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Testosterone metabolism in primary cultures of human prostate epithelial cells and fibroblasts
Delos S.; Carsol J.-L.; Ghazarossian E.; Raynaud J.-P.; Martin P.-M.
Lab. de Cancerologie Experimentale, Faculte de Medecine Secteur Nord, Bd Pierre Dramard, 13916 Marseille Cedex 20 France
Journal of Steroid Biochemistry and Molecular Biology (United Kingdom), 1995, 55/3-4 (375-383) 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 (Delta4) formed by oxidation of T by 17beta-hydroxysteroid dehydrogenase (17beta-HSD) represented 80% of the metabolites recovered. The amounts of 5alpha-dihydrotestosterone (DHT), formed by reduction of T by 5alpha-reductase (5alpha-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 5alpha-reductase type 1 isozyme and oxidative activity to the 17beta-HSD type 2. In cancer fibroblasts, only little 17beta-HSD type 2 mRNA was detected. The 5alpha-reductase inhibitors, 4-MA (17beta-(N,N-diethyl)carbamoyl-4-methyl-4 -aza-5alpha-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 Delta4 formation. In the other hand, the lipido-sterol extract of Serenoa repens (LSESr, Permixon (R)) inhibited the formation of all the T metabolites studied (IC50 s = 40 and 200 microg/ml (BPH) and 90 and 70 microg/ml (adenocarcinoma) in epithelial cells and fibroblasts, respectively). These results have important therapeutic implications when selecting appropriate treatment options for BPH.
Inhibition of the activity of 'basic' 5alpha-reductase (type 1) detected in DU 145 cells and expressed in insect cells
Delos S.; Iehle C.; Martin P.-M.; Raynaud J.-P.
ARIBIO, 67 Boulevard Suchet, 75016 Paris France
J. STEROID BIOCHEM. MOL. BIOL. (United Kingdom), 1994, 48/4 (347-352) The purpose of this study was 2-fold: (1) to identify the 5alpha-reductase (5alpha-R) isozyme(s) present in DU 145 cells, a human cell-line of low androgen sensitivity derived from a cerebral metastasis of an epithelial prostate cancer; and (2) to compare the inhibitory potencies of three compounds on the 'basic' 5alpha-R isozyme expressed in a baculovirus-directed insect cell system. Conversion of testosterone (T) into 5alpha-dihydrotestosterone (DHT) in DU 145 cells was measured by HPLC coupled to a Flo-one HP radioactivity detector. DU 145 cells exhibited 5alpha-R activity (21 pmol DHT/min/mg protein) at pH 7.4 which disappeared at pH 5.5 suggesting that, of the two genomically distinct human isozymes identified so far, type 1 5alpha-R is expressed in DU 145 cells. This was confirmed by at least two observations: first, 5alpha-R activity in DU 145 cells was inhibited with much higher potency by 4-MA than by finasteride which is known to be a very poor competitor of the 'basic' enzyme (IC50s = 2.8 plus or minus 0.2 and 264 plus or minus 55 nM, respectively). Second, only the type 1 5alpha-R cDNA and not type 2 5alpha-R cDNA hybridized with DU 145 RNA. A high potency differential was also recorded for the inhibition of 'basic' type 1 5alpha-R expressed in a baculovirus-directed-insect cell system by these two compounds, 4-MA being considerably more active than finasteride (K(i) = 8.4 plus or minus 2.3 and 330 plus or minus 9 nM, respectively). This inhibition was competitive. On the other hand, inhibition by an n-hexane lipid/sterol extract of Serenoa repens (LSESr) was non-competitive and, when expressed in terms of recommended therapeutic doses, was 3-fold greater for LSESr than for finasteride. These studies suggest that LSESr might exert a regulatory inhibitory activity due to its specific lipid/sterol composition.
Inhibition of androgen metabolism and binding by a liposterolic extract of 'Serenoa repens B' in human foreskin fibroblasts
Sultan C.; Terraza A.; Devillier C.; et al.
INSERM U. 58, 34100 Montpellier FRANCE
J. STEROID BIOCHEM. (ENGLAND), 1984, 20/1 (515-519) We previously suggested (Steroids 33, (1979) 3; Steroids 37, (1981) 6) that cultured genital skin fibroblasts should prove useful for screening of potential antiandrogens in human and living target cells. 'Serenoa repens' lipidic extract (S.R.E.) was recently reported (Br. J. Pharmacol., in press) to inhibit androgen action in animals. The present investigation was designed to study the antiandrogenicity of this compound in human cells; we therefore analyzed the effects of S.R.E. on the intracellular conversion of testosterone (T) to 5alpha-reduced derivatives, and we investigated interaction of S.R.E. with the intracellular androgen-receptor complex. Since the chemical structure of the active component of S.R.E. is still unknown, results are expressed in U/ml (one unit is defined as the amount of S.R.E. required to inhibit 50% of the specific binding (ICsub 5sub 0) of (sup 3H)1881 to rat prostate cytosol). S.R.E. at different dilutions (5.7 to 28.6 U/ml) is added to culture media containing (sup 3H)T or (sup 3H)dihydrotestosterone (DHT) and incubated at 37degr.C with cultured fibroblasts. 28.6 U/ml S.R.E. significantly alters the formation of DHT and strongly inhibits 3 ketosteroid reductase mediated conversion of DHT to 5alpha-androstane-3alpha, 17beta-diol, characterized radiochemically by thin-layer chromatography. S.R.E. is a good competitor for the whole cell androgen receptor: 7.1 U/ml S.R.E. gives 50% inhibition of the binding of 2 x 10sup -sup 9 M (sup 3H)DHT to its receptor. Competitive binding assays after cell fractionation indicate that S.R.E. is less potent in nuclear than in cytosol receptors. Sucrose gradient centrifugation of the radioactive cell lysate of fibroblast demonstrates that 28.6 U/ml S.R.E. abolishes 70% of the 3.6 S receptor-complex radioactive peak. The present studies show that S.R.E. inhibits 5alpha-reductase, 3-ketosteroid reductase and receptor binding of androgens in cultured human foreskin fibroblasts. As the search for the ideal antiandrogen continues, S.R.E. appears to be a new type of antiandrogenic compound as therapeutics for the treatment of benign prostatic hypertrophy, hirsutism and so forth.
Saw Palmetto, African prune and stinging nettle for Benign Prostatic Hyperplasia (BPH)
Awang D.V.C.
Canadian Pharmaceutical Journal (Canada), 1997, 130/9 (37-44+62) No abstract.
Phytotherapy in the treatment of benign prostatic hyperplasia
Bracher F.
Germany
Urologe - Ausgabe A (Germany), 1997, 36/1 (10-17) Phytopharmaceutical agents have been used for a long time in the treatment of symptomatic benign prostatic hyperplasia (BPH). However, until recently, it has been questioned whether phytotherapy is superior to a placebo treatment. In this article, the most widely used phytopharmaceutical agents, such as saw palmetto berry extracts, Radix urticae extracts pumpkin seeds, pollen extracts and different phytosterols, are described. In addition, both in vitro and in vivo studies are discussed in an attempt to explain a possible mechanism of action. There are several new clinical studies which demonstrate a significant benefit compared with placebo treatment. Based on these results, the use of phytopharmaceutical agents for the treatment of mild to moderate symptomatic BPH seems to be well justified. So far, no significant inhibition of further prostate growth has been demonstrated. For this, a careful follow-up of the patients is necessary so as not to miss a deterioration and perhaps the need for an operation.
The market of herbal remedies in the USA. Market development, users, legislation and organization
Grunwald J.; Goldberg A.
Dr. J. Grunwald, PhytoPharm Consulting GmbH, Institut fur Phytopharmaka, Olafstr. 6-10, D-13467 Berlin Germany
Pharmazeutische Industrie (Germany), 1997, 59/6 (485-490) In the last years the American market of herbal remedies is growing very fast. The lotal turn over is estimated at 1.6 to 2.5 billion US-$ in public prices with an annual growth between 15 and 20%. The leading medicinal plants are echinacea, garlic, goldenseal, ginseng and ginkgo each with a market share between 5 and 10% of the total market of herbal remedies. Several European companies are represented on the US market with their products and several of them are leading their category. In the US several medicinal plants are cultivated and partially also exported to Europe e.g. echinacea, ginkgo and peppermint. Saw palmetto is wildcrafted and also exported to Europe. American ginseng is mainly exported to Asia. Due to a new legal situation in 1994 the status of herbal remedies was defined as dietary supplements and the possibilities for claims are laid down in the Dietary Supplement Health and Education Act (DSHEA). According to these regulations structure function claims related to the medicinal plants and general claims regarding well-being are permitted. Several trade associations and botanical research organisations have been indispensable in helping to provide more information to the public and improve the science behind botanical products. There is great interest in the European experiences regarding registration and quality insurance of phytomedicines, which are insufficiently regulated in the US momentarily.
Biologically active acylglycerides from the berries of saw-palmetto (Serenoa repens)
Shimada H.; Tyler V.E.; McLaughlin J.L.
J.L. McLaughlin, DMCMP, Sch. of Pharmacy/Pharmacal Sciences, Purdue University, West Lafayette, IN 47907 USA
Journal of Natural Products (USA), 1997, 60/4 (417-418) Brine shrimp lethality-directed fractionation of the 95% EtOH extract of the powdered, dried berries of Serenoa repens (Bart.) Small (saw-palmetto) (Palmae) led to the isolation of two monoacylglycerides, 1-monolaurin (1) and 1-monomyristin (2). Compounds 1 and 2 showed moderate biological activities in the brine shrimp lethality test and against renal (A-498) and pancreatic (PACA-2) human tumor cells; borderline cytotoxicity was exhibited against human prostatic (PC-3) cells. The fruits and extracts of saw-palmetto are taken orally as an herbal medicine to prevent prostatic hyperplasias.
The lipidosterolic extract from Serenoa repens interferes with prolactin receptor signal
Vacher P.; Prevarskaya N.; Skryma R.; Audy M.C.; Vacher A.M.; Odessa M.F. ; Dufy B.
Laboratoire Neurophysiologie, CNRS URA 1200, Universite de Bordeaux II, 146 Rue Leo-Saignat, F-33076 Bordeaux Cedex France
Journal of Biomedical Science (Switzerland), 1995, 2/4 (357-365) The lipidosterolic extract from the saw palmetto Serenoa repens (LSESr) is commonly used for medical treatment of benign prostatic hypertrophia due to its ability to inhibit 5alpha-reductase which permits the conversion of testosterone to dihydrotestosterone, the active androgen on prostate cell proliferation. However, the complete action mechanism of LSESr is still unknown. Several lines of evidence suggest that, in addition to inhibition of 5alpha-reductase, it may interfere with the action of prolactin (PRL). We therefore investigated a possible interference of this plant extract with another hormone that controls prostate gland growth, PRL. As the action mechanism of PRL is now fully documented in Chinese hamster ovary cells expressing the PRL receptor, we have conducted our experiments on these cells. In this study, using electrophysiological (whole-cell recording and single-channel recording), microspectrofluorimetric and biochemical techniques, we show that LSESr (1-30 microg/ml) reduced the basal activity of a K+ channel and of protein kinase C (PKC) in CHO cells. In addition, pretreatment of the cells with 1-10 microg/ml LSESr for 6-36 h abolished the effects of PRL on (Ca2+)(i), K+ conductance and PKC. LSESr may block PRL-induced prostate growth by inhibiting several steps of PRL receptor signal transduction. LSESr may also be useful for diseases implicating PRL.
The place of phytotherapy in the treatment of benign prostatic hyperplasia
Dreikorn K.; Schonhofer P.S.
Urologische Klinik, Zentralkrankenhaus St-Jurgen-Strasse, D-28205 Bremen Germany
Urologe - Ausgabe A (Germany), 1995, 34/2 (119-129) Phytotherapeutic preparations are still commonly used for the treatment of symptomatic benign prostate hyperplasia (BPH) in Germany; in recent years there has even been an increase in their use, so that sales now amount to more than DM 220 millions per year. The preparations most frequently used are extracts of Hypoxis rooperi, the roots of the stinging nettle, the fruits of the saw palmetto, pumpkin seeds and rye pollen. The suggested mechanisms of action have not been documented by scientific observation. This applies especially to the blocking effect on 5alpha-reductase postulated with the doses used. Moreover, a critical analysis of the data available suggests that the effects of phytotherapy are no better than those of placebo treatment. Further studies are urgently needed, to compare the effects of phytotherapy with those of chemically defined drugs (alpha1-receptor antagonists, 5alpha-reductase blocker) that seem to have a beneficial influence on the pathomechanism underlying symptomatic BPH.
Effect of the lipidosterolic extract of Serenoa repens (Permixon (R)) and its major components on basic fibroblast growth factor-induced proliferation of cultures of human prostate biopsies
Paubert-Braquet M.; Cousse H.; Raynaud J.-P.; Mencia-Huerta J.M.; Braquet P.
M. Paubert-Braquet, Bio-Inova EuroLab Research Lab., 48-52 rue de la Gare, F-78380 Plaisir France
European Urology (Switzerland), 1998, 33/3 (340-347) Objective: To assess the effect of the lipidosterolic extract of Serenoa repens (LSESr) on in vitro cell proliferation in biopsies of human prostate. Material and Methods: Cell proliferation was assessed by incorporation of (3H)thymidine followed by historadiography. Results: Basic fibroblast growth factor (b-FGF) induced a considerable increase in human prostate cell proliferation (from +100 to +250%); the glandular epithelium was mainly affected, minimal labeling being recorded in the other regions of the prostate. Similar results were observed with epidermal growth factor (EGF), although the increase in cell proliferation was not recorded in some cases. Lovastatin, an inhibitor of hydroxymethylglutaryl coenzyme A, antagonized both the basal proliferation and the growth factor-stimulated proliferation of human prostate epithelium (EGF, mean inhibition similar 80-95%; b-FGF, mean inhibition similar 40-90%). Geraniol, a precursor of both farnesyl pyrophosphate and geranylgeranyl pyrophosphate, and farnesol, the precursor of farnesyl pyrophosphate, increased cell proliferation only in some prostate specimens, this effect being antagonized by lovastatin. LSESr did not affect basal prostate cell proliferation, with the exception of two prostate specimens in which a significant inhibition of basal proliferation was observed with the highest concentration of LSESr (30 microg/ml). In contrast, LSESr inhibited b-FGF-induced proliferation of human prostate cell cultures; this effect was significant for the highest concentration of LSESr (30 microg/ml). In some prostate samples, a similar inhibition was also noted with lower concentrations. Unsaturated fatty acids (UFA), in the range 1-30 ng/ml, did not affect the basal prostate cell proliferation, only a slight increase in cell proliferation was noted in 1 prostate specimen. UFA (1, 10 or 30microg/ml) markedly inhibited the b-FGF-induced cell proliferation down to the basal value. Lupenone, hexacosanol and the unsaponified fraction of LSESr markedly inhibited the b-FGF-induced cell proliferation, whereas a minimal effect on basal cell proliferation was noted. Conclusions: Despite the large variability in the response of the prostate samples to b-FGF, these results indicate that LSESr and its components affect the proliferative response of prostate cells to b-FGF more than their basal proliferation.
Efficacy and safety of the extract of Serenoa repens in the treatment of benign prostatic hyperplasia: Therapeutic equivalence between twice and once daily dosage forms
Braeckman J.; Bruhwyler J.; Vandekerckhove K.; Geczy J.
J. Bruhwyler, Therabel Research S.A., Rue Van Ophem 110, 1180 Brussels Belgium
Phytotherapy Research (United Kingdom), 1997, 11/8 (558-563) The efficacy and safety of two dosage forms (160 mg b.i.d. and 320 mg o.d.) of the extract of Serenoa repens were compared during a 1-year treatment in 132 patients suffering from benign prostatic hyperplasia (BPH). Both dosage forms induced a significant improvement in the efficacy variables: international prostate symptom score (60% after 1 year), quality of life score (85% of patients were satisfied after 1 year of treatment), prostatic volume (12% after 1 year), maximum flow rate (22% after 1 year), mean flow rate (17% after 1 year) and residual urinary volume (16% after 1 year). No significant differences were found between the two dosage forms. The percentage of patients or investigators evaluating that the treatment had a medium or bad tolerance was never superior to 4%. Nineteen side effects were observed in 16 patients (12.1%), 8 patients in each group. The majority of these side effects (at least 75%) were related to the natural evolution of the disease itself rather than to the medication. We conclude that the extract of Serenoa repens in its two dosage forms is a safe and effective treatment for the mictional problems associated with BPH. Consequently, it appears to offer a potential pharmacologic alternative capable of improving BPH symptoms in patients with mild- to-moderate disease.
Effect of the lipid lipidosterolic extract of Serenoa repens (Permixon (R)) on the ionophore A23187-stimulated production of leukotriene B4 (LTB4) from human polymorphonuclear neutrophils
Paubert-Braquet M.; Mencia Huerta J.-M.; Cousse H.; Braquet P.
Dr. M. Paubert-Braquet, Bio-Inova, Life Sciences International, 48-52 Rue de la Gare, F78370 Plaisir France
Prostaglandins Leukotrienes and Essential Fatty Acids (United Kingdom), 1997, 57/3 (299-304) Although the lipidic extract of Serenoa repens (LESSr, Permixon (R), Sereprostat (R)) is widely used in patients suffering from benign prostatic hypertrophy (BPH), its mechanism of action is not fully elucidated. It has been demonstrated that infiltration of the prostate by inflammatory cells is one of the aetiologic factors involved in the development of BPH. These inflammatory cell types, such as polymorphonuclear neutrophils (PMNs), produce chemotactic mediators and contribute to the development of the disease. Among the chemotactic factors generated by inflammatory cell types, the derivatives of arachidonic acid have been extensively studied. For instance, leukotriene (LT) B4 is one of the most potent chemotactic factors for PMNs and also exhibits a wide range of biological activities. In order to investigate the potential action of LESSr on arachidonate metabolism, and particularly on the synthesis of LTB4, the effect of this extract on the in vitro synthesis of LT by human PMNs stimulated with the calcium ionophore A23187 was investigated. LESSr significantly inhibits the production of 5-lipoxygenase metabolites (5-HETE, 20- COOH LTB4, LTB4 and 20-OH LTB4) at concentrations as low as 5 microg/ml. Such an effect of LESSr was also observed in the presence of exogenous arachidonic acid (20 microg/ml) and when fMLP was used as the agonist, suggesting that inhibition of LTB4 production by the extract was unrelated to phospholipase A2 blockade and independent of the stimulating agent. The capability of LESSr to antagonize 5-lipoxygenase metabolites production may contribute, at least partly, to the understanding of its therapeutic activity on the inflammatory component of BPH.
Serenoa repens (Bartram) J.K. Small
Bombardelli E.; Morazzoni P.
E. Bombardelli, INDENA S.p.A., Scientific Department, Viale Ortles 12, 20139 Milan Italy
Fitoterapia (Italy), 1997, 68/2 (99-113) S. repens is a low shrubby palm native to the southern regions of North America. Preparations from the fruit have been used in traditional American medicine in the treatment of bladder, urethra and prostate irritations. Today, lipophilic extracts of the S. repens fruit are widely used in the therapy of urological symptoms associated with BPH. The clinical efficacy of these extracts and their good tolerability have been demonstrated in numerous clinical trials, including double-blind studies. Inhibition of 5alpha-reductase activity, antagonism of dihydrotestosterone binding to androgen receptors, double blocking of cycloxygenase and lipoxygenase pathways are the main mechanisms involved in the antiprostatic effect of the S. repens extracts.
Biologically active acylglycerides from the berries of saw-palmetto (Serenoa repens)
Shimada H.; Tyler V.E.; McLaughlin J.L.
J.L. McLaughlin, DMCMP, Sch. of Pharmacy/Pharmacal Sciences, Purdue University, West Lafayette, IN 47907 USA
Journal of Natural Products (USA), 1997, 60/4 (417-418) Brine shrimp lethality-directed fractionation of the 95% EtOH extract of the powdered, dried berries of Serenoa repens (Bart.) Small (saw-palmetto) (Palmae) led to the isolation of two monoacylglycerides, 1-monolaurin (1) and 1-monomyristin (2). Compounds 1 and 2 showed moderate biological activities in the brine shrimp lethality test and against renal (A-498) and pancreatic (PACA-2) human tumor cells; borderline cytotoxicity was exhibited against human prostatic (PC-3) cells. The fruits and extracts of saw-palmetto are taken orally as an herbal medicine to prevent prostatic hyperplasias.
Phytotherapy of benign prostatic hyperplasia (BPH) with Cucurbita, Hypoxis, Pygeum, Urtica and Sabal serrulata (Serenoa repens)
Odenthal K.P.
K.P. Odenthal, Dept. Exp. Biology, Pharmacology, MADAUS AG, Ostmerheimerstr. 198, D-51109 Cologne Germany
Phytotherapy Research (United Kingdom), 1996, 10/SUPPL. 1 (S141-S143) The enlargement of prostate (BPH) is accompanied by urge, reduced urinary flow and increased residual urine volume. The etiology is not yet clear, though many results speak for hormonal imbalance. Several herbal drugs have been applied traditionally in the therapy of BPH, i.e., preparations of Cucurbita, Hypoxis, Pygeum, Urtica and from Sabal serrulata. Among the discussed mechanisms, phytosterols are considered as active and have been found in experimental as well as in clinical investigations to interfere with either reduction of testosterone to dihydrotestosterone, sexual hormone binding globulin, aromatization of testosterone or growth factors like EGF. Additional effects have been documented in experiments speaking for immunomodulation and anti-inflammatory qualities. We demonstrate that smooth muscle contraction of rat deferential duct, guinea-pig ileum and bladder is reduced by lipophilic extract of Sabal. Both noradrenaline-induced contractions of rat deferential duct as well as contractions elicited by electrical stimulation could be reduced concentration-dependently following addition of less than or equal to 0.33 mg/ml of lipophilic Sabal serrulata extract into the bath medium. Cumulative dosing of less than or equal to 0.15 mg/ml of Sabal extract antagonized in guinea-pig ileum and bladder smooth muscular tissue contracted in KCl salt solution. Sabal extract, in concentrations identical to those published for the so-called anti-androgenic and anti-inflammatory effects, is therefore characterized by alpha-adrenoceptor antagonistic as well as calcium blocking activities. Furthermore, these findings could explain the clinically demonstrated symptomatic relief or so called release of dynamic component of BPH.
Effect of Serenoa repens extract (Permixon (R)) on estradiol/testosterone-induced experimental prostate enlargement in the rat
Paubert-Braquet M.; Richardson F.O.; Servent-Saez N.; Gordon W.C.; Monge M.-C.; Bazan N.G.; Authie D.; Braquet P.
France
Pharmacological Research (United Kingdom), 1996, 34/3-4 (171-179) 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.
Serenoa repens (Permixon (R)). A review of its pharmacology and therapeutic efficacy in benign prostatic hyperplasia
Plosker G.L.; Brogden R.N.
Adis International Limited, 41 Centorian Drive, Mairangi Bay, Auckland 10 New Zealand
Drugs and Aging (New Zealand), 1996, 9/5 (379-395) Serenoa repens (Permixon (R)) has been available for several years for the treatment of men with benign prostatic hyperplasia (BPH). The drug is the n-hexane lipidosterolic extract of the dwarf American palm (also known as Serenoa repens) and is a complex mixture of various compounds. A number of pharmacodynamic effects have been demonstrated with the lipidosterolic extract of Serenoa repens (LSESR), suggesting multiple mechanisms of action including in vitro inhibition of both type 1 and type 2 isoenzymes of 5alpha-reductase and interference with binding of dihydrotestosterone to cytosolic androgen receptors in prostate cells. In controlled clinical trials in men with BPH, oral administration of Serenoa repens 160 mg twice daily for 1 to 3 months was generally superior to placebo in improving subjective symptoms, such as dysuria, as well as objective parameters. The frequency of nocturia was reduced by 33 to 74%, while urinary frequency during the day decreased by 11 to 43% and peak urinary flow rate increased by 26 to 50% with Serenoa repens. Corresponding values for placebo were 13 to 39%, 1 to 29% and 2 to 35%. The only large comparative trial conducted to date, in which > 1000 men with moderate BPH were randomised to receive Serenoa repens 160 mg twice daily or finasteride 5 mg once daily for 6 months, demonstrated similar efficacy between the two drugs. No statistically significant difference was demonstrated between treatment groups for improvement in patient self-rated quality-of-life scores and the primary end-point of objective symptoms score; International Prostate Symptom Score improved by 37% with Serenoa repens compared with 39% with finasteride. In much smaller comparative trials, few significant differences were demonstrated between Serenoa repens and alpha1-receptor antagonists, and larger randomised trials of adequate duration are required to better compare the clinical efficacy of these drugs. The most frequently reported adverse events in clinical trials with Serenoa repens have been minor gastrointestinal problems (e.g. nausea and abdominal pain). In conclusion, Serenoa repens is well tolerated and has greater efficacy than placebo and similar efficacy to finasteride in improving symptoms in men with BPH. Although there is a need for further comparative studies, particularly with alpha1-receptor antagonists, available data indicate that Serenoa repens is a useful alternative to alpha1-receptor antagonists and finasteride in the treatment of men with BPH.
Effects of the lipidosterolic extract of Serenoa repens (Permixon (R)) on human prostatic cell lines
Ravenna L.; Di Silverio F.; Russo M.A.; Salvatori L.; Morgante E.; Morrone S.; Cardillo M.R.; Russo A.; Frati L.; Gulino A.; Petrangeli E.
Istituto Tecnologie Biomediche, via G. B. Morgagni 30/E, 00161 Roma Italy
Prostate (USA), 1996, 29/4 (219-230) BACKGROUND. Permixon (R) is a drug used in the treatment of benign prostatic hyperplasia. We studied its androgenic and antiandrogenic effects in the prostatic cell line LNCaP and PC3, respectively responsive and unresponsive to androgen stimulation. METHODS. We performed FACScan analysis to investigate toxicity, 3H thymidine and 35S methionine incorporation to determine antiproliferative and metabolic effects, electron microscopy to study ultrastructural changes and cotransfection experiments to elucidate the role of wild type androgen receptor. RESULTS. In LNCaP cell line, Permixon (R) induced a double proliferative/differentiative effect, not observed in PC3 cells. In PC3 cells cotransfected with wild-type androgen receptors and CAT reporter genes under the control of a androgen responsive element, the drug inhibited androgen-induced CAT transcription. CONCLUSIONS. Our data indicate a role of the androgen receptor in mediating the effects of Permixon (R) in LNCaP cells. Cotransfection experiments in PC3 cells support a clear antiandrogenic action of the drug.
Testosterone metabolism in primary cultures of human prostate epithelial cells and fibroblasts
Delos S.; Carsol J.-L.; Ghazarossian E.; Raynaud J.-P.; Martin P.-M.
Lab. de Cancerologie Experimentale, Faculte de Medecine Secteur Nord, Bd Pierre Dramard, 13916 Marseille Cedex 20 France
Journal of Steroid Biochemistry and Molecular Biology (United Kingdom), 1995, 55/3-4 (375-383) 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 (Delta4) formed by oxidation of T by 17beta-hydroxysteroid dehydrogenase (17beta-HSD) represented 80% of the metabolites recovered. The amounts of 5alpha-dihydrotestosterone (DHT), formed by reduction of T by 5alpha-reductase (5alpha-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 5alpha-reductase type 1 isozyme and oxidative activity to the 17beta-HSD type 2. In cancer fibroblasts, only little 17beta-HSD type 2 mRNA was detected. The 5alpha-reductase inhibitors, 4-MA (17beta-(N,N-diethyl)carbamoyl-4-methyl-4 -aza-5alpha-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 Delta4 formation. In the other hand, the lipido-sterol extract of Serenoa repens (LSESr, Permixon (R)) inhibited the formation of all the T metabolites studied (IC50 s = 40 and 200 microg/ml (BPH) and 90 and 70 microg/ml (adenocarcinoma) in epithelial cells and fibroblasts, respectively). These results have important therapeutic implications when selecting appropriate treatment options for BPH.
Human prostatic steroid 5alpha-reductase isoforms - A comparative study of selective inhibitors
Iehle C.; Delos S.; Guirou O.; Tate R.; Raynaud J.-P.; Martin P.-M.
Lab de Cancerologie Experimentale, Faculte de Medecine, Secteur Nord, Bd Pierre Dramard, 13916 Marseille Cedex 20 France
Journal of Steroid Biochemistry and Molecular Biology (United Kingdom), 1995, 54/5-6 (273-279) The present study describes the independent expression of the type 1 and 2 isoforms of human 5alpha-reductase in the baculovirus-directed insect cell expression system and the selectivity of their inhibition. The catalytic properties and kinetic parameters of the recombinant isozymes were consistent with published data. The type 1 isoform displayed a neutral (range 6-8) pH optimum and the type 2 isoform an acidic (5-6) pH optimum. The type 2 isoform had higher affinity for testosterone than did the type 1 isoform (K(m) = 0.5 and 2.9 microM, respectively). Finasteride and turosteride were selective inhibitors of the type 2 isoform (K(i) (type 2) = 7.3 and 21.7 nM compared to K(i) (type 1) = 108 and 330 nM, respectively). 4-MA and the lipido-sterol extract of Serenoa repens (LSESr) markedly inhibited both isozymes (K(i) (type 1) = 8.4 nM and 7.2 microg/ml, respectively; K(i) (type 2) = 7.4 nM and 4.9 microg/ml, respectively). The three azasteroids were competitive inhibitors vs substrate, whereas LSESr displayed non-competitive inhibition of the type 1 isozyme and uncompetitive inhibition of the type 2 isozyme. These observations suggest that the lipid component of LSESr might be responsible for its inhibitory effect by modulating the membrane environment of 5alpha-reductase. Partially purified recombinant 5alpha-reductase type 1 activity was preserved by the presence of lipids indicating that lipids can exert either stimulatory or inhibitory effects on human 5alpha-reductase.
The lipidosterolic extract from Serenoa repens interferes with prolactin receptor signal
Vacher P.; Prevarskaya N.; Skryma R.; Audy M.C.; Vacher A.M.; Odessa M.F. ; Dufy B.
Laboratoire Neurophysiologie, CNRS URA 1200, Universite de Bordeaux II, 146 Rue Leo-Saignat, F-33076 Bordeaux Cedex France
Journal of Biomedical Science (Switzerland), 1995, 2/4 (357-365) The lipidosterolic extract from the saw palmetto Serenoa repens (LSESr) is commonly used for medical treatment of benign prostatic hypertrophia due to its ability to inhibit 5alpha-reductase which permits the conversion of testosterone to dihydrotestosterone, the active androgen on prostate cell proliferation. However, the complete action mechanism of LSESr is still unknown. Several lines of evidence suggest that, in addition to inhibition of 5alpha-reductase, it may interfere with the action of prolactin (PRL). We therefore investigated a possible interference of this plant extract with another hormone that controls prostate gland growth, PRL. As the action mechanism of PRL is now fully documented in Chinese hamster ovary cells expressing the PRL receptor, we have conducted our experiments on these cells. In this study, using electrophysiological (whole-cell recording and single-channel recording), microspectrofluorimetric and biochemical techniques, we show that LSESr (1-30 microg/ml) reduced the basal activity of a K+ channel and of protein kinase C (PKC) in CHO cells. In addition, pretreatment of the cells with 1-10 microg/ml LSESr for 6-36 h abolished the effects of PRL on (Ca2+)(i), K+ conductance and PKC. LSESr may block PRL-induced prostate growth by inhibiting several steps of PRL receptor signal transduction. LSESr may also be useful for diseases implicating PRL.
Rectal bioavailability and pharmacokinetics in healthy volunteers of serenoa repens new formulation
De Bernardi Di Valserra M.; Tripodi A.S.
Cattedra di Tossicologia II, Istituto di Farmacologia II, Universita di Pavia, Pavia Italy
ARCH. MED. INTERNA (Italy), 1994, 46/2 (77-86) The bioavailability and pharmacokinetic profile of a new developed 640 mg rectal Serenoa repens extract preparation were determined in 12 healthy male volunteers. Drug was administered at dose of 640 mg, blood samples were collected at 0,5-1-1,5-2-3-4-6-8 and 10 hours after, and plasma concentrations of Serenoa repens 2nd component were quantified by a HPLC-method. Mean maximum concentration of 2nd component in plasma of nearly 2.60 microg/ml about 3 hours after drug intake with mean value for the area under the curve AUC(0-inf) of 10microg*h/ml were observed. The bioavailability and pharmacokinetic profile of a 640 mg rectal Serenoa repens extract preparation were quite similar to those observed after oral Serenoa repens administration, only T(max) occurred about 1 h later and Serenoa repens 2nd component plasma concentration 8 hours after drug administration was still quantified. The drug tolerability was good and no adverse effect were observed.
Clinical controlled trial on therapeutical bioequivalence and tolerability of Serenoa repens oral capsules 160 mg or rectal capsules 640 mg
Roveda S.; Colombo P.
Catt di Gastroenterologia Chirurgica, Ist di Clinica Chirurgica Generale, Universita di Pavia, Pavia Italy
ARCH. MED. INTERNA (Italy), 1994, 46/2 (61-75) An open, randomized, controlled study was performed in 60 benign prostatic hypertrophy patients. The patients were randomized into two groups, the 1st (30 cases) receiving Serenoa repens oral capsules (160 mg four times a day) for 30 days and 2nd (30 cases) receiving Serenoa repens rectal capsules (640 mg once a day) for 30 days. Clinical efficacy was evaluated by means of diminution of scores assigned to dysuria, pollakiuria, prostate dimension and micturation residue. No significant differences were found between the two groups and therefore the postulated therapeutic bioequivalence between the two therapies was demonstrated.
Prostaserene (R). Treatment for BPH
Bruhwyler J.
Therabel Research Biostatistics, Chaussee d'Alsemberg 1001, B-1180 Bruxelles Belgium
DRUGS FUTURE (Spain), 1994, 19/5 (452-453) Serenoa repens extract is a potential therapeutic alternative for the treatment of mild to moderate symptoms of benign prostatic hyperplasia, and appears to be safe and effective in the treatment of micturition problems associated with BPH.
The The extract of serenoa repens in the treatment of benign prostatic hyperplasia: A multicenter open study
Braeckman J.
Department of Urology, AZ, VUB, Laarbeeklaam 101, 1090 Brussels Belgium
CURR. THER. RES. CLIN. EXP. (USA), 1994, 55/7 (776-785) Because prostatic surgery is not the treatment of choice for most patients with benign prostatic hyperplasia (BPH), the therapeutic effect of a 160-mg, twice-daily, oral dose of Serenoa repens extract was studied during a 3-month open trial in 505 patients with mild-tomoderate symptoms of BPH. The efficacy of the regimen was evaluated in 305 of these patients. Traditional parameters for quantifying prostatism, such as the International Prostate Symptom Score, the quality of life score, urinary flow rates, residual urinary volume, and prostate size, were found to be significantly improved after only 45 days of treatment. After 90 days of treatment, a majority of patients (88%) and treating physicians (88%) considered the therapy effective. In addition, the serum prostate-specific antigen concentration was not modified by the drug, thus limiting the risk of masking any possible development of prostate cancer during treatment. The incidence of side effects (5%) was low and compares favorably with that reported for existing medical therapies used in BPH patients. The extract of Serenoa repens appears to be an effective and well-tolerated pharmacologic agent in treating the mictional problems accompanying BPH.
Pharmacological combinations in the treatment of benign prostatic hypertrophy
Di Silverio F.; D'Eramo G.; Flammia G.P.; Buscarini M.; Frascaro E.; Mariani M.; Sciarra A.
Department of Urology 'U. Bracci', University 'La Sapienza', V. Le Policlinico, 00161 Rome Italy
J. UROL. (France), 1993, 99/6 (316-320) In the development of the obstructive symptomatology of benign prostatic hypertrophy (BPH), two components may be identified, mechanical and dynamic. In the mechanical component, the interaction of a stromal and a epithelial compartment determines prostatic mass growth. The dynamic component involves smooth muscle tone in the prostate and urethra. The consideration that prostatic disease is not only epithelial in origin, but also stromal, leads to the association of an antiandrogen (which acts on the epithelial component) and an antiestrogen (active on the stromal component) in the medical therapy of BPH. In 1985 we carried out a randomized study on 256 BPH patients treated with Cyproterone acetate (CPA) plus Tamoxifen (TAM). Recently, we performed a multicenter double blind study on BPH patients treated with the association CPA plus Serenoa Repens. A statistically significant difference in prostate volume reduction between the groups treated with the combinations and those with the monotherapies was observed. The development of new compounds, such as 5 alpha reductase and aromatase inhibitors, consents to introduce a combination therapy with less side effects. A second pharmacological association may be obtained with drugs actings on the mechanical and others acting on the dynamic (alpha blockers) component of BPH. This combination may associate the early symptomatic effect of alpha blockers with the long term results of a 5 alpha reductase inhibitor, antiestrogen or aromatase inhibitor.
The effect of Permixon on androgen receptors
El-Sheikh M.M.; Dakkak M.R.; Saddique A.
Department of Obsterics and Gynaecology, King Khalid University Hospital, Riyadh Saudi Arabia
ACTA OBSTET. GYNECOL. SCAND. (Sweden), 1988, 67/5 (397-399) Permixon, the liposterolic extract of the plant Serenoa Repens is a recently introduced drug for the treatment of benign prostatic hyperplasia. The effect of Permixon on dihydrotestosterone and testosterone binding by eleven different tissue specimens was tested. The drug reduced the mean uptake of both hormones by 40.9% and 41.9% respectively in all tissue specimens. Since hirsutism and virilism are among other gynecological problems caused either by excessive androgen stimulation or excess endorgan response, we suggest that Permixon could be a useful treatment in such conditions and recommend further investigations of the possible therapeutic values of the drug in gynecological practice.
Binding of permixon, a new treatment for prostatic benign hyperplasia, to the cytosolic androgen receptor in the rat prostate
Carilla E.; Briley M.; Fauran F.; et al.
Centre de Recherches Pierre Fabre, 81106 Castres Cedex FRANCE
J. STEROID BIOCHEM. (ENGLAND), 1984, 20/1 (521-523) The benign hyperplasia of the prostate is a manifestation of aging, involving the accumulation within the gland, of dihydrotestosterone, the probable mediator of the hyperplasia. Binding studies were performed on the cytosolic androgenic receptor of the rat prostate using (sup 3H)methyltrienolone as a ligand. The binding of (sup 3H)methyltrienolone at 5 nM, was inhibited by various drugs, such as methyltrienolone and cyproterone acetate. Permixon, a liposterolic extract of the plant, Serenoa Repens B, inhibits competitively the binding to the cytosolic receptor of the rat prostate. Various vegetable and mineral oils, the plant steroid: beta sitosterol and the antiprostatic drug: Tadenan, were all found to be inactive. The antiprostatic activity of Permixon shown in animal studies and controlled clinical trials, may thus result from a direct action at the cytosolic receptor.
Inhibition of androgen metabolism and binding by a liposterolic extract of 'Serenoa repens B' in human foreskin fibroblasts
Sultan C.; Terraza A.; Devillier C.; et al.
INSERM U. 58, 34100 Montpellier FRANCE
J. STEROID BIOCHEM. (ENGLAND), 1984, 20/1 (515-519) We previously suggested (Steroids 33, (1979) 3; Steroids 37, (1981) 6) that cultured genital skin fibroblasts should prove useful for screening of potential antiandrogens in human and living target cells. 'Serenoa repens' lipidic extract (S.R.E.) was recently reported (Br. J. Pharmacol., in press) to inhibit androgen action in animals. The present investigation was designed to study the antiandrogenicity of this compound in human cells; we therefore analyzed the effects of S.R.E. on the intracellular conversion of testosterone (T) to 5alpha-reduced derivatives, and we investigated interaction of S.R.E. with the intracellular androgen-receptor complex. Since the chemical structure of the active component of S.R.E. is still unknown, results are expressed in U/ml (one unit is defined as the amount of S.R.E. required to inhibit 50% of the specific binding (ICsub 5sub 0) of (sup 3H)1881 to rat prostate cytosol). S.R.E. at different dilutions (5.7 to 28.6 U/ml) is added to culture media containing (sup 3H)T or (sup 3H)dihydrotestosterone (DHT) and incubated at 37degr.C with cultured fibroblasts. 28.6 U/ml S.R.E. significantly alters the formation of DHT and strongly inhibits 3 ketosteroid reductase mediated conversion of DHT to 5alpha-androstane-3alpha, 17beta-diol, characterized radiochemically by thin-layer chromatography. S.R.E. is a good competitor for the whole cell androgen receptor: 7.1 U/ml S.R.E. gives 50% inhibition of the binding of 2 x 10sup -sup 9 M (sup 3H)DHT to its receptor. Competitive binding assays after cell fractionation indicate that S.R.E. is less potent in nuclear than in cytosol receptors. Sucrose gradient centrifugation of the radioactive cell lysate of fibroblast demonstrates that 28.6 U/ml S.R.E. abolishes 70% of the 3.6 S receptor-complex radioactive peak. The present studies show that S.R.E. inhibits 5alpha-reductase, 3-ketosteroid reductase and receptor binding of androgens in cultured human foreskin fibroblasts. As the search for the ideal antiandrogen continues, S.R.E. appears to be a new type of antiandrogenic compound as therapeutics for the treatment of benign prostatic hypertrophy, hirsutism and so forth.
Effects of a saw palmetto herbal blend in men with symptomatic benign prostatic hyperplasia J Urol 2000 May;163(5):1451-6 PURPOSE: We tested the effects of a saw palmetto herbal blend in men with symptomatic benign prostatic hyperplasia (BPH) via a randomized, placebo controlled trial. MATERIALS AND METHODS: We randomized 44 men 45 to 80 years old with symptomatic BPH into a trial of a saw palmetto herbal blend versus placebo. End points included routine clinical measures (symptom score, uroflowmetry and post-void residual urine volume), blood chemistry studies (prostate specific antigen, sex hormones and multiphasic analysis), prostate volumetrics by magnetic resonance imaging, and prostate biopsy for zonal tissue morphometry and semiquantitative histology studies. RESULTS: Saw palmetto herbal blend and placebo groups had improved clinical parameters with a slight advantage in the saw palmetto group (not statistically significant). Neither prostate specific antigen nor prostate volume changed from baseline. Prostate epithelial contraction was noted, especially in the transition zone, where percent epithelium decreased from 17.8% at baseline to 10.7% after 6 months of saw palmetto herbal blend (p <0.01). Histological studies showed that the percent of atrophic glands increased from 25. 2% to 40.9% after treatment with saw palmetto herbal blend (p <0.01). The mechanism of action appeared to be nonhormonal but it was not identified by tissue studies of apoptosis, cellular proliferation, angiogenesis, growth factors or androgen receptor expression. We noted no adverse effects of saw palmetto herbal blend. When the study was no longer blinded, 41 men elected to continue therapy in an open label extension. CONCLUSIONS: Saw palmetto herbal blend appears to be a safe, highly desirable option for men with moderately symptomatic BPH. The secondary outcome measures of clinical effect in our study were only slightly better for saw palmetto herbal blend than placebo (not statistically significant). However, saw palmetto herbal blend therapy was associated with epithelial contraction, especially in the transition zone (p <0.01), indicating a possible mechanism of action underlying the clinical significance detected in other studies.
Chronic Venous Insufficiency [Effects of horse-chestnut seed extract on transcapillary filtration in chronic venous insufficiency] (Published in German)
J Am Osteopath Assoc 2000 Feb;100(2):89-96 European physicians treat benign prostatic hyperplasia (BPH) with saw palmetto extract (SPE), while American physicians generally disregard SPE because "research is lacking." The authors investigated this discrepancy with a literature search and a clinical trial. The literature search began with MEDLINE, then expanded to "alternative" databases, including AGRICOLA, EMBASE, IBIS, and Cochrane, plus a manual search of unindexed herbal journals. The clinical trial was an experimental case study in which a 67-year-old man with symptomatic BPH was randomly administered SPE (160 mg standardized extract twice daily) or placebo. Outcome measures included the American Urological Association Symptom Index (AUASI), serum prostate-specific antigen, and prostate volume. Our expanded literature search revealed 58 clinical trials, whereas MEDLINE yielded only 19 clinical trials, or 33% of the total. Our clinical trial measured a baseline AUASI score of 20, which improved to 7 after unblinded administration of SPE. Subsequent double-blinded placebo produced a score of 14, and final single-blinded allotment of SPE produced a score of 11. Prostate-specific antigen was 10.3 ng/mL at baseline and 10.7 ng/mL at trial's conclusion. Baseline prostatic volume was 92 mL, and end volume was 75 mL. In conclusion, MEDLINE proved inadequate as a stand-alone search engine for locating information about an herbal medicine. Our experimental case study, similar to N = 1 research methodology, proved suitable for clinical evaluation of an herbal medicine in a rural private practice. SPE improved the patient's BPH. Unstandardized look-alike herbs may act as nontherapeutic placebos and may undermine consumer confidence in herbal medicine.
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