeptides and enzyme preparations, in the presence of a hyperactivity component – M-anticholinergics and / or a selective agonist of β3 adrenoreceptors. Patients of the second (main) group (n=56) for the purpose of long-term anti-inflammatory effects and reduce the pharmacological load additionally received the phytocomplex «Profilaprost» 1 capsule per day for 2 months. Result. In the main group of patients who received the «Profilaprost» complex, after 2.5 months from the start of therapy, we recorded an improvement in the reservoir function of the bladder. In 65% of patients, complete continence was achieved, in 20% – stabilization of incontinence at a mild degree, requiring no more than one safety pad per day, in another 10% the result can be described as not quite satisfactory – the frequency and degree of incontinence decreased, but persisted the level of symptoms was considered unacceptable by the patients and insisted on continuing treatment. And only in 5% of patients, complex therapy had no effect. A decrease in IPSS and QoL indices, an improvement in continence significantly correlated with a decrease in the degree of leukocyturia. Conclusion. The herbal-mineral complex «Profilaprost» showed good efficacy with no side effects and adverse events in the treatment of urinary incontinence after TURP.
... In addition to conventional pharmacological therapy, the number of men interested in or currently using phytotherapy for BPH/LUTS as alternative and/or complementary treatments is increasing steadily worldwide [17]. The rational use of plant extracts in LUTS/BPH relies, at least in vitro, on (i) anti-inflammatory, anti-androgenic and estrogenic effects; (ii) inhibition of lipoxygenase, aromatase, growth factor-stimulated proliferation of prostatic cells, α1-adrenoceptor, 5α-reductase, and vanilloid receptors; (iii) reduction of sexual hormone binding globulin; (iv) neutralization of free radicals [9,[17][18][19]. ...
We aim to assess the effect of Cavacurmin® on prostate volume (PV), lower urinary tract symptoms (LUTS) and micturition parameters in men after 1 year of therapy. From September 2020 to October 2021, data from 20 men with LUTS/benign prostatic hyperplasia and PV ≥40 mL who were on therapy with α1-adrenoceptor antagonists plus Cavacurmin® were retrospectively compared with 20 men on only α1-adrenoceptor antagonists. Patients were evaluated at baseline and after 1 year using the International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA), maximum urinary flow (Qmax) and PV. A Mann–Whitney U-test and Chi-square were used to assess the difference between the two groups. A comparison of paired data was performed with the Wilcoxon signed-rank test. Statistical significance was set at p-value < 0.05. There was no statistically significant difference in baseline characteristics between the two groups. At the 1-year follow-up, PV [55.0 (15.0) vs. 62.5 (18.0) mL, p = 0.04)], PSA [2.5 (1.5) ng/mL vs. 3.05 (2.7) vs. p = 0.009] and IPSS [13.5 (3.75) vs. 18 (9.25) p = 0.009] were significantly lower in the Cavacurmin® group. Qmax was significantly higher in the Cavacurmin® group [15.85 (2.9) vs. 14.5 (4.2), p = 0.022]. PV was reduced to 2 (5.75) mL in the Cavacurmin® group from baseline, while it increased to 12 (6.75) mL in the α1-adrenoceptor antagonists group (p < 0.001). PSA decreased in the Cavacurmin® group [−0.45 (0.55) ng/mL], whereas it increased in the α1-adrenoceptor antagonists group [0.5 (0.30) ng/mL, p < 0.001]. In conclusion, one-year Cavacurmin® therapy was able to block prostate growth with a concomitant decrease in PSA value from baseline. The association of Cavacurmin® with α1-adrenoceptor antagonists had a more beneficial effect compared to patients on α1-adrenoceptor antagonists alone but this needs further larger studies to be confirmed, particularly in the long-term.
... Despite slight decrease in levels of testosterone associated with PA administration, inhibition of 5-aR by PA is considered minimal and not clinically significant [46]. Antiandrogenic and antiestrogenic effects (which may block the initiation of hyperplasia), were also achieved through the activity of ferulic esters which decrease prolactin (which stimulates intraprostatic dihydrotestosterone synthesis and testosterone uptake) and cholesterol (which increases the binding sites for dihydrotestosterone), though such effects do not appear to reverse the progression of BPH [47]. An anti-inflammatory effect attributed to several contents of PA extract -such as pentacyclic triterpenes and ferulic esters-was proposed to explain -in part-the in vitro therapeutic effect of Pygeum [48]. ...
Introduction /Aim: Serenoa repens (SR) and Pygeum Africanun (PA) exhibit marked anti-inflammatory, anti-androgenic and anti-proliferative effects. For this reason, they have been subject of research as potential treatment of benign prostatic hypertrophy (BPH). The aim of this study is to present current knowledge on the topic.
Methods: A non-systematic search was performed in electronic libraries for clinical trials, experimental studies and systematic reviews on the topic using the terms: “prostate”, “benign prostatic hypertrophy”, “lower urinary tract symptoms” combined with the key words: “phytotherapy”, “Saw palmetto”, “Serenoa repens”, “Serenoa serrulata”, “Pygeum Africanum”, “Prunus africana” in various combinations. Results: A sufficient number of studies of the efficacy of SR for the treatment of LUTS and BPH exists. Most of them examine the role of saw palmetto as add-on to other agents and less as monotherapy. Few similar studies for PA have been published up to date. Αlmost all examine its role as monotherapy. According to our research, there is no clear evidence of clinical superiority
of phytotherapy over conventional treatment however a potent synergistic effect was shown. SR seems to be more efficient than PA though non produce some of the therapeutic effects of PA. Conclusions: Combination of SR and PA with other medications
can offer significant improvements of urinary status while having a favourable safety profile and for this reason may be considered a viable therapy for treating LUTS in certain groups of patients.
... Traditionally, IMI was treated by using antioxidant compounds like vitamin C (Kartikeya et al. 2009), vitamin E (Keskes-Ammar et al. 2003, and GSH/selenium (Chris et al. 2004) or by terrestrial natural products which have antioxidant activity like Maca (Neelesh et al. 2011), Ginseng (Chen et al. 1999), Pygeum (Levin and Das 2000) and extract of onion and garlic (El-Demerdash et al. 2005). ...
Aim: This study designated to investigate and compare the therapeutic effect of Ulva lactuca methanolic extract against oxidative stress (OS)-infertility induced by naturally occurring prooxidants (gossypol) and selenium- vitamins A, C, and E (selenium-ACE) drug.
Methods: Male infertility was induced in rat by intraperitoneal injection of 5 mg/kg gossypol eight times then the treatment was carried out with 100 mg/kg ulva methanolic extract oral administration for one or two weeks, after this period OS, and male infertile markers were detected in blood and/or testes.
Results: Gossypol stimulated male infertility by increasing testicular OS markers and decreasing semen quality, hyaluronidase enzyme activity, and blood testosterone level. The treatment with ulva methanolic extract improved gossypol related adverse effects. The treatment period for two weeks with extract was the most potent one.
Conclusions: Ulva methanolic extract could be considered as good antioxidant therapeutic candidate for OS linked male infertility.
... Examples of preparations containing saw palmetto extract, available in Polish pharmacies[19][20][21]. ...
... Olası ilgili bileşikler arasında fitosteroller, ß-sitosterol, yağ asitleri , likopen , selenyum, soy izoflavonlar ve lektinler bulunur [1]. İn vitro koşullarda, bitki ekstreleri; anti-inflamatuar, anti-androjenik ve östrojenik etkilere sahip olabilir; bunlar seks hormon bağlayıcı globulini azaltır; aromatazı , lipoksijenazı, prostatik hücrelerin büyüme faktörü ile uyarılmış proliferasyonunu, alfa-adrenoseptörleri, 5 alfa-redüktazı , muskarinik kolinoseptörleri, dihidropiridin reseptörlerini ve vanilloid reseptörlerini inhibe eder ve serbest radikalleri nötralize eder [1][2][3]. Ancak bu etkiler in vivo olarak doğrulanmamıştır ve bitki ekstrelerinin kesin mekanizmaları açık değildir. ...
... Побочные эффекты при фитотерапии обычно слабо выражены и сопоставимы с эффектами при приеме плацебо. С исследуемыми препаратами серьезные побочные эффекты не были связаны [15,16]. ...
Introduction. Lower urinary tract symptoms (LUTS) are a common complaint in patients with benign prostatic hyperplasia (BPH), and they significantly affect patients’ quality of life. According to the guidelines of the European Association of Urology on management of LUTS (2016), herbal drug preparations can be used as monotherapy and as a part of combination therapy. Plant extracts with anti-inflammatory, spasmolytic, anti-oedemic, anti-androgenic, estrogenic effect can inhibit prostatic growth, stimulation, proliferation factors, α-adrenoreceptors, 5α-reductase, muscarine acetylcholine receptors. The article describes experience of using the «De Alex» bio complex as monotherapy and in combination with tamsulosin in patients with BPH.The study objective is to evaluate effectiveness and safety of the "De Alex" bio complex as monotherapy and in combination with tamsulosin in patients with BPH.Materials and methods. Clinical and laboratory examinations of 30 patients with BPH were performed. The patients were selected at the stage of primary clinical screening in Moscow city polyclinics (branch No. 1 of the City Polyclinic No. 62 of the Moscow Healthcare Department) and Moscow Region polyclinics (City Polyclinic No. 3 of the Orekhovo-Zuyevo Central City Hospital of the Moscow Region). The study duration was 12 weeks.Results. Based on the obtained data, the "De Alex" bio complex has significant anti-inflammatory, spasmolytic effect, can affect prostate volume, increase urine flow rate and control (which was confirmed by the results of the follow-up examination) and therefore increase patients’ quality of life.Conclusion. The "De Alex" bio complex has shown a high level of safety: during the study, the dietary supplement didn’t cause any side effects. Furthermore, the bio complex didn’t significantly affect the total and free levels of prostate-specific antigen and testosterone. The patients demonstrated high compliancy since "De Alex" has proved to be an effective and safe supplement with fast effect. Considering the above, we can recommend the "De Alex" bio complex at dose 1 tablet 2 times a day for 3 months (1–2 courses a year) as an effective and safe preparation that can be used as monotherapy or in combination with alpha-blockers to manage LUTS.
... However, for the folk medicine, there are few evidences provided by modern laboratory technology of the effectiveness of herb treatment. I/R has been utilized effectively in rabbits to evaluate the ability of drugs and supplements to reduce oxidative stress [5][6][7]. The current study was designed to prove that Ganoderma Lucidum (GL) reduces the damage from I/R. ...
Oxidative stress plays an important role in specific disease pathophysiology and the aging process. In the history of human kind, many herbs were utilized for disease prevention and anti-aging treatment. However, there are few direct evidences provided by modern laboratory technology. The current study was designed to evaluate Ganoderma Lucidum's (GL) ability to reduce the damage from in vivo ischemia/reperfusion (I/R) using a rabbit model of I/R that has been effectively utilized to prove the effects of drugs and supplements to reduce oxidative stress. Urinary bladder dysfunction secondary to benign prostatic hyperplasia (BPH) is a major affliction of aging men. One of the major etiologies of obstructive bladder dysfunction (OBD) is oxidative stress induced by I/R. Pharmaceutical studies and clinical research have proven that GL is useful in helping to prevent certain types of pathology and also helpful in prolonging human life in part by acting as an antioxidant. Using an in vivo model of I/R, we have investigated the ability of GL to protect bladder function from oxidative damage mediated by I/R. Our studies demonstrated that ischemia followed by reperfusion resulted in a significant decrease in bladder compliance and decreases in the contractile responses to a variety of forms of contractile stimulation. Pretreatment of rabbits with Ganoderma Lucidum prior to subjecting the rabbits to I/R completely inhibited the negative effects of I/R on both the compliance and contractile responses. These results demonstrate that Ganoderma provides excellent protection of bladder function following I/R (oxidative stress).
... Chez les animaux, le PA améliore la contractilité de la vessie, a un effet anti-inÁ ammatoire, diminue la production de leucotriènes et des autres métabolites issus de l'activité de la 5-lipoxygénase, inhibe la production de À broblastes, affecte les androgènes surrénaliens, et restaure l'activité sécrétoire de l'épithélium de la prostate [2,3]. On a dernièrement démontré les effets antiprolifératifs et anti-apoptotiques du PA en ayant recours à des cellules prostatiques bénignes humaines fraîches [4,5], et à des lignées cellulaires humaines prostatiques cancéreuses LNCaP et PC-3 [6]. ...
... Pygeum africanum (Tadenan ® ), has been postulated to have additional beneficial effects on BPH/LUTS [60]. Levin et al. using a rabbit model with partial bladder outlet obstruction, demonstrated that pretreatment with P. africanum exerted changes in bladder mass, decrease in compliance, and alterations in contractile response to adrenergic agonists and electrostimulation [61]. ...
... Literatürde yaklaşık 30 civarında fitoterapötik ajanın semptomatik BPH tedavisinde kullanıldığı anlaşılmaktadır (Tablo 1). Fitoterapötiklerin en sık bilinen etki mekanizmaları arasında; anti-enflamatuvar, anti-androjenik, östrojenik etkileri, seks hormon bağlayıcı globülinleri azaltması, prostatik hücrelerin büyümesini uyaran aromataz lipooksigenazı inhibe etmesi, 5α-redüktaz, α-adrenoreseptör ve muskarinik, reseptörleri inhibe etmesi, detrusör fonksiyonlarını düzenlemesi, serbest oksijen radikallerini nötralize ederek multikompleks etkilere yol açması sayılabilir (Tablo 2) (7,8,9). Bu makalede fitoterapötik ajanlardan en yaygın kullanım alanına sahip olanların klinik etkinliği, güvenilirliği, bileşenleri, kullanım dozları ve yan etkileri gözden geçirilerek tartışılmıştır. ...
... 101,102 However, effective treatment for P. africanum individually or in combination is worth further discussed. 103 Stinging nettle (Urtica dioica) was used as a traditional remedy in Europe 104 and commercialized in many dosage forms 102 as it posses anti-androgenetic effects [105][106][107] according to its biologically active phenolics, fatty acids, phytosterols, and lignans. [108][109][110][111][112] Although an adverse effect of its treatment is very low, complete clinical safety should be conducted. ...
Baldness:
or androgenetic alopecia directly distresses self-confidence affecting the individual's quality of life. Hair loss is therefore a significant psychosocial manifestation that worth much expense on treatment. Androgenetic alopecia is noticed as a slow transformation of large scalp terminal hair follicles to shorter, thinner, and less deep vellus hair with a much shorter anagen. Although minoxidil, finasteride, and dutasteride including other synthetic therapeutic agents are mostly used for alopecia treatment, their adverse effects encourage sorting of alternative efficient treatment agent with a limited side effect particularly herbs. Thus, this review briefly summarized causes of hair loss and emphasized on active ingredients for treatment in particular currently used herbs and the potential candidates. Treatment choices will be further wider and conclusively select herbs that fitting the consumers' preference.
... serenoa repens, saw palmetto. [6]. 36 DHT . . (myelo- peroxidase) , - – . / 5alpha-reductase [ , ]. IGF-I (Insulin-Like Growth Factor) MCP-1/CCL2 (- -1/ CL2), [ , ]. . 1-5-11 30-5-12. , - , . (/). H ( ) prulifloxacin 600mg 15 ( ) prulifloxacin 600mg 15 serenoa repens 8 . , . (-CPSI), (IPSS), (IIEF-5). -CPSI, IPSS, IIEF-5 4 8 (15 serenoa repens). H 3-6 . Stamey-Meares : ...
Introduction: Chronic prostatitis displays a variety of symptoms (mainly local pain exhibiting variability in
origin and intensity). The purpose of this article is to briefly present the preliminary results of our study
examining the role of phytotherapeutic agents in the treatment of chronic prostatitis patients.
Material and Method. The study was designed as a prospective, randomized, single blind and included in
total fifty-six patients who visited the outpatient department. Subjects were randomized in two groups. Subjects
of the first group (29 patients) received prulifloxacin 600mg for 15 days, while subjects of the second group (27
patients) received prulifloxacin 600mg for 15 days and serenoa repens extract for 8 weeks. The response was
tested with laboratory and clinical criteria.
Results. We found statistically significant differences between the two groups regarding pain and discomfort in
urination but no differences were found regarding erectile or sexual dysfunction.
Conclusions. Serenoa repens extract for 8 weeks seems to improve pain and prostatitis related difficulty in
urination. Further randomized placebo-controlled studies are needed to substantiate safer conclusions.
... A decreased expression of COX, p21, and p27 caused by saw palmetto extracts has also been suggested as an alternative mechanism [5,6]. Saw palmetto fruit extracts also show anti-androgenic, anti-proliferative, and anti-inflammatory effects [7][8][9][10]. ...
The fruits of saw palmetto have been used for the treatment of a variety of urinary and reproductive system problems. In this study we investigated whether the fruit extracts affect in vitro adipogenesis. Saw palmetto ethanol extract inhibited the lipid droplet accumulation by induction media in a dose-dependent manner, and it also attenuated the protein expressions of C-EBPα and PPARγ. Phosphorylation of Erk1/2 and Akt1 were also decreased by saw palmetto ethanol extract. This report suggests that saw palmetto extracts selectively affect the adipocyte differentiation through the modulation of several key factors that play a critical role during adipogenesis.
... Phytotherapy for treatment of LUTS is popular in some countries, notably France and Germany with upto one third of the market share of all preparation used for treatment of symptomatic BPH in western countries taken by these. [94] Numerous agents like palm plant, nettle, rye grass, pumpkin seed and cactus flower derivatives have been used for centuries. Each of these preparations contains single or a combination of active compounds. Though their mode of action remains unclear, these products are thought to produce their effects through hormonal effects and interf ...
Benign prostatic hyperplasia (BPH) is an age-related androgen dependent progressive disease. It is associated with bothersome lower urinary tract symptoms which prove detrimental to the quality of life for both the effected men and their partners. With an aging population elderly people constituting greater proportion of population, the prevalence of BPH is on the rise with a significant impact on medical sector. Initial investigations using simple diagnostic tools can be offered to the patient suspected of having BPH as first diagnostic step in primary care setting and can help in minimizing the delay in diagnosis and management. Due to extensive work done recently in understanding the natural history of BPH and the knowledge of physiological effects of various medical interventions has greatly helped us in choosing therapeutic options for individualized treatment. This has resulted inconsiderable reduction in the rate of transurethral prostatectomy seen during the last couple of decades. Development of adrenoceptor blockade and hormonal manipulation has moved increasing number of men away from surgery towards pure medical management of BPH. We reviewed the current status of medical management in light of the evidence in support of each agent, and the correct selection of treatment.
Non‐alcoholic fatty liver diseases (NAFLD) is manifested in the absent of alcohol abuse. This disease is the major cause of liver failure and death among adults and children worldwide, including South Africa. Its increasing prevalence urges the need of therapeutic intervention. The main objectives of this study were to investigate the following: (1) The effect of 38.9% high fat diet (HFD)‐induced insulin resistance and fatty liver in male Wistar rats, (2) The efficacy of aqueous extracts from Sutherlandia frutescens leaves and Prunus africana bark and metformin in the treatment of HFD‐induced insulin resistance and fatty liver. Male Wistar rats were fed on HFD (the HF group)or normal rat chow (the LF group) for 12 weeks. Even though the HFD‐fed rats had developed insulin resistance by week 12, fatty liver developed by week 16. After week 12, the HF group was divided into four groups of 6‐7 rats each and three of those groups were gavaged with either 0.125 mg P. africana extract/kg bwt/day (the HF+Pa group) or 50 mg S. frutescens extract kg bwt/day (the HF+Sf group) or 16 mg metformin/ kg bwt/day (HF+Met group), while kept on the same diet for an additional of 4 weeks, to investigate whether two medicinal plant extracts and metformin can prevent HFD to induce fatty liver or not. After 16 weeks, the liver histological images revealed that the HF group developed fatty liver in the form of both microsteatosis and macrosteatosis. Fatty live was confirmed by significant increased liver total lipid (TL) and activities of glucose‐6‐phosphate dehydrogenase (cG6PD) and xanthine oxidase (XO), mitochondrial NADH oxidase (mNOX) and by a decrease (P<0.05) in the activities of the homogenate superoxide dismutase (hSOD) and mitochondrial complex II in the HF group, when compared to the LF group. Since the activities of mCS and cACL enzymes were not changed in the HF group, hence increased cG6PD activity in the HF group indicates that there was increased NADPH demand for lipid accumulation from activated NEFAs taken up by the liver from circulation and for maintenance of the NADPH‐dependent antioxidants and oxidants, respectively. The obtained data also show that mitochondria of the HFD‐fed rats adapted to an increase in energy availability, thereby compensation through decreasing complex II activity, to allow electron flux from β‐oxidation to respiratory chain in the HF group. Liver TL content was significantly decreased in the rats treated with metformin and P. africana extract, but not in the rats treated with S. frutescens when compared to the HF group (P < 0.05). However, the TL content remained >5% per liver weight in all treated groups. The present study demonstrates that these two plant extracts and metformin have different glucogenic and lipogenic effects from that presented by HFD alone when compared to the LFD alone. In conclusion, metformin and P. africana extract can attenuate HFD‐induced fatty liver without changing the dietary habits. Hence S. frutescens extract is less effective in the prevention of HFD‐induced fatty liver. A change in the dietary habits is recommended to be considered during the use of these three remedies in the treatment of HFD‐induced insulin resistance and fatty liver. All three treatments enhanced antioxidant capacity, and may improve insulin resistance and fatty liver mediated by the present HFD through different mechanism of actions in the liver.
Prostate smooth muscle contraction and prostate growth are central topics in pharmacology of benign prostatic diseases. Both may drive urethral obstruction in benign prostatic hyperplasia (BPH), resulting in impairments of voiding and bladder emptying, and finally lower urinary tract symptoms (LUTS). Available drugs for medical treatment include α1-adrenoceptor antagonists and the phosphodiesterase-5 inhibitor tadalafil, improving symptoms and urinary flow by relaxation of prostate smooth muscle, and 5α-reductase inhibitors reducing the risk for progression, complications and surgery by inhibition of androgen-dependent growth. However, improvements by available medications are limited, so that surgery due to BPH is still inevitable in numerous patients. Ongoing experimental and clinical research aims to identify alternatives, and to understand current limitations of medical therapy. Non-adrenergic contractions of prostate smooth muscle recently moved into the focus of preclinical research, as they induce prostate smooth muscle contraction in parallel to α1-adrenoceptors. At molecular level, connections between regulation of prostate smooth tone and growth become increasingly obvious. This article summarizes principles underlying regulation of prostate smooth muscle contraction and prostate growth, available medications and clinical aspects, and recent attempts to identify novel targets and compounds for inhibition of smooth muscle contraction and proliferation in the prostate.
Bladder outlet obstruction (BOO) is a pathological condition characterized by obstruction during voiding, increased detrusor pressure associated to reduced urine flow rate. OAB is defined as urinary urgency, usually with frequency and nocturia, with or without urgency urinary incontinence. In males, there is often an overlap of these two pathological conditions (up to 50%), clinically represented by the coexistence of urinary symptoms of both storage and voiding phase. The proposed pathophysiological mechanisms underlying the development of OAB in males with BOO include the myogenic, neurogenic and urothelial factors. Diagnosis is based on history, physical examination, validated questionnaires, bladder diary, post-void residual urine, and noninvasive urodynamics such uroflowmetry. Invasive urodynamics is the most accurate investigation for these males, but it is not routinely scheduled. Management comprises conservative approach as a first step in males with mild symptoms. Pharmacological therapy, mono- or combination therapy, is usually administered. Surgical procedures are indicated in males’ refractory to first-line therapy or with severe urinary symptoms and/or clinical condition.
Saw palmetto berries (Serenoa repens) are used today for treatment of symptoms of benign prostatic hyperplasia (BPH) which is an age dependent disease leading to lower urinary tract symptoms (LUTS) and impacts negatively sexual functions. I carried out the first clinical pilot trial to assess if a saw palmetto treatment in patients with BPH and concomitant sexual dysfunctions (SDys) is effective and safe in both groups of symptoms. After 8 weeks of treatment with 320mg saw palmetto extract daily, BPH symptoms measured with the International Prostate Symptom Score IPSS were reduced from 14.4 ± 4.7 to 6.9 ± 5.2 (p<0.0001). At the same time SDys measured with the brief Sexual Function Inventory bSFI improved from 22.4 ± 7.2 to 31.4 ± 9.2 (p<0.0001), and with the Urolife BPH QoL-9 sex questionnaire from 137.3 ± 47.9 to 195.0 ± 56.3 (p<0.0001). The treatment was very well tolerated and accepted by the patients. Another subject of this thesis was to examine the quality of commercial preparations from eight countries which contained saw palmetto and are sold as treatments for BPH symptoms. For each of the 46 analysed products the amount of the main active constituents, the fatty acids was determined using gas chromatography. The quantity of fatty acids per daily dosage varied widely between the products and also the composition of the samples was very heterogeneous. A medico-historical investigation how saw palmetto was introduced firstly into U.S. American medicine and how the plant became popular as a treatment in Germany was the last aspect of the thesis. The eclectic physicians pioneered in using this plant in the United States supported by homeopathic doctors and pharmacists. In Germany, mainly the homeopaths favoured the use of saw palmetto and were the trailblazers making it a popular treatment for BPH symptoms. In conclusion, this thesis shows comprehensively how saw palmetto made its way into medical practice in the United States and Germany, that preparations on the markets containing saw palmetto differ widely in their content of the main active constituents, the fatty acids, and thus higher quality demands from regulatory authorities are warranted, and in a pilot trial it could be shown that saw palmetto is not only an effective and safe treatment for BPH symptoms but also for concomitant SDys.
Abstract“Lower urinary tract symptoms” (LUTS) are among the most common complaints of urological patients. Benign prostate enlargement represents the most common cause of LUTS in men and treatment should only be initiated in patients with bothering symptoms. There are various different therapeutic strategies to choose from: phytotherapeutic drugs significantly improve obstructive symptoms (IPSS [“international prostate symptome score”]) and maximum urinary flow (Qmax), yet disease progression is not inhibited. The same applies to the group of the rapid-acting α1-blockers, which are considered as first-line therapy in patients with a prostate volume <40 ml. The 5α-reductase inhibitors are another important therapeutic option for men with symptoms of LUTS and a prostate volume >40 ml, accompanying the effect of prostate volume reduction and concomitant prevention of disease progression—onset of these favorable effects are expected after a therapy period of 3 months. Tadalafil, a phosphodiesterase type 5 (PDE 5) inhibitor, has its main indication in the treatment of erectile dysfunction, yet a daily oral dose of 5 mg was also shown to significantly improve LUTS. Patients predominantly suffering from storage symptoms can benefit from oral therapy with a muscarinic receptor antagonist. Here, infravesical obstruction should be ruled out in advance and the absence of increased post-void residual urine volume is necessary. Mirabregone, a beta-3 agonist, can be used as a safe alternative in individuals with persistent side effects like xerostomia or constipation, yet is not recommended for patients with severe hypertension. Combination therapies have been subject to many studies in the past and have been shown to achieve more symptom relief when the higher rate of side effects is well tolerated by the patient.
In this chapter the beneficial effects of Serenoa repens on human health are presented. In particular, attention has been focused on its role in the treatment of benign prostatic hyperplasia (BPH). Much evidence has shown the capacity of this plant to exert its effects, through specific mechanisms of action, in much the same way as the synthetic pharmacological molecules currently used in this pathological condition, including stimulation of apoptosis in cancer cells, inhibition of 5-alpha-reductase, and blocking the interaction of dihydrotestosterone (DHT) with its receptor. S. repens is a well-tolerated plant and few side effects have been reported. Thus, S. repens is considered to be an effective and safe natural remedy for BPH treatment.
Androgenetic alopecia (AGA) is a common form of scalp hair loss that affects up to 50% of males between 18-40 years old. Several molecules are commonly used for the treatment of AGA, acting on different steps of its pathogenesis (Minoxidil, Finasteride, Serenoa repens) and show some side effects.
In literature, on the basis of hypertrichosis observed in patients treated with analogues of prostaglandin PGF2α, was supposed that prostaglandins would have an important role in the hair growth: PGE and PGF2α play a positive role, while PGD2 a negative one.
We carried out a pilot study to evaluate the efficacy of topical cetirizine versus placebo in patients with androgenetic alopecia.
We found that the main effect of cetirizine was an increase of total hair density, terminal hair density and diameter variation from T0 to T1, while the vellus hair density shown an evident decrease.
The use of a molecule as cetirizine, with no notable side effects, make possible a good compliance by patients. Our results have shown that topical cetirizine 1% is responsible for a significant improvement of the initial framework of androgenetic alopecia.
The human reproductive system may be considered “silent” until puberty, when a trigger activates the genetic code responsible for the production and secretion of hormones responsible for the initiation and continuation of this developmental stage. The reproductive system consists of primary sex organs, the male testes and the female ovaries, collectively called the gonads. Male sexual organs include the testes (which produce sperm and sex hormones), vas deferens and urethra (which carry sperm out of the body), prostate and glands seminal vesicles (which contribute to the majority of fluid within the semen), penis (which is an organ of copulation and excretion) and scrotum (housing the testes outside the pelvic cavity which is essential for viable sperm production). Female sexual organs include the ovaries (which produce ova and sex hormones), the uterine tubes (which carry ova from the ovary to the uterus), the uterus (which represents the house and nourishes developing embryo), the vagina (which receives sperm during intercourse and which also represents the exit point for menstrual flow), the vulva (which serves as a protection) and mammary glands (which produce milk). As with any organ system failure, imbalances include a wide number of conditions, both for male and female. This chapter will focus on menopausal symptoms, premenstrual syndrome and benign prostatic hyperplasia.
The greatest risk factor for developing benign prostatic hyperplasia (BPH) is advanced age. Potential molecular and physiologic contributors to the frequency of BPH occurrence in older individuals include the oxidative stress, chronic inflammation, and alterations in tissue microenvironment. As BPH and aberrant changes in reactive oxygen species become more common with aging, oxygen species signaling may play an important role in the development and progression of this disease. Increased oxidative stress is a result of either increased reactive oxygen species generation or a loss of antioxidant defense mechanisms. Oxidative stress is associated with several pathological conditions including inflammation and infection. Oxygen species are byproducts of normal cellular metabolism and play vital roles in stimulation of signaling pathways in response to changing intra and extracellular environmental conditions. This review is aimed to explore the mechanism of oxidative stress in prostate and the possibility of drug development against oxidative stress for prostatic disease prevention.
Purpose:
Chronic bacterial prostatitis displays a variety of symptoms (mainly local pain exhibiting variability in origin and intensity). These symptoms often persist despite bacterial eradication. The purpose of this article is to exam the role of phytotherapeutic agents as complementary treatment in patients with bacterial prostatitis.
Materials and methods:
The material consisted of individuals with reported pelvic discomfort and genital pain with or without lower urinary tract symptoms (LUTS) and sexual dysfunction visiting our department from March 2009 to March 2011. Patients underwent Stamey-Meares test (several cases underwent the two glass test). Depending on history and specific symptoms urethral smear and semen cultures were additionally obtained from several patients. All patients were randomized into two groups. Subjects in the first group (72 patients) received appropriate antibiotic (according to the sensitivity test) for 15 days, while subjects in the second group (72 patients) received phytotherapeutic agents for 30 days, additionally the conventional 15 days antibiotic treatment. The response was tested using laboratory and clinical criteria.
Results:
We found no statistically significant differences between the two groups regarding bacterial and symptom persistence rate, however, symptoms burden was lower in patients receiving combinational treatment.
Conclusion:
Phytotherapeutic agents may improve pain and prostatitis related difficulty in urination. Further randomized, placebo-controlled studies are needed to substantiate safer conclusions.
A GC/selected ion monitoring mode-MS (GC/SIM-MS) method was developed to chemically distinguish saw palmetto and pygeum in dietary supplements. A sample set including authenticated plant samples, commercial plant extracts, a National Institute of Standards and Technology standard reference material extract, and commercial dietary supplements purported to contain either saw palmetto, pygeum, or both was investigated. Fatty acid methyl esters (FAMEs) were analyzed by GC/SIM-MS. The ability to selectively monitor each solute allowed accurate quantitation of all detected FAMEs, even those that were not chromatographically resolved. The major fatty acid components that were common to both saw palmetto and pygeum were oleic, linoleic, and palmitic acids. The major component characteristic of pygeum was stearic acid. Lauric and myristic acids were observed predominantly in saw palmetto samples. Principal component analysis was used for interpretation of the analytical results. A distinct cluster was observed for the samples containing pygeum alone. A separate cluster was observed for the samples containing saw palmetto alone or mixed with pygeum. The proposed GC/MS method is useful for chemical fingerprint analysis and QC of dietary supplements claiming to contain pygeum and/or saw palmetto.
We report the case of a 52-year-old man with hyperazotemia of indeterminate source, who had a history of benign prostatic hypertrophy and chronic prostatitis, which was treated for several months with SAW PALMETTO, a medicine based on extracts from the American dwarf palm fruit. During the last week the patient had received high doses (960 mg/day). Laboratory workup revealed a glomerular filtration rate of 60 milliliters per minute; the suspension of this herbal remedy achieved restoration of renal function to normal levels.
One etiology related directly to obstructive urinary bladder dysfunction is ischemia/reperfusion resulting in significant oxidative stress to the bladder. Grapes, a natural source of antioxidants, have been proven effective in preventing obstructive and ischemic bladder dysfunction. Many investigators believe that resveratrol is the primary active antioxidant ingredient in grapes. We compared the ability of a whole-grape suspension with pure resveratrol in their ability to protect the bladder from in vitro oxidative stress mediated by hydrogen peroxide (H2O2). Four male rabbit bladders were used. Two strips from each bladder were incubated in the presence of 1 mg/mL grape suspension for 30 min, another two strips were incubated in the presence of 1 mg/mL resveratrol solution, and the last two strips were incubated in the presence of 1 mg/mL sucrose/and fructose as controls. The rest of the bladder was separated into muscle and mucosa, frozen and stored for biochemical evaluation. (1) Chemically, resveratrol has about 20 times the antioxidant capacity of the grape suspension. (2) The grape suspension had significant protective effects when the rate of tension was quantitated at all concentrations of H2O2, while the resveratrol had no effect. (3) Citrate synthase activities of the muscle and mucosa were significantly protected by the grape suspension but not by resveratrol. These data demonstrate that the grape suspension protects the mitochondria to a significantly greater degree than resveratrol, which suggests that the antioxidant activities are due to the combination of active components found in the grape suspension and not just resveratrol.
Despite an unremitting increase in the number of patients presenting symptoms of benign prostate hyperplasia (BPH), the viable treatment options remain relatively limited when compared to other disorders of aging. This has spurred an interest in so-called alternative medicines, many of which continue to be used in spite of the more recent emergence of rationally targeted therapies. Nonetheless, in the case of plant extracts, the vast majority of these have not been subjected to the same rigorous pre-clinical pharmacological testing and large-scale clinical trials now required by health authorities. Furthermore, demonstration of their clinical efficacy in BPH has been hindered by trials of limited duration with a high placebo response. Beginning with a preliminary demonstration of in vitro inhibition of growth factor-mediated fibroblast proliferation with Pygeum africanum extract, a detailed series of in vitro and in vivo studies on prostate growth and bladder function were undertaken. These studies, reviewed herein, have permitted the identification of putative molecular targets of Pygeum africanum extract affecting both growth factor-mediated prostate growth as well as specific parameters of bladder function. These results, corroborated in part by short-term clinical efficacy, set the stage for a large-scale clinical trial to investigate the efficacy of Pygeum africanum extract in the treatment of lower urinary tract symptoms.
Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in reproductive age women. PCOS is characterized by the absence of menstruation or irregular and abnormal menstruation, excessive amounts of body hair, excessive body weight, and infertility. Women with PCOS often have multiple ovarian cysts, high levels of androgen hormones, insulin resistance and metabolic syndrome. This review is focused on the dietary approaches and alternative therapies which have been proved to play major roles in the treatment of PCOS. The ideal diet for PCOS is one that promotes weight loss and then weight maintenance. In addition, some of the essential nutrients may improve associated risk factors of PCOS. Among them are chromium, omega 3 fattyacids, antioxidants, phytosterols, magnesium, calcium, potassium and other essential vitamins and minerals. The most important aspect of treatment is managing cardiovascular risks, such as obesity, high blood cholesterol, diabetes and high blood pressure. Early recognition and aggressive lifestyle interventions are the cornerstones of PCOS treatment. Treating individual risk factors might help to reduce overall risk of PCOS. Some of the PCOS risk factors are modifiable. Aggressive medical nutritional therapy may be appropriate in early conditions than advanced stages.
Prostate cancer is a leading cause of cancer death in men in Western countries. Although progress has been made in therapies
for cases where there is early diagnosis and disease is localized, current therapies for advanced prostate cancer still remain
inadequate and do not provide a cure. Due to the particularly long latency and unpredictable, slow progression of prostate
cancer, herbal medicine may be a suitable alternative for protection against the disease with potential for development for
long-term use without significant side-effects. Research on potential drug molecules from herbal medicines is slowly emerging
for prostate cancer treatment; however, investigations are still hampered by various technical concerns such as a lack of
validated drug targets, lack of animal models relevant to the human disease, as well as a lack of strategies and methodologies
to effectively analyze the active ingredients contained in herbal medicines, their pharmacokinetics, pharmacodynamics and
so on. Here, we summarize recent advances in anticancer herbal medicine research for in vivo prostate cancer treatment. The most promising candidates are currently at the preclinical study stage and include the ethanol
extracts of ka-mi-kae-kyuk-tang, a cocktail of ten Chinese and Korean herbs; honokiol, a biphenolic compound isolated from
Magnolia officinalis (Hòupò in Chinese); and Wedelia chinensis. Potential toxicities or severe side effects as a result of long-term use, which are the main concerns that still need to
be investigated prior to the commencement of clinical studies of these herbs and herbal formulas are discussed in this chapter.
Pygeum africanum (Tadenan) is a popular phytotherapeutic agent used in the treatment of symptomatic benign prostatic hyperplasia. The active compounds of the drug have not been identified, and determining the plasma concentration of the drug is, therefore, not possible. Because there are conflicting results on the efficacy of this drug, we aimed to investigate its effect on prostate cell growth in vitro using human serum collected before and after Pygeum africanum intake. We used primary and organotypic cultures of human prostatic stromal myofibroblast cell line WPMY and prostatic epithelial cell line PNT2. We also used fresh benign prostatic tissue. The serum of a treated man induced decreases in the proliferation of primary cells, organotypic cells and WPMY cells but not PNT2 cells. We also analysed the effect of treated serum on the gene expression profile of WPMY cells. The transcriptome analysis revealed an upregulation of genes involved in multiple tumour suppression pathways and a downregulation of genes involved in inflammation and oxidative-stress pathways. The oral intake of Pygeum africanum resulted in serum levels of active substances that were sufficient to inhibit the proliferation of cultured myofibroblasts prostatic cells. This inhibition was associated with changes in the transcriptome.
Here, the synthesis and the evaluation of novel 20-aminosteroids on androgen receptor (AR) activity is reported. Compounds 11 and 18 of the series inhibit both the wild type and the T877A mutant AR-mediated transactivation indicating AR antagonistic function. Interestingly, minor structural changes such as stereoisomers of the amino lactame moiety exhibit preferences for antagonism among wild type and mutant AR. Other tested nuclear receptors are only weakly or not affected. In line with this, the prostate cancer cell growth of androgen-dependent but not of cancer cells lacking expression of the AR is inhibited. Further, the expression of the prostate specific antigen used as a diagnostic marker is also repressed. Finally steroid 18 enhances cellular senescence that might explain in part the growth inhibition mediated by this derivative. Steroids 11 and 18 are the first steroids that act as complete AR antagonists and exhibit AR specificity.
Human prostate was used as a source of 5α reductase. Compounds were incubated with an enzyme preparation and [3H]testosterone. [3H]-dihydrotestosterone production was measured to calculate 5ã reductase activity. IC50 values (ng/ml) were finasteride = 1; Permixon = 5,600; Talso = 7,000; Strogen Forte = 31,000; Prostagutt = 40,000; and Tadenan = 63,000. Bazoton and Harzol had no activity at concentrations up to 500,000 ng/ml. In castrate rats stimulated with testosterone (T) or dihydrotestosterone (DHT), finasteride, but not Permixon or Bazoton, inhibited T stimulated prostate growth, while none of the three compounds inhibited DHT stimulated growth. These results demonstrate that finasteride inhibits 5α reductase, while Permixon and Bazoton have neither anti-androgen nor 5α reductase inhibitory activity. In addition, in a 7 day human clinical trial, finasteride, but not Permixon or placebo, decreased serum DHT in men, further confirming the lack of 5α reductase inhibition by Permixon. Finasteride and the plant extracts listed above do not inhibit the binding of DHT to the rat prostatic androgen receptor (concentrations to 100 μg/ml). Based on these results, it is unlikely that these plant extracts would shrink the prostate by inhibiting androgen action or 5α reductase. © 1993 Wiley-Liss, Inc.
Although dihydrotestosterone (DHT) is the principal androgen in the prostate, testosterone can also act as an androgen in this tissue. To determine the relative potencies of testosterone and DHT in preventing prostate regression, castrated rats were implanted for 4 d with varying doses of testosterone in the presence or absence of the 5alpha-reductase inhibitor finasteride. In the absence of finasteride, testosterone in the prostate is converted to DHT, creating an intraprostatic DHT dose response. In the presence of finasteride, this conversion is blocked, and an intraprostatic testosterone dose response is achieved. DHT was 2.4 times more potent than testosterone at maintaining normal prostate weight and duct lumen mass, a measure of epithelial cell function. The two androgens were equipotent at preventing DNA fragementation and expression of testosterone-repressed prostate message, two measures of apoptosis (cell death). The intraprostatic testosterone concentration that results from finasteride treatment in rats is sufficient to inhibit apoptosis but will not maintain normal epithelial cell activity. In conclusion, whereas DHT is more potent than testosterone at stimulating prostate epithelial cell function as measured by ductal mass, the two androgens are equipotent at preventing prostate cell death after castration. These results explain why finasteride causes prostate involution in the rat with minimal evidence of prostate cell death.
Objectives. To compare the long-term effects of finasteride (5 mg/day) and placebo in patients with moderate symptoms of benign prostatic hyperplasia (BPH).Methods. Patients aged 50 to 75 years, with at least two urinary symptoms indicating moderate BPH, and an enlarged prostate, were followed in a 2-year double-blind, randomized, placebo-controlled multicenter study. The effects of finasteride versus placebo were assessed by total symptom score (modified Boyarsky), obstructive symptom score, maximal urinary flow rate, prostate volume, and urologic end points (acute urinary retention, BPH-related surgical intervention).Results. Of the 3270 men enrolled, 3168 contributed data to the safety analysis, and 2902 to the efficacy evaluation. Significantly greater improvement with finasteride compared to placebo was observed at 12 and 24 months for total symptom score (mean −2.9 versus −1.9 at 12 months, P ≤0.001; −3.2 versus −1.5 at 24 months, P ≤0.001), obstructive symptom score (mean −1.9 versus −1.3 at 12 months, P ≤0.001; −2.1 versus −1.1 at 24 months, P ≤0.001), maximal urinary flow rate (mean +1.2 versus +0.6 mL/s at 12 months, P = 0.010; +1.5 versus +0.7 mL/s at 24 months, P = 0.002), and prostate volume (mean −14.2 versus +5.4% at 12 months, P ≤0.01; −15.3 versus +8.9% at 24 months, P ≤0.001). Greater improvements in placebo-adjusted total symptom score occurred in men with large prostates than in men with small prostates (mean −2.4 versus −1.1 at 12 months; −3.2 versus −1.3 at 24 months, placebo-adjusted data, P = 0.053). Fifteen of 1450 men (1.0%) in the finasteride group experienced an acute urinary retention event, compared with 37 of 1452 (2.5%) in the placebo group, and the corresponding figures for surgery were 51 of 1450 (3.5%) and 86 of 1452 (5.9%), respectively. The hazard rate for occurrence, computed using the log-rank statistic, decreased by 57% for acute urinary retention and by 40% for surgery accompanied by finasteride therapy compared to placebo.Conclusions. Finasteride causes long-term symptomatic improvement and reduces the risk of acute urinary retention or surgery. Men with enlarged prostates benefit most from finasteride treatment.
This study was undertaken to evaluate a possible effect of the extracts PY102 of Pygeum africanum (Hook), and UR 102 of Urtica dioica L. as well as their combination PHL-00801 (Prostatonin®) on the enzymes 5 α-reductase (5 α-RE) and aromatase (AR): Inhibition of 5 α-RE: Pygeum africanum extract PY 102, and Urtica dioica extract UR 102, inhibited the 5 α-RE activity in a concentration dependent manner. Whereas UR102 extract was only able to influence the enzyme activity at high concentrations (≥ 12mg/ml) and its ED(50) being calculated as 14.7mg/ml, the PY102 extract showed a much higher activity starting with low concentrations (0.1 mg/ml) its ED(50) being calculated as 0.78 mg/ml. When compared with the effects of UR 102, the combination of both extracts, PHL-00801 (Prostatonin®), led to a similar inhibition of the enzyme (ED(50) 14.15 mg/ml). Inhibition of AR: The PY 102 extract showed a concentration dependent and strong activity (ED(50) = 0.98 mg/ml). The activity of the UR 102 extract was also concentration dependent (ED(50) = 3.58 mg/ml). The combination of both extracts, PHL-00801 (Prostatonin®) showed a synergistic action and significantly (p = 0.05) increased the AR-inhibitory activity in concentrations as low as 0.1 mg/ml (ED(50) 0.24 mg/ml). These observations are an explanation for the beneficial effects of PHL-00801 (Prostatonin®) observed in the clinical studies on BPH.
Partial outlet obstruction of the rabbit bladder induces a rapid and significant increase in bladder mass. This increase in mass is associated with a variety of specific contractile dysfunctions, characterized by a marked decrease in the response to field stimulation (acting through the release of neurogenic transmitters). There is histological evidence indicating that the decrease in the contractile response of isolated strips of rabbit urinary bladder to field stimulation is associated with a degeneration of synaptic membranes within the bladder detrusor (neuropathy). In the current experiments, the effect of partial outlet obstruction in rabbit and rat urinary bladders on choline acetyltransferase activity (ChAT) were determined and correlated with both the level of bladder hypertrophy (increase in mass) and the contractile response to field stimulation. The results can be summarized as follows: In the rabbit, partial outlet obstruction induced a rapid 5-fold increase in bladder mass over the 7 day period of study. This increase in mass was associated with a decrease in the contractile response of isolated strips of bladder body and base to field stimulation and a decrease in ChAT activity. Interestingly, the rabbit bladder base showed a significantly higher ChAT activity than the bladder body, although the contractile response to muscarinic stimulation was significantly greater in the bladder body than in the base. In the rat, partial outlet obstruction induced a mild 2-fold increase in bladder mass. No change in ChAT activity was observed in the obstructed bladder. Consistent with this finding, there was no dysfunction in the response to field stimulation in the obstructed rat bladder.
Micturition is a complex neuromuscular process. Although control mechanisms have been identified at several levels of the central nervous system and spinal cord, the final pathway in the control of micturition is the autonomic innervation of the urinary bladder and related structures. Following this line of reasoning further, micturition is ultimately dependent on the ability of the urinary bladder to both contract and generate intravesical pressure, and to modify its shape in such a way as to efficiently expel its contents without leaving a high residual volume.
In order to understand the various elements of micturition, a wide variety of both in vivo and in vitro animal models has been developed. In many cases, animal models have been utilized to describe the effect of specific experimental pathologies on the lower urinary tract. The current review of the use of the rabbit in urological research is not meant to be a comprehensive treatise on the topic, but should provide a rational description of the how this species can be utilized to study both normal and pathological function. © 1994 Wiley‐Liss, Inc.
Previous studies demonstrated that one of the most significant cellular responses of the rabbit urinary bladder to partial outlet obstruction is a 50% decrease in the activities of the mitochondrial enzymes citrate synthase and malate dehydrogenase, when calculated as either activity per unit mass or activity per mg protein. A major question arose from these studies: Are the mitochondrial enzyme activities per mitochondrion reduced, or is the number of mitochondria per unit tissue mass reduced? The current experiments were designed to study the sequential changes in the activities of mitochondrial oxidative enzymes following partial outlet obstruction.The activities of NADH-cytochrome c reductase (NCCR), cytochrome oxidase (CO), citrate synthase (CS) and malate dehydrogenase (MDH) were measured in whole tissue homogenates and in mitochondrial preparations of separated bladder mucosa and muscle, from normal bladders, and, from hypertrophied bladders at 1, 3, and 7 days following partial outlet obstruction. The results can be summarized as follows:1)
Whole tissue homogenates: Activities of all enzymes were reduced to approximately 50% of control at 1 day following partial outlet obstruction. NCCR and CO activities returned to 75 and 85% of control respectively by 7 days post-obstruction; CS activity did not show any significant recovery over the 7 day period.
2)
Mucosal and smooth muscle mitochondrial preparations: Activities of all enzymes were decreased significantly by 50% or greater at 1 day following partial outlet obstruction. The cytochrome (NCCR and CO) enzyme activities returned to control levels by 7 days post-obstruction; CS activity showed only a minor recovery over this time period.
These results show that mitochondrial enzyme activity is significantly impaired immediately following partial outlet outlet obstruction, and whereas the activity of the cytochrome enzymes NCCR and CO recover to control levels (in the mitochondiral preparations) within 7 days post obstruction, the Krebs cycle enzymes (CS and MD) show no significant recovery. Thus, the regulatory mechanisms for the cytochromes is significantly different from that for the enzymes of the krebs cycle.
The hormones of the pituitary gland are capable of directly influencing the function of male accessory sex organs. Among these hormones, prolactin in particular has been observed to enhance consistently the effects of androgens in the prostate gland and/or the seminal vesicles of rats, mice, and guinea pigs as well as in the accessory sex organs of other species. Prolactin-mediated augmentation of testosterone's effects upon these tissues is related primarily to the growth-promoting influences of this steroid. However, under certain experimental conditions, the androgen-dependent production of secretions by these organs has also been enhanced by prolactin treatment. Studies in the mouse have indicated that prolactin primarily enhances the proliferative phase of androgen action in male accessory sex tissues. Testosterone stimulation of RNA synthesis was unaffected by simultaneous administration of prolactin. The mechanism by which prolactin causes enhanced androgen responses in the prostate gland and seminal vesicles is not well understood. It would appear, however, that prolactin neither stimulates increased accumulation of androgen into the accessory sex organs, nor does it enhance the conversion of testosterone to the more "active" androgen, dihydrotestosterone. The effects of prolactin on these tissues are, however, dependent upon the presence of dihydrotestosterone. Uncertain, at present, are the possible effects of prolactin on the binding or retention of androgens (dihydrotestosterone?) in the prostate gland or in the seminal vesicles. There is evidence that hypophysectomy reduces the nuclear binding of dihydrotestosterone in the cells of the prostate gland. Perhaps prolactin is a pituitary factor(s) which is important in regulating nuclear binding of dihydrotestosterone in male accessory sex organs. The direct influences of prolactin upon androgen action in the cells of the accessory sex organs may involve several sites of action (Figure 2). For example, it is currently understood that when testosterone enters the cell cytoplasm it is subsequently converted to the more "active" androgen, dihydrotestosterone (DHT), by reduction at the 5alpha position. Dihydrotestosterone is then either bound to a cytoplasmic "receptor" protein (Rc) or is further metabolized to either 5alpha-androstane-3alpha,17beta-diol or 5alpha-androstane-3beta,17beta-diol (DIOL). The binding of DHT to its cytoplasmic receptor protein results in translocation of the steroid-receptor complex into the nucleus where presumably the complex dissociates and DHT exerts its androgenic effects. The transport of DHT to the nucleus can also result from the conversion of testosterone to DHT by nuclear membrane-bound 5alpha-reductase. Prolactin augmentation of DHT effects is envisioned as resulting from interaction of prolactin with its receptor, which due to the large size of the prolactin molecule is probably located in or on the plasma membrane...
Previous studies have demonstrated that partial outlet obstruction in rabbits induced a significant decrease in oxidative metabolism in urinary bladder smooth muscle. The current experiments were designed to determine whether the decreased oxidative metabolism of obstructed bladder tissue is associated with alterations in the activities of specific mitochondrial enzymes. The activities of two important enzymes in the tricarboxylic acid cycle, malate dehydrogenase and citrate synthase, were measured in samples of bladder body and base from normal bladders and in bladders from rabbits in which partial outlet obstruction had been produced seven days prior to the experiments. The results can be summarized as follows: malate dehydrogenase activity was similar in bladder body and base isolated from control rabbits; and decreased by approximately 40% in both segments of the bladder isolated from obstructed rabbits. In contrast to malate dehydrogenase, citrate synthase activity was significantly higher in the bladder body than in the base of normal rabbits. Outlet obstruction caused about a 50% decrease in activity of this enzyme in the bladder body, but had no significant effect on citrate synthase activity of the bladder base. These findings demonstrate that the deficiency in bladder function following partial outlet obstruction is associated with a marked decrease in the activities of two essential enzymes in oxidative metabolism: malate dehydrogenase and citrate synthase. This decrease in enzyme activity is consistent with the previously observed decrease in oxidative metabolism and would be expected to lead to an inability of the tissue to supply sufficient metabolic energy for proper contractile function.
The pathogenesis of benign prostatic hyperplasia (BPH) is still poorly understood: there is, however, general acceptance that the condition is not premalignant and that it has an etiology distinct from that of cancer. Interest now focuses on the biochemistry of the target prostate cells and the propensity of the gland for uncontrolled growth. Dihydrotestosterone (DHT) is the active intracellular androgen formed from testosterone by 5 alpha-reductase. DHT concentrations appear a little higher in BPH tissue than in normal tissue, and there is no doubt that DHT-receptor complex modulates gene expression. Current studies suggest that DHT is essential but not sufficient for proliferation, and that other regulatory factors, including peptide growth factors, are prerequisite. The growth responsiveness of prostate tissue to androgens may be dependent on the balance between epithelial and stromal tissues, with biologic processes in the epithelium indirectly controlled by androgen-dependent mediators of stromal origin.
The presence of the prostate is universal in mammals; when compared among species the prostate is marked by variations in its anatomy, biochemistry and pathology. The epithelial cells provide secretions that empty through ducts into the urethra to form a major component of the seminal plasma of the ejaculate. The prostate is stimulated to grow and is maintained in size and function by the presence of serum testosterone. Several protein-type growth factors, such as urogastrone and prostatropin, may also affect prostatic growth. After testosterone from the plasma has entered the prostatic cell through diffusion it is metabolized to other steroids by a series of enzymes. Over 95% of testosterone is converted to the most important prostatic androgen dihydrotestosterone. DHT then binds to the activated androgen receptor. The hormone receptor complex undergoes transformation and translocation into the nucleus. In the nucleus RNA-polymerase is activated followed by the synthesis of mRNA. The noncellular stroma and connective tissue compose the extracellular matrix. The extracellular matrix plays an important role in development and control of cellular functions.
In vitro pharmacological studies were performed on endoscopic detrusor biopsies from patients with bladder outflow obstruction. Urodynamic studies had been undertaken to detect the presence of bladder instability. Muscle strips from patients with instability demonstrated supersensitivity to acetylcholine and reduction in nerve mediated responses, as compared with strips from stable bladders. These changes are interpreted as suggesting the presence of cholinergic denervation in obstructed patients with bladder instability.
In a group of patients in whom bladder outflow obstruction had been confirmed urodynamically, quantitative assessment of the amount of autonomic nerve in detrusor biopsy samples has been carried out using light and electron microscope techniques. In each specimen allowance was made for muscle cell hypertrophy and increases in connective tissue, both of which occurred in response to bladder outflow obstruction. Similar quantitative assessment was performed on bladder biopsy samples from a group of unobstructed 'control' patients. When the results from the two groups were compared a statistically significant reduction in the amount of autonomic nerve supplying detrusor muscle was demonstrated in the obstructed group. This finding provides additional evidence that functional impairment of the urinary bladder occurs in response to outflow obstruction and emphasizes the need for prompt relief of the condition.
As part of an ongoing study on trabeculation of the human urinary bladder, morphological and morphometric techniques have been employed on biopsy samples of detrusor muscle removed from control and urodynamically obstructed patients. In control material the mean profile area, profile diameter and nucleated profile percentage of bladder smooth muscle cells were determined. The values of the same parameters were obtained for smooth muscle cells in samples from urodynamically obstructed and endoscopically trabeculated patients. Comparison of the results obtained from the two groups showed that smooth muscle cells undergo compensatory hypertrophy in response to outflow obstruction. Furthermore, connective tissue infiltration of detrusor muscle bundles is a characteristic of those bladders which possess cells showing the largest increase in cell size.
The light and electron microscopic structure of biopsy samples of trabeculated urinary bladder from patients with proven outlfow obstruction due to prostic hypertrophy has been compared with the morphology of control bladder specimens. In the latter the detrusor muscle bundles were composed of smooth muscle cells closely packed together with very little intervening connective tissue. In contrast, irrespective of age, detrusor muscle from trabeculated bladders contained many muscle bundles in which the constituent cells were of relatively small diameter and were widely separated from each other by dense masses of connective tissue. No morphological evidence for smooth muscle hypertrophy or hyperplasia was obtained in the present study. In the electron microscope the connective tissue between the smooth muscle cells of trabeculated bladders was seen to contain, in addition to collagen fibrils, an extensive meshwork of electron-dense microfibrils apparently in continuity with the basal laminae of the smooth muscle cells. Regions of close approach between smooth muscle cells were seemingly unaffected by trabeculation as was the distrubution and fine structure of autonomic nerve terminals. These observations are intended to form a baseline for comparision with the results of future morphological studies of trabeculation arising in response to different aetiological factors.
Concentrations of fatty acids (FA) in prostatic tissue of patients with either benign or malignant prostatic disease have previously been shown to be significantly different. In particular, there was a significant reduction in arachidonic acid (AA, C20:4n-6) and docosapentaenoic acid (DPA, C22:5n-6) concentrations in malignant prostatic tissue (PCa) phospholipids (PL). It was suggested that the decreased AA concentration in PCa may be due to its increased metabolism via the cyclooxygenase (CO) and/or lipoxygenase (LO) pathways to produce eicosanoids such as prostaglandins (PGs) and/or leukotrienes (LTs) rather than an impairment in desaturase activity in situ. The eicosanoid production in benign prostatic tissue (BPH) and PCa was determined using [3H]AA. The only eicosanoid produced in significant amounts by either tissue was PGE2 and PCa converted radiolabelled AA to PGE2 at an almost 10-fold higher rate than BPH. PGE2 production from [3H]AA by PCa was investigated in the presence of oleic acid (OA, C18:1n-9), eicosapentaenoic acid (EPA, C20:5n-3), docosahexaenoic acid (DHA, C22:6n-3), dihomo-gamma-linolenic acid (DGLA, C20:3n-6), eicosatetraynoic acid (ETYA) and ketoprofen (KPN) respectively. OA was found to be the most effective inhibitor of PGE2 production by PCa compared with DHA, EPA, ETYA and KPN, while DGLA was the least effective. Diacylglycerol (DAG) formation from labelled AA by PCa was about 4-fold greater than in BPH. Such high levels of DAG may be a means of promoting tumorigenesis through activation of protein kinase C as found with phorbol esters which can be regarded as DAG analogues.
Sixty-three patients suffering from benign prostatic hyperplasia (BPH) entered a double-blind, comparative, parallel-groups study lasting 3 weeks, carried out to compare the efficacy and safety of alfuzosin 2.5 mg tid (n = 32) vs serenoa repens 160 mg bid (n = 31) in BPH.
Efficacy was assessed both on clinical symptoms (Boyarsky's scale, visual analogue scale, clinical global impression), urinary flow rates (uroflowmetry) and residual urinary volume (transabdominal ultrasound). Events and reported signs were recorded throughout the entire study.
Statistically significant and clinically relevant differences were found between the two treatments in favour of alfuzosin for Boyarsky's total score (decrease from 9.6 +/- 3.0 to 5.9 +/- 3.0, 38.8% for alfuzosin and from 9.3 +/- 2.5 to 6.8 +/- 2.8, 26.9% for serenoa repens) and obstructive score (decrease from 4.9 +/- 2.1 to 3.0 +/- 1.9, 37.8% for alfuzosin; from 4.4 +/- 1.7 to 3.4 +/- 1.8, 23.1% for Serenoa repens; p = 0.01 for both). Clinically relevant differences were found between the two treatments for visual analogue scale and overall clinical impression at the end of the study. Furthermore, the increase in quality of micturition was better with alfuzosin. The proportion of responders (increase on day 21 in peak flow rate of at least 25% relative to the baseline values) was in favour of alfuzosin (71.8% and 48.4% for alfuzosin and Serenoa repens, respectively; p = 0.057). Both treatments were well tolerated. No patient treated with alfuzosin complained of any adverse event at any time during the study. One patient in the Serenoa group complained of mild pruritus which cleared spontaneously. Systolic, diastolic blood pressure and heart rate did not show any clinically relevant change during treatment with alfuzosin.
The findings confirm the efficacy and safety of alfuzosin in symptomatic BPH and indicate the superiority of alfuzosin over Serenoa repens in the treatment of urinary signs and symptoms of BPH.
Partial outlet obstruction of rabbit bladder induces serosal thickening and smooth muscle (SM) cell hypertrophy that are accompanied by phenotypic changes in the expression of cytoskeletal and cytocontractile proteins. In the present study, we compare the observed progressive phenotypic changes with the contractile responses of strips of the thickened serosa. At 15 days after partial outlet obstruction, although cells in thickened serosa demonstrate the presence of nonmuscle (NM) myosin of A-like type, vimentin, and SM alpha-actin, no contractile responses of this tissue were noted. At later times (30 days), this tissue expressed in addition SM myosin, and this pattern was paralleled by the development of KCl-stimulated contractility. It is only after 60 days that the serosa demonstrated the expression of desmin, phosphoglucomutase (PGM)-related protein, and was locally negative for NM myosin, indicating a maturation toward adult SM cells. Concomitant to this phenotypic change, the response to KCl increased, and a bethanechol-stimulated contractile response developed. At no time period did the serosal layer react with anti-synaptophysin or anti-neurofilament proteins nor did the strips respond to field stimulation (via release of neurotransmitters), showing that SM cell differentiation and development of contractile responses during serosal thickening are independent of innervation.
This study investigated the effects of outlet obstruction on blood flow and high energy phosphates content in the rabbit urinary bladder. Mild bladder outlet obstruction was induced by placing a silicon ring (diameter 7 mm) around the bladder neck of each male New Zealand White rabbit (n = 7). Before and immediately after inducing obstruction, and 2 weeks later, the bladders were emptied and regional blood flow measured using laser Doppler flowmetry (LASERFLO BPM2, Vasamedics Inc., St. Paul, Minnesota). Six different areas of each bladder were measured, and the average blood flow calculated for each rabbit. Then, the animals were sacrificed, the bladder excised, and the tissue content of high energy phosphates determined by high performance liquid chromatography (HPLC). Six normal male New Zealand White rabbits served as controls. The results can be summarized as follows: (1) Before surgery, bladder blood flow was similar in all animals (16.3 ml/min/100 g); positioning the silicon ring around the bladder neck did not affect blood perfusion, two weeks after the induction of outlet obstruction, bladder blood flow was significantly decreased (4.9 ml/min/100 g). (2) There was no significant difference between control and obstructed bladders in NAD, AMP, or ADP content. However, the obstructed bladders contained significantly less phosphocreatine (12.0 vs 21.9 nmol/mg protein) and ATP (4.0 vs. 6.1 nmol/mg protein) than control bladders. In summary, this study showed that urinary bladder blood flow was reduced by outlet obstruction, and the reduction in blood flow was associated with decreased tissue high energy phosphates content.(ABSTRACT TRUNCATED AT 250 WORDS)
Urinary bladder outlet obstruction is a common medical problem. In order to understand the effects of outlet obstruction on bladder morphology, physiology, and pharmacology, several animal models of obstruction have been developed using a variety of species. Although there are marked differences in bladder size, capacity, compliance, physiology, and pharmacology among these species, responses to outlet obstruction have many common characteristics. This article will be separated into six areas: introduction, genetic factors mediating the response during the initial period of partial outlet obstruction and overdistension, cytostructural alterations that accompany compensated bladder function, alterations in innervation accompanying bladder hypertrophy secondary to partial outlet obstruction, alterations in calcium translocation during bladder hypertrophy, and metabolic factors involved in the response to partial outlet obstruction.
Pygeum africanum extract has been used for more than 20 years in France in patients suffering from benign prostatic hypertrophy (BPH). The extract displays anti-inflammatory activity and inhibits bladder hyperreactivity during the above conditions. However, the mechanism of action of P. africanum extract has never been clearly resolved. It has been recently demonstrated that infiltration by inflammatory cells may be involved in the development of BPH. Certain of these cell types, such as macrophages, are known to produce chemotactic mediators including leukotrienes, and thus may contribute to the development of the disease. In order to investigate the potential effect of P. africanum extract on arachidonate metabolism, we examined its effect in vitro on leukotriene (LT) synthesis in human polymorphonuclear cells stimulated with the calcium ionophore A23187. Two formulations of the extract were tested, one dissolved in DMSO and one aqueous solution obtained after alkalinization (0.1 N; NaOH/acidification (0.1 N; HCl). Neither formulation had any effect on cell viability which was above 95% in both cases. P. africanum extract dissolved in DMSO significantly inhibited the production of 5-lipoxygenase metabolites (5-HETE, 20-COOH LTB4, LTB4 and 20-OH LTB4) at concentrations as low as 3 micrograms/ml (p < 0.01), while the same extract dissolved in NaOH/HCl only exhibited an inhibitory effect at 10 micrograms/ml (p < 0.01). This difference apparently reflects the greater solubility of the active components in the extract in DMSO. The ability of P. africanum to antagonize 5-lipoxygenase metabolite production may contribute, at least in part, to its therapeutic activity in inflammatory component of BPH.
Micturition is a complex neuromuscular process. Although control mechanisms have been identified at several levels of the central nervous system and spinal cord, the final pathway in the control of micturition is the autonomic innervation of the urinary bladder and related structures. Following this line of reasoning further, micturition is ultimately dependent on the ability of the urinary bladder to both contract and generate intravesical pressure, and to modify its shape in such a way as to efficiently expel its contents without leaving a high residual volume. In order to understand the various elements of micturition, a wide variety of both in vivo and in vitro animal models has been developed. In many cases, animal models have been utilized to describe the effect of specific experimental pathologies on the lower urinary tract. The current review of the use of the rabbit in urological research is not meant to be a comprehensive treatise on the topic, but should provide a rational description of the how this species can be utilized to study both normal and pathological function.
Partial outlet obstruction of the rabbit urethrovesical junction (UVJ) has been used to induce pathology in the urinary bladder characteristic of obstructive damage observed in humans. The purpose of the experiments reported here was to compare the ³H-thymidine (³H-TdR) labelling of DNA in urinary bladders of male New Zealand White (NZW) rabbits subjected to partial outlet obstruction or overdistension. A total of 18 animals was used. Two normal controls, and 12 partially obstructed animals (at I day [D], 3D, 5D, 7D, 14D, and 2ID) were injected (i.v.) with ³H-TdR at a dose of 0.5 μ-Ci/g body weight. An additional 4 were overdistended to volumes 120% of maximum intravesical pressure, immediately emptied via the catheter, and injected with ³H-TdR 24 hr (ID) later. All animals were sacrificed up to 3.5 hr after injection of the label.
Partial obstruction of the rabbit urethra induces rapid bladder growth. This growth is characterized by hypertrophy of smooth muscle cells in addition to hyperplasia of cells in the urothelium and serosa. The local synthesis of growth factors has been proposed to be influential in this growth since partial outlet obstruction rapidly increases the bladder's expression of basic fibroblast growth factor, while suppressing the expression of transforming growth factor-beta. Upon release of the outlet obstruction, the hypertrophied bladder regresses to its normal weight. Here, we examined whether regression of the hypertrophied rabbit bladder involves apoptosis (programmed cell death) of specific cellular elements and whether the expression of growth factors is altered concomitant with apoptotic cell deletion.
Regressing rabbit bladders were analyzed for markers of apoptosis, including DNA fragmentation and histology. An in situ enzymatic immuno-histochemical procedure was utilized to localize apoptotic cells in these tissues. Finally, Northern blot analysis was used to identify changes in the expression of basic fibroblast growth factor and transforming growth factor-beta during bladder regression.
Regressing rabbit bladders demonstrated the characteristic electrophoretic "ladder" pattern of DNA fragmentation associated with apoptosis. An in situ technique to distinguish cells with degraded nuclear DNA identified apoptosis only within the urothelium and serosal lamina of the regressing bladders. RNAs extracted from regressing bladders exhibited decreased expression of basic fibroblast growth factor mRNA as well as increased expression of transforming growth factor-beta 1 mRNA when compared with RNAs from hypertrophied bladders.
We conclude that hyperplasia and apoptosis are opposing cellular processes that mediate the bladder's response to short-term obstructive stimuli and that local synthesis of growth-promoting and growth-inhibitory factors may be responsible for initiating both of these responses.
We compare testosterone (T) metabolism in primary cultures of epithelial cells and fibroblasts separated from benign prostate hypertrophy (BPH) and prostate cancer tissues. In all cultures, androstenedione (delta 4) formed by oxidation of T by 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) represented 80% of the metabolites recovered. The amounts of 5 alpha-dihydrotestosterone (DHT), formed by reduction of T by 5 alpha-reductase (5 alpha-R), were small: 5 and 2% (BPH) and 8 and 15% (adenocarcinoma) for epithelial cells and fibroblasts, respectively. Northern blot analysis of total RNA from epithelial cells (BPH or adenocarcinoma) attributed the reductive activity to the 5 alpha-reductase type 1 isozyme and oxidative activity to the 17 beta-HSD type 2. In cancer fibroblasts, only little 17 beta-HSD type 2 mRNA was detected. The 5 alpha-reductase inhibitors, 4-MA (17 beta-(N,N-diethyl)carbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one) and finasteride, inhibited DHT formation with a preferential action of 4-MA on epithelial cells (BPH or adenocarcinoma) and of finasteride on fibroblasts from adenocarcinoma. Neither inhibitor acted on delta 4 formation. On the other hand, the lipido-sterol extract of Serenoa repens (LSESr, Permixon) inhibited the formation of all the T metabolites studied [IC50 S = 40 and 200 micrograms/ml (BPH) and 90 and 70 micrograms/ml (adenocarcinoma) in epithelial cells and fibroblasts, respectively]. These results have important therapeutic implications when selecting appropriate treatment options for BPH.
Extract from fruit of Sabal serrulata are used in the treatment of human benign prostate hyperplasia (BPH). Therefore, it is of interest whether this phytopharmacon has any influence on the androgen metabolism in the human prostate. It was found that the extract IDS 89 of Sabal serrulata inhibited dose dependently 5 alpha-reductase activity in the epithelium and stroma of human BPH, the mean inhibition being 29% and 45%, respectively. This inhibitory effect is mainly due to the saponifiable subfraction of IDS 89 showing a mean 5 alpha-reductase inhibition of 39% and 38% in epithelium and stroma, respectively. The inhibition was dose dependent and noncompetitive. At a testosterone concentration of 580 nM as substrate for 5 alpha-reductase, the main fatty acids of the extract IDS 89 gave rise to a percentual enzyme inhibition in the epithelium and stroma as follows: 51% and 42% (lauric acid), 5% and 0% (oleic acid), 43% and 34% (myristic acid), 2% and 0% (palmitic acid), respectively. The inhibitory effect of lauric acid was noncompetitive and dose dependent up to a concentration of 0.2 nM, the maximal inhibition in the epithelium and stroma being 52% and 45%, respectively. The nonsaponifiable subfraction, consisting mainly of phytosterols, showed a mean inhibition of 5 alpha-reductase in the epithelium and stroma of 15% and 10%, respectively. Finally, the hydrophilic subfraction, containing carbohydrates, amino acids, and polysaccharides, showed no inhibitory effect. The present in vitro studies suggest that the Sabal serrulata extract IDS 89 has an inhibitory effect on 5 alpha-reductase in the epithelium and stroma of human BPH. This inhibition is mainly due to the fatty acids of the saponifiable subfraction.
Tadenan (DEBAT, Paris, France) is a pharmaceutical agent used in the treatment of benign prostatic hyperplasia (BPH). The specific aim of this study was to determine if pretreatment of rabbits with Tadenan reduced either the hypertrophic response of the bladder to partial outlet obstruction or the accompanying contractile dysfunction.
Twenty-five male New Zealand rabbits (3 to 5 kg.) were separated into 5 groups of 5 rabbits each. Each rabbit in groups 1,2, and 3 received Tadenan orally at 1, 10 and 100 mg./kg./day for 3 weeks. Group 4 received vehicle only (peanut oil); Group 5 were controls. The bladders were evaluated (in vitro studies) after 2 weeks of obstruction.
1) Tadenan did not reduce the effect of partial outlet obstruction on bladder mass. 2) Tadenan pretreatment resulted in a significant protective effect on the contractile responses to field stimulation, bethanechol and KCl.
These results clearly demonstrate that Tadenan pretreatment protected the bladder from the contractile dysfunctions induced by partial outlet obstruction.
To study changes in bladder blood flow and oxygenation associated filling, contraction and outlet obstruction.
Intravesical pressure, bladder flow, bladder wall oxygen tension, iliac artery blood flow and systemic blood pressure were measured simultaneously in anesthetized dogs (N = 18).
In the empty bladder, blood flow and oxygen tension in the bladder were greater than at the dome with and without outlet obstruction. Bladder filling caused a significant decrease in bladder wall blood flow and oxygen tension with or without outlet obstruction. Spontaneous bladder contractions resulted in a marked decrease in bladder wall perfusion in the obstructed bladder but not in the unobstructed bladder. Pelvic nerve stimulation produced strong bladder contractions associated with significant drop in bladder wall perfusion and bladder oxygenation in both the open and closed bladder neck models. Little change was noted after stimulation of the hypogastric nerve.
Bladder distention and contraction, especially against a closed bladder neck, induce significant ischemia and hypoxia of the bladder wall. These findings may be important in the pathophysiology of a variety of common clinical problems.
The aim of the present study was to evaluate the usefulness of ultrasonic estimation of bladder weight as a measure of bladder hypertrophy using transabdominal ultrasonography in men with infravesical obstruction. Ultrasonically estimated bladder weight (UEBW) was calculated from the thickness of the bladder wall measured ultrasonically and the intravesical volume at the ultrasonic measurement, assuming a spheric bladder. There was a statistically significant correlation (r = 0.970, P <0.001) between the actual bladder weight of cadaver bladders and the UEBW. The UEBW did not change with bladder filling. The UEBW in the obstructed group (group O, 49.7 +/- 19.5 g, mean +/- SD) was significantly greater than that in the normal control group (group NC, 25.6 +/- 5.7 g; P <0.001) or the nonobstructed group (group NO, 28.4 +/- 4.2 g; P <0.001). The greatest UEBW was 34.8 g in group NC and 35.2 g in group NO, whereas 94% (45 of 48) of group O had a UEBW greater than 35.0 g. In all 5 patients with benign prostatic hyperplasia (BPH), the increased UEBW decreased to a normal control level at 3 months after treatment of BPH. This new noninvasive method may be useful in investigation of bladder hypertrophy.
While it may lack the classic morphological pattern in striated muscle systems, there is ample evidence that smooth muscle also contains sarcoplasmic reticulum. These intracellular storage sites release calcium into the cytosol to generate contractile force in response to various stimuli. A major component of the sarcoplasmic reticulum is an adenosine triphosphate dependent ion pump, which serves to drive free calcium out of the cytosol back into this intracellular reservoir. This ion pump serves to maintain the intracellular calcium storage sites, and also as a marker of the sarcoplasmic reticulum.
Muscle strip studies were performed to stratify the data into 3 major groups (controls, and compensated and decompensated obstructions) based on physiological performance. These were correlated with biochemical and molecular determinations of sarcoplasmic endoplasmic reticulum calcium, magnesium-adenosinetriphosphatase expression.
Our results demonstrate a remarkable loss of sarcoplasmic endoplasmic reticulum calcium-adenosinetriphosphatase activity in the decompensated group and a moderate loss in the compensated group.
These data provide molecular support for our previous physiological studies in which we demonstrated an important role for intracellular calcium storage and release with normal bladder smooth muscle function. These data strongly support our contention that contractile dysfunction in bladder smooth muscle following outlet obstruction is partially mediated by changes in the mechanisms of intracellular calcium homeostasis.
The contractile response of the smooth muscle of the urinary bladder is dependent upon both the entrance of extracellular calcium through receptor-operated calcium channels and the stimulated release of calcium from the sarcoplasmic reticulum. In addition, partial outlet obstruction induces marked alterations in the utilization of intracellular calcium. Although calcium ATP-ase provides the energy for the translocation of intracellular free calcium into storage sites within the sarcoplasmic reticulum, very little is known about the properties of this enzyme in bladder muscle and mucosa. As an initial study, divalent ion specific ATP-ase activity was measured in extracts of rabbit bladder muscle and mucosa from control animals and from rabbits following partial urinary outlet obstruction. In both normal bladder muscle and mucosa, magnesium and calcium ions were equally effective in activating the enzyme. Seven days following partial urinary outlet obstruction, the ATP-ase activity in both bladder muscle and mucosa was significantly depressed by over 70%. The degree of the decreased enzyme activities observed within the muscularis and mucosa would indicate that specific membrane functions supported by divalent-ion-ATP-ase are dysfunctional. This hypothesis is supported by marked alterations in the utilization of intracellular calcium following partial outlet obstruction and the marked dysfunctions in both mucosal permeability and bacterial adherence to mucosa observed following partial outlet obstruction.
Objectives:
In the rabbit, both experimental ischemia and partial outlet obstruction of the urinary bladder induce similar dysfunctions with regard to the contractile responses to both field (neuronal) stimulation and postsynaptic receptor stimulation. Circumstantial evidence indicates that the pathologic response to both conditions is related to two connected processes-tissue ischemia and reperfusion injury-that result in a marked increase in intracellular calcium ([Ca2+]i), followed by the activation of the Ca(2+)-dependent neutral protease calpain. Calpain activation results in the proteolysis of specific membrane proteins, including those of neuronal membranes (resulting in progressive denervation of the detrusor) and the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), resulting in the previously reported decrease in SERCA. The current study is designed to generate direct support for the theory that both ischemia and partial outlet obstruction result in the activation of calpain.
Methods:
Separate sets of rabbits were subjected to 1 or 2 hours of ischemia, followed by reperfusion for different lengths of time, or partial outlet obstruction for different lengths of time. We determined the state of calpain activation by quantitating tissue proteolysis of alpha-spectrin by Western blot analysis. Correlative organ bath studies were conducted to observe the contractile responses of bladder strips to field stimulation and bethanechol administration.
Results:
(1) Sixty minutes of ischemia followed by 30 minutes of reperfusion resulted in (a) a reduction in the contractile responses to field stimulation and bethanechol (89% and 57%, respectively), and (b) a 72% decrease in native alpha-spectrin, with a concomitant 300% increase in its breakdown products (BDPs). Neither alpha-spectrin nor its BDPs had returned to control levels after 72 hours of reperfusion. (2) Twenty-four hours after the creation of a partial obstruction, alpha-spectrin BDP levels were increased 330%, then gradually fell to 130% of control levels by 14 days after obstruction. Concomitantly, the native alpha-spectrin level was decreased 74% 24 hours after obstruction and remained low through 7 days after obstruction. At 14 days after obstruction, the alpha-spectrin levels had recovered to 75% of control levels.
Conclusions:
These findings suggest that Ca(2+)-dependent proteolysis of the preferred calpain substrate alpha-spectrin in urinary bladder tissues is increased significantly by both ischemia/reperfusion and partial outlet obstruction. Temporally, proteolysis precedes the reduced muscle function resulting from these pathologic conditions.
The effect of the lipidosterolic extract of Serenoa repens (LSESR) on experimental prostate enlargement was investigated in three groups of rats: shams treated with LSESR (sham rats), castrated animals treated with estradiol and testosterone (castrated rats), castrated animals treated with estradiol/testosterone and treated with LSESR (castrated and treated rats). Following three months of continuous hormonal treatment, the weight of prostates in estradiol/testosterone-treated castrated rats was significantly increased in comparison with sham-operated rats. Such an increase started rapidly, reached a maximum by 30 days and remained at a plateau or slightly declined thereafter. The increase of prostate total weight induced by the hormone treatment was inhibited by administration of LSESR. Indeed, the weight was significantly lower at day 60 and day 90 for the dorsal and lateral regions of the prostate. The weight of the ventral region of the prostate was significantly lower after 30 and 60 days treatment with LSESR. These results demonstrate that administering LSESR to hormone-treated castrated rats inhibits the increase in prostate wet weight. This effect of LSESR may explain the beneficial effect of this extract in human benign prostatic hypertrophy.
The effect of a Pygeum africanum extract (Tadenan) (Pa), used in the treatment of micturition disorders associated with BPH, has been examined on the proliferation of rat prostatic stromal cells stimulated by different growth factors. EGF, bFGF, and IGF-I but not KGF are mitogenic for prostatic fibroblasts in culture. Pygeum africanum inhibits both basal and stimulated growth with IC50 values of 4.5, 7.7 and 12.6 micrograms./ml. for EGF, IGF-I and bFGF, respectively, compared to 14.4 micrograms./ml. for untreated cells, the inhibition being stronger towards EGF. Pygeum africanum inhibited the proliferation induced by TPA or PDBu in a concentration-dependent manner with IC50 values of 12.4 and 8.1 micrograms./ml. respectively. The antiproliferative effects of Pa were not ascribed to cytotoxicity. These results show that Pygeum africanum is a potent inhibitor of rat prostatic fibroblast proliferation in response to direct activators of protein kinase C, the defined growth factors bFGF, EGF and IGF-I, and the complex mixture of mitogens in serum depending on the concentration used. PKC activation appears to be an important growth factor-mediated signal transduction for this agent. These data suggest that therapeutic effect of Pygeum africanum may be due at least in part to the inhibition of growth factors responsible for the prostatic overgrowth in man.