MALE HORMONE MODULATION
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Andro M.-C.; Riffaud J.-P.
Laboratoires DEBAT, Medical Department, 153, Rue de Buzenval,92380 Garches France
Current Therapeutic Research - Clinical and Experimental (United States) 1995, 56/8 (796-817)

Pygeum africanum bark extract has been used to treat mild and moderate symptomatic benign prostatic hyperplasia (BPH) in France since 1969. The extract has several potentially relevant pharmacologic properties: modulation of age-related hypercontractility of the bladder detrusor muscle; anti-inflammatory activity, including inhibition of chemotactic activity of leukotrienes; inhibition of fibroblast proliferation; and improvement of prostatic histology and secretion. The constituents of the extract have a safe toxicologic profile, and some of them have anticarcinogenic and antimutagenic properties. Published clinical experience includes 2262 patients, of whom 452 received the active product in comparative studies. Global outcome scores are rated as good or better in at least half the patients in most studies. Objective parameters were measured in some open-label and all comparative studies and included maximum flow rate, voided volume, residual volume, nocturia, daytime frequency, and other symptoms. The placebo effect on these parameters was often large. Nonetheless, the majority of placebo-controlled studies, which compared changes from baseline in patients who received placebo versus patients who received P africanum extract, showed a statistically significant advantage for most objective parameters with the active compound. This finding was particularly true of more recent and larger studies. Clinical tolerability of the extract was excellent, with most studies reporting the complete absence of any adverse effects. Thus published clinical data from 2262 patients during the last 25 years show that P africanum bark extract is an effective and exceptionally well-tolerated treatment for mild and moderate symptomatic BPH. P africanum extract has a pharmacologic profile distinct from other classes of drugs now being proposed for BPH treatment (alpha-adrenoceptor antagonists and 5-alpha-reductase inhibitors). The recent resurgence of interest in nonsurgical treatments for this condition should prompt a reappraisal of P africanum extract, perhaps in comparative trials with these other drug classes.

Paubert-Braquet M.; Monboisse J.C.; Servent-Saez N.; Serikoff A.; Cave A. ; Hocquemiller R.; Dupont Ch.; Fourneau C.; Borel J.P.
Bio-Inova, Laboratoire de Recherche, 48-52, rue de la Gare,78370 Plaisir France
Biomedicine and Pharmacotherapy (France) 1994, 48/Suppl. 1 (43S-47S)

An extract of Pygeum africanum bark (Tadenan(R)) is prescribed for older men suffering from micturitional difficulties due to benign prostatic hyperplasia (BPH). Its mechanism of action is not completely understood. Basic fibroblast growth factor (bFGF) probably plays a role in the development of BPH. We have examined the effects of P africanum extract on basal cell proliferation and on the proliferation induced by bFGF, epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1). The proliferation of 3T3 fibroblasts was measured by the incorporation of tritiated methylthymidine and staining nuclei with crystal violet. P africanum extract slightly inhibited the basal growth of fibroblasts. However, it had a much larger inhibitory effect on cell proliferation induced by bFGF with 0.5 mug/ml, and the effect was significant at 1 mug/ml. Pygeum africanum extract also inhibited cell proliferation induced with EGF, but to a lesser extent. This suggests that the therapeutic effect of P africanum extract may be partly due to inhibition of cell growth induced by certain growth factors.

Dutkiewicz S.; Kalczak M.
Department of Urology, Ministry of Internal Affairs, Central Clinical Hospital,Warsaw Poland
International Urology and Nephrology (Hungary) 1994, 26/4 (455-460)

Transvesical adenectomy was done in 60 men with prostatic adenomas, including 40 pretreated medically (20 with prazosin, 20 with Tadenan). The resected material was sampled for histologic examination. Glandular, smooth muscle and fibrotic tissues as well as inflammatory foci were assessed quantitatively by planimetry . No adenomas consisting solely of glandular hyperplasia were found. In adenomas from patients pretreated with prazosin smooth muscle tissue was predominant and postinflammatory lesions were the least frequently observed. In Tadenan-pretreated patients quantitative predominance of glandular and fibrotic tissues was found and smooth muscle constituted the smallest pair of the adenomas. Patients who had undergone surgery only had adenomas in which focal inflammation predominated.

Paubert-Braquet M.; Cave A.; Hocquemiller R.; Delacroix D.; Dupont C.; Hedef N.; Borgeat P.
BIO-INOVA Research Laboratories, 48-52 Rue de la Gare,F 78370 Plaisir France
Journal of Lipid Mediators and Cell Signalling (Netherlands) 1994, 9/3 (285-290)

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 LTBinf 4, LTB4 and 20-OH LTBinf 4) at concentrations as low as 3 mug/ml (p < 0.01), while the same extract dissolved in NaOH/HCl only exhibited an inhibitory effect at 10 mug/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.

Krzeski T.; Kazon M.; Borkowski A.; Witeska A.; Kuczera J.
Warsaw School of Medicine,Warsaw Poland
Clinical Therapeutics (United States) 1993, 15/6 (1011-1020)

The 134 patients (aged 53 to 84 years) with symptoms of benign prostatic hyperplasia were drawn from two medical centers in Warsaw. The patients were randomly assigned to receive two capsules of the standard dose of an urtica/pygeum preparation (300 mg of Urtica dioica root extract combined with 25 mg of Pygeum africanum bark extract) or two capsules containing half the standard dose twice daily for 8 weeks. After 28 days' treatment, urine flow, residual urine, and nycturia were significantly reduced in both treatment groups. After 56 days' treatment, further significant decreases were found in residual urine (half-dose group) and in nycturia (both groups). There were no between-group differences in these measures of efficacy. Five patients reported adverse effects of treatment; treatment was not discontinued in any patient because of side effects. It is concluded that half doses of the urtica/pygeum extract are as safe and effective as the recommended full doses.

Barlet A.; Albrecht J.; Aubert A.; Fischer M.; Grof F.; Grothuesmann H.G. ; Masson J.-C.; Mazeman E.; Mermon R.; Reichelt H.; Schonmetzler F.; Suhler A.
Laboratoires Debat, 60 Rue de Monceau,F-75008 Paris France
Wiener Klinische Wochenschrift (Austria) 1990, 102/22 (667-673)

The efficacy of an extract of Pygeum africanum in the treatment of micturitional disorders due to benign prostatic hyperplasia was tested in a multicentre double-blind trial versus placebo. Capsules containing 50 mg of Pygeum africanum extract or placebo were administered at a dosage of 1 capsule in the morning and 1 capsule in the evening over aperiod of 60 days. 263 patients were included in this study, which was carried out in 8 centres in Germany, France, and Austria. Evaluation was mainly based on quantitative parameters such as residual urine, uroflowmetry and the precise monitoring of diurnal and nocturnal pollakiuria. Treatment with the Pygeum africanum extract led to a marked clinical improvement: a comparison of the quantitative parameters showed a significant difference between the Pygeum africanum group and the placebo group with respect to therapeutic response. The characteristic subjective symptoms of micturitional disorders, which were evaluated by the patients in a qualitative manner, were also significantly improved by administration of Pygeum africanum extract. Overall assessment at the end of therapy, showed that micturition improved in 66% of the patients treated with Pygeum africanum extract, as compared with an improvement of 31% in the placebo group. The difference was significant at the statistical level of p < 0.001. During therapy with Pygeum africanum extract, gastrointestinal side effect occurred in 5 patients. Treatment was discontinued in three of those cases.

Carilla E.; Briley M.; Fauran F.; et al.
Centre de Recherches Pierre Fabre, 81106 Castres Cedex France
Journal of Steroid Biochemistry (United Kingdom) 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.

Flamm J.; Kiesswetter H.; Englisch M.
Urol. Abt., Wilhelminenspit., Wien Austria
Wiener Klinische Wochenschrift (Austria) 1979, 91/18 (622-627)

Conservative therapy of benign prostatic hypertrophy comprises the administration of oestrogens, gestagens, androgens and anti-androgens. Phytodrugs, which contain an extract of Sabal serrulatum or Pygeum Africana as active substance are without side effects and are, therefore, being used increasingly. 74 patients with irritable or obstructive bladder symptoms due to benign prostatic hypertrophy were treated with a phytodrug (Sabal serrulatum) or with testosterone throughout a period of three months. In group one (20 patients given phytodrugs and 10 patients given testosterone) clinical symptoms and measurements of residual urine, residual urine quotient, bladder capacity, micturition pressure and maximum urethral closure pressure were recorded at the beginning and at the end of therapy. In group two 28 patients were treated with the phytodrug in the first and third months with an intervening placebo trial lasting four weeks and 16 patients were given testosterone. Clinical symptoms and uroflow and residual urine only were charted in this group. None of the patients in either group showed an improvement in the urodynamic parameters of obstruction, but all patients felt a subjective alleviation of their symptoms.

Goepel M; Hecker U; Krege S; Rubben H; Michel MC
Department of Urology, University of Essen, Germany.
mark.goepel@uni-essen.de
Prostate (United States) Feb 15 1999, 38 (3) p208-15

BACKGROUND: We wanted to test whether phytotherapeutic agents used in the treatment of lower urinary tract symptoms have alpha1-adrenoceptor antagonistic properties in vitro.

METHODS: Preparations of beta-sitosterol and extracts of stinging nettle, medicinal pumpkin, and saw palmetto were obtained from several pharmaceutical companies. They were tested for their ability to inhibit [3H]tamsulosin binding to human prostatic alpha1-adrenoceptors and [3H]prazosin binding to cloned human alpha1A- and alpha1B-adrenoceptors. Inhibition of phenylephrine-stimulated [3H]inositol phosphate formation by cloned receptors was also investigated.

RESULTS: Up to the highest concentration which could be tested, preparations of beta-sitosterol, stinging nettle, and medicinal pumpkin were without consistent inhibitory effect in all assays. In contrast, all tested saw palmetto extracts inhibited radioligand binding to human alpha1-adrenoceptors and agonist-induced [3H]inositol phosphate formation. Saturation binding experiments in the presence of a single saw palmetto extract concentration indicated a noncompetitive antagonism. The relationship between active concentrations in vitro and recommended therapeutic doses for the saw palmetto extracts was slightly lower than that for several chemically defined alpha1-adrenoceptor antagonists.

CONCLUSIONS: Saw palmetto extracts have alpha1-adrenoceptor-inhibitory properties. If bioavailability and other pharmacokinetic properties of these ingredients are similar to those of the chemically defined alpha1-adrenoceptor antagonists, alpha1-adrenoceptor antagonism might be involved in the therapeutic effects of these extracts in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction.

Bombardelli E.; Morazzoni P.
E. Bombardelli, Indena S.p.A., Scientific Department, Viale Ortles 12, 20139 Milan Italy
Fitoterapia (Italy) 1997, 68/5 (387-402)

U. dioica L. was used as medicinal plant since ancient times. Hydroalcoholic extract of the nettle root (Urticae radix) are currently used in the therapy of micturition disorders associated with slight and moderate BPH.

Gansser D.; Spiteller G.
Lehrstuhl Organische Chemie 1, Universitat Bayreuth, NW I,
Universitatsstrasse 30,D-95440 Bayreuth Germany
Planta Medica (Germany) 1995, 61/2 (138-140)

Methanolic extracts of stinging nettle (Urtica dioica L.) roots were investigated for aromatase inhibition. Enzyme inhibition was detected only after appropriate chromatographic separation. Inhibitory effects on aromatase could be demonstrated in vitro for a variety of compounds belonging to different classes. The following compounds developed weak to moderate activity: secoisolariciresinol (1), oleanolic and ursolic acid (2 and 3), (9Z,11E)-13-hydroxy-9,11-octadecadienoic acid (4), and 14-octacosanol (5). Inhibitory effects on aromatase have been known to date neither for pentacyclic triterpenes nor for secondary fatty alcohols. The potential physiological significance of the above findings is discussed. Compound 5 is a previously unknown constituent of plants.

Hirano T.; Homma M.; Oka K.
Dept. of Clinical Pharmacology, Tokyo College of Pharmacy, 1432-1 Horinouchi,Hachioji, Tokyo 192-03 Japan
Planta Medica (Germany) 1994, 60/1 (30-33)

The effects of organic-solvent extracts of Urtica dioica (Urticaceae) on the Nasup +,Ksup +-ATPase of the tissue of benign prostatic hyperplasia (BPH) were investigated. The membrane Nasup +,Ksup +-ATPase fraction was prepared from a patient with BPH by a differential centrifugation of the tissue homogenate. The enzyme activity was inhibited by 10sup -sup 4-10sup -sup 5 M of ouabain. The hexane extract, the ether extract, the ethyl acetate extract, and the butanol extract of the roots caused 27.6-81.5% inhibition of the enzyme activity at 0.1 mg/ml. In addition, a column extraction of stinging nettle roots using benzene as an eluent afforded efficient enzyme inhibiting activiry. Steroidal components in stinging nettle roots, such as stigmast-4-en-3-one, stigmasterol, and campesterol inhibited the enzyme activity by 23.0-67.0% at concentrations ranging from 10sup -sup 3-10sup -sup 6 M. These results suggest that some hydrophobic constituents such as steroids in the stinging nettle roots inhibited the membrane Nasup +,Ksup +-ATPase activity of the prostate, which may subsequently suppress prostate-cell metabolism and growth.

Yablonsky F; Nicolas V; Riffaud JP; Bellamy F
Laboratoires Debat, groupe Fournier, Garches, France.
J Urol; 157(6):2381-7 1997
[published erratum appears in J Urol 1997 Sep;158(3 Pt 1):889]

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.

Casella G; Barbaro A
Clinica 'Villa S. Anna', Reggio Calabria, Italy
Arch Sci Med (Torino); 135(1):95-98 1978

A Chloroform extract of Pygeum africanum and mepartricin were used to treat 22 patients with prostatic hypertrophy. Both substances were active against urinary symptomatology, and the polyene also induced a significant decrease in prostate size. Excellent results were obtained in 77% of the patients. (6 Refs)

Thieblot L, Grizard G, Boucher D
Therapie (Paris) 32 (1). 1977 99-110.

In castrated rats, an extract of P. africanum (V 1326) stimulates the secretory activity of the prostate and seminals vesicles but it appears as an antagonist of testosterone in these organs. In castrated adrenalectomized rats, V 1326 stimulates the action of testosterone on target organs and increases pituitary gonadotropin content. The action of V 1326 stimulates the adrenals and pituitary.

Moyad MA
Section of Urology, University of Michigan, Ann Arbor 48109-0330, USA.
Semin Urol Oncol 1999 May;17(2):97-102

Population-based studies from around the world support the theory that soy products and their constituents, primarily the isoflavones or phytoestrogens, are partly responsible for the lower rates of certain chronic diseases in different areas of the world. Cardiovascular disease and hormonally induced cancers are just a few of the conditions lower in Asian countries that consume large quantities of soy per average person. Genistein, one of soy's individual phytoestrogens, has been found to inhibit numerous breast and prostate cancer cell lines. A limited amount of clinical evidence also points to a beneficial role of soy in reducing hormonal levels and exhibiting weak estrogen and antiestrogen-like qualities. Other phytoestrogens found in nature, such as lignans, may also have a future role in cancer. Collectively, these phytoestrogens, like genistein, have enough evidence to warrant their use in a number of clinical trials as a potential chemopreventive agent or adjunct to prostate cancer treatment.

Jacobsen BK, Knutsen SF, Fraser GE
Institute of Community Medicine, University of Tromso, Norway.
Cancer Causes Control 1998 Dec;9(6):553-7

OBJECTIVES: Recent experimental studies have suggested that isoflavones (such as genistein and daidzein) found in some soy products may reduce the risk of cancer. The purpose of this study was to evaluate the relationship between soy milk, a beverage containing isoflavones, and prostate cancer incidence.

METHODS: A prospective study with 225 incident cases of prostate cancer in 12,395 California Seventh-Day Adventist men who in 1976 stated how often they drank soy milk.

RESULTS: Frequent consumption (more than once a day) of soy milk was associated with 70 per cent reduction of the risk of prostate cancer (relative risk = 0.3, 95 percent confidence interval 0.1-1.0, p-value for linear trend = 0.03). The association was upheld when extensive adjustments were performed.

CONCLUSIONS: Our study suggests that men with high consumption of soy milk are at reduced risk of prostate cancer. Possible associations between soy bean products, isoflavones and prostate cancer risk should be further investigated.

Dalu A, Haskell JF, Coward L, Lamartiniere CA
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 35294, USA.
Prostate 1998 Sep 15;37(1):36-43

BACKGROUND: Epidemiological reports suggest that Asians consuming a diet high in soy have a low incidence of prostate cancer. In animal models, soy and genistein have been demonstrated to suppress the development of prostate cancer. In this study, we investigate the mechanism of action, bioavailability, and potential for toxicity of dietary genistein in a rodent model.

METHODS: Lobund-Wistar rats were fed a 0.025-1.0-mg genistein/g AIN-76A diet. The dorsolateral prostate was subjected to Western blot analysis for expression of tyrosine-phosphorylated proteins, and of the EGF and ErbB2/Neu receptors. Genistein concentrations were measured from serum and prostate using HPLC-mass spectrometry. Body and prostate weights, and circulating testosterone levels, were measured.

RESULTS: Increasing concentrations of genistein in the diet inhibited tyrosine-phosphorylated proteins with molecular weights of 170,000 and 85,000 in the dorsolateral prostate. Western blot analysis revealed that the 1-mg genistein/g AIN-76A diet inhibited by 50% the expression of the EGF receptor and its phosphorylation. In rats fed this diet, serum-free and total genistein concentrations were 137 and 2,712 pmol/ml, respectively. The free and total genistein IC50 values for the EGF receptor were 150 and 600 pmol/g prostate tissue, respectively. Genistein in the diet also inhibited the ErbB2/Neu receptor. Body and dorsolateral prostate weights, and circulating testosterone concentrations, were not adversely effected from exposure to genistein in the diet for 3 weeks.

CONCLUSIONS: We conclude that genistein in the diet can downregulate the EGF and ErbB2/Neu receptors in the rat prostate with no apparent adverse toxicity to the host. The concentration needed to achieve a 50% reduction in EGF receptor expression can be achieved by eating a diet high in soy products or with genistein supplementation. Genistein inhibition of the EGF signaling pathway suggests that this phytoestrogen may be useful in both protecting against and treating prostate cancer.

Geller J, Sionit L, Partido C, Li L, Tan X, Youngkin T, Nachtsheim D, Hoffman RM
AntiCancer, Inc., San Diego, California 92111, USA.
Prostate 1998 Feb 1;34(2):75-9

BACKGROUND: There is strong epidemiological evidence that prostate disease is significantly less prevalent in the Orient, where the intake of soy products is very high, than in the United States. We therefore undertook a study of the effects of genistein, a major component of soy, on growth of human-patient benign prostatic hypertrophy (BPH) and prostate cancer tissue in three-dimensional collagen gel-supported histoculture.

METHODS: Surgical specimens of human BPH and cancer were histocultured for 5 days to study the effects of genistein on growth, as measured by inhibition of 3H-thymidine incorporation per microgram protein on day 5.

RESULTS: Genistein in doses of 1.25-10 micrograms/ml decreased the growth of BPH tissue in histoculture in a dose-dependent manner, with little additional effect at higher doses. Prostate cancer tissue in histoculture was similarly inhibited by these doses of genistein.

CONCLUSIONS: Genistein decreases the growth of both BPH and prostate cancer tissue in histoculture. The data suggest that genistein has potential as a therapeutic agent for BPH and prostate cancer.

Kyle E, Neckers L, Takimoto C, Curt G, Bergan R
Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Mol Pharmacol 1997 Feb;51(2):193-200

Genistein (5,7,4'-trihydroxyisoflavone), an isoflavinoid found in soy beans, has been identified as potentially causal for the low incidence of metastatic prostate cancer (PCa) in certain countries. Although genistein-induced PCa cell adhesion has been identified as a possible causative mechanism, direct growth inhibition by genistein has been reported and also could be causal. If in vivo growth inhibition was significant, then growth inhibition should occur at concentrations attained with dietary consumption, the mechanism of growth inhibition should be relevant to PCa, and genistein (a broad-spectrum in vitro protein-tyrosine kinase inhibitor) should have relatively specific kinase inhibitory effects in vivo. These considerations were investigated by measuring growth inhibitory activity in a variety of PCa cell lines. Growth inhibitory effects were shown not to occur with concentrations below the low micromolar range (i.e., 3 logs above that attained in serum). In-depth mechanistic studies with the PC3-M metastatic variant cell line demonstrated that growth inhibition was independent of genistein's estrogenic effects. Genistein was shown to decrease the viability of nonadherent cells, suggesting a lack of dependence on cell adhesion for growth inhibition. However, important molecular and kinetic differences between genistein's effects on growth in adherent versus nonadherent cells were identified. Specific suppression of focal adhesion kinase activity (without global decreases in phosphotyrosine) was shown to precede induction of apoptosis, which was responsible for growth inhibition in adherent cells. These findings do not support an in vivo growth inhibitory role by genistein consumed in quantities associated with a soy-based diet. They do, however, identify genistein as a potential therapeutic agent for PCa and as a tool with which to study the control of apoptosis in PCa.

Andriole GL, Guess HA, Epstein JI, Wise H, Kadmon D, Crawford ED, Hudson P, Jackson CL, Romas NA, Patterson L, Cook TJ, Waldstreicher J
Division of Urology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Urology 1998 Aug;52(2):195-201; discussion 201-2

OBJECTIVES: To evaluate prostate cancer detection and prostate-specific antigen (PSA) among men with benign prostatic hyperplasia treated with finasteride.

METHODS: Three thousand forty men 45 to 78 years of age with PSA less than 10 ng/mL and no history of prostate cancer were randomized in a double-blind, placebo-controlled trial to finasteride (n = 1524) or placebo (n = 1516) for up to 4 years. A prerandomization biopsy negative for prostate cancer was obtained in 98% of patients with a screening PSA of 4.0 ng/mL or more, and an end-of-study biopsy was requested of all such patients without a recent second negative biopsy or a prostate cancer diagnosis.

RESULTS: Overall, 644 patients (21%) underwent biopsy and 201 (6.6%) underwent transurethral resection of the prostate. Prostate cancer was diagnosed in 4.7% of men on finasteride and 5.1% on placebo (P = 0.7). Elevated PSA prompted diagnosis in 35% of cases on finasteride and 34% on placebo. The area under the receiver operating characteristic curve for last PSA was 0.84 on finasteride and 0.79 on placebo (P = 0.07). Use of an upper limit of normal for last PSA of 2.0 ng/mL for finasteride and 4.0 ng/mL for placebo yielded similar sensitivity (66% versus 70%, P = 0.6), higher specificity (82% versus 74%, P < 0.0001), and a higher likelihood ratio (3.6 versus 2.7, P < 0.05) for finasteride than for placebo.

CONCLUSIONS: In men treated with finasteride, multiplying PSA by 2 and using normal ranges for untreated men preserves the usefulness of PSA for prostate cancer detection.

Habib FK, Ross M, Tate R, Chisholm GD
University Department of Surgery (WGH), Western General Hospital, Edinburgh, Scotland.
Clin Endocrinol (Oxf) 1997 Feb;46(2):137-44

OBJECTIVE: The 5 alpha-reductase inhibitor, finasteride, provides a logical medical treatment for benign prostatic hyperplasia (BPH). However, the effects of chronic finasteride treatment on prostatic androgen levels, 5 alpha-reductase activity and tissue prostatic specific antigen (PSA) have not been studied. We have examined prostate tissue androgen concentrations and 5 alpha-reductase activity of the gland in men with BPH treated with the drug for 3 months.

DESIGN AND PATIENTS: Twenty-eight patients with clinically diagnosed BPH, awaiting transurethral resection of the prostate, were entered in a double-blind placebo controlled study. Nineteen patients were randomly allocated to treatment with finasteride (5 mg daily) and 9 received placebo for 3 months.

MEASUREMENTS: Prostate specimens were collected immediately following surgery and analysed for testosterone, dihydrotestosterone (DHT), androstenedione, 5 alpha-reductase activity and PSA. Blood specimens obtained before the start and immediately following treatment were also tested for steroid hormone concentrations and PSA levels.

RESULTS: There was no significant difference in the median levels of intraprostatic testosterone (P = 0.77), DHT (P = 0.46) and androstenedione (P = 0.09) between the finasteride and placebo groups. However, the 5 alpha-reductase activity of the placebo group (237.9 pmol DHT/g tissue/30 min) was approximately 10 times that of the finasteride group (21.5 pmol DHT/g tissue/30 min; P = 0.0008). Although we were unable to detect any differences in the PSA concentrations of the prostate glands, there was a significant difference (P = 0.0002) in the median percentage change of serum PSA concentrations for the two patient groups. Serum DHT levels were also depleted (P = 0.038) whilst serum testosterone was increased (P = 0.054) in the finasteride patients when compared to the placebo group. Furthermore our study demonstrated no correlation between the in vitro 5 alpha-reductase activity of the gland and tissue DHT concentrations.

CONCLUSIONS: Whilst finasteride treatment induced a reduction in serum dihydrotestosterone and prostatic specific antigen levels with a concomittant increase in blood testosterone concentrations, the impact of the drug on tissue androgen concentrations varied considerably from one patient to another. The differential effect of the drug on tissue androgen concentrations suggests that in the human prostate there are possibly more than one isoform of 5 alpha-reductase responsible for the accumulation of DHT in the gland.

[Article in Spanish]
Morote J, Lorente JA, Raventos CX, Lopez MA, Encabo G, De Torres I, Lopez M, De Torres JA
Servicio de Urologia, Hospital General Vall d'Hebron, Universidad Autonoma, Barcelona.
Actas Urol Esp 1998 Nov-Dec;22(10):835-9

OBJECTIVE: To analyze the behaviour of free PSA percentage in finasteride-treated patients and to evaluate whether this ratio allows an increased PSA specificity in the early diagnosis of prostate cancer.

MATERIAL AND METHODS: Evaluation of PSA serum levels and free PSA ratio in 336 patients initially diagnosed with prostate benign hyperplasia (PBH). A group of 82 patients were treated with finasteride for 14 to 58 months. A second group of 254 patients received no treatment. All patients were within the same age range and had similar PSA serum levels. In total, 141 prostate biopsies were performed: 19.5 (16/82) and 49.1 (125/254) respectively.

RESULTS: Median PSA level in PBH patients was 1.6 ng/mL for the finasteride-treated group and 3.5 for the untreated group, p < 0.0001. Free PSA ratio was 18.6 and 18.8%, respectively, p > 0.05. Carcinoma detection rate was 25% (4/16) for the finasteride group and 27.2% (34/125) for the untreated group. If biopsy had been requested when PSA percentage was below 25%, 17.7 and 19.8% respectively would have been prevented and all carcinoma detected.

CONCLUSION: Long-term treatment with finasteride reduces PSA serum concentration about 50% without changing the free PSA ratio. Carcinoma detection rate was similar in finasteride-treated and untreated patients. Free PSA ratio allows to increase PSA specificity and avoid unnecessary biopsied also in finasteride-treated patients.

Brawer MK, Lin DW, Williford WO, Jones K, Lepor H
Northwest Prostate Institute and Pacific Northwest Cancer Foundation, Seattle, Washington 98133, USA.
Prostate 1999 Jun 1;39(4):234-9

BACKGROUND: Medical management of benign prostatic hyperplasia (BPH) giving rise to lower urinary tract symptomatology (LUTS) has emerged as the mainstay for first-line therapy. Prostate-specific antigen (PSA) is the most important method of detecting prostate carcinoma. The effect of finasteride on PSA has been widely reported. Little data exist with respect to alpha-adrenergic blocking therapy in men treated for BPH. In the present investigation we set out to evaluate the effect of these two forms of therapy.

METHODS: Patients enrolled in the VA Cooperative Study #359 trial were evaluated. This study evaluated men with moderate LUTS owing to BPH in four treatment groups: placebo (P), finasteride (F), terazosin (T), and combination of finasteride plus terazosin (C). Men were recruited at 31 VA medical centers and had a baseline in 52-week PSA determination at the respective sites.

RESULTS: There was no significant difference in baseline PSA between four groups (mean range, 2.0-2.9 ng/ml). Statistically significant reduction in PSA levels was observed at 52 weeks in the F and C arms (P < 0.001), whereas significant increases were observed in the T and P arms (P < 0.01). Additionally, there was no significant difference in PSA response between the T and P arms. Thirty percent of men in the C or F arms had more than 40-60% reduction of PSA. In contrast, the majority of men on T or P had less than 40% change in PSA. Only 35% of men on F or C had the expected 40-60% reduction in PSA level.

CONCLUSIONS: These data demonstrate no clinically significant effect of T on PSA level. The heterogeneity of PSA response to F may make monitoring patients for the development of prostate cancer problematic.

George FW
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8857, USA.
george02@utsw.swmed.edu
Endocrinology 1997 Mar;138(3):871-7

Previous work has clearly demonstrated that inhibition of 5 alpha-dihydrotestosterone (DHT) formation in vivo is not as effective as total androgen ablation (castration) in causing involution of the prostate. It is likely that this is due to the fact that testosterone is partially effective in maintaining androgen action. To provide insight into this observation, the androgenic metabolites of testosterone, androstenedione, and 5 alpha-DHT, were measured in prostate tissue and in blood of 5 alpha-reductase inhibitor (finasteride)-treated adult male rats. Finasteride treatment caused a significant decrease in prostatic DHT levels and a profound increase in prostatic testosterone and androstenedione levels. Similarly, circulating DHT levels were decreased in finasteride-treated rats (0.02 ng/ml compared with 0.05 ng/ml seen in control rats); and circulating androstenedione and testosterone levels were significantly elevated in finasteride-treated animals compared with controls. The in vitro effects of finasteride were assessed on the metabolism of [3H]testosterone in a tissue-slice assays. In the prostate, the inhibition of 5 alpha-reductase activity resulted not only in the decreased formation of 5 alpha-reduced metabolites (primarily DHT and 5 alpha-androstanedione), but also an increase in the 17-oxo metabolite androstenedione. In contrast, the tissues derived from the embryonic wolffian duct (seminal vesicle and epididymis) formed relatively low amounts of 17-keto steroids. Because DHT is a high affinity ligand for the androgen receptor and androstenedione shows very little, if any, affinity for the receptor, these studies suggest that 5 alpha-reduction of testosterone may be a mechanism to amplify androgen action in urogenital tissues such as the prostate by preventing catabolism of testosterone to the inactive androgen, androstenedione, at the site of hormone action.

Weisser H; Krieg M
Institut fur Klinische Chemie, Transfusions- und Laboratoriumsmedizin, Berufsgenossenschaftliche Kliniken Bergmannsheil, Universitatsklinik der Ruhr-Universitat, Bochum.
Urologe A 1997 Jan;36(1):3-9

Although human benign prostatic hyperplasia (BPH) is the most common tumor in men, its etiology is still unclear. At present, it is only widely accepted that BPH is under the endocrine control of the testes and strongly associated with aging. Therefore, in the human prostate we describe the impact of aging on the activity of various androgen metabolizing enzymes as well as on the endogenous androgen and estrogen levels. Moreover, the inhibition of 5 alpha-reductase by finasteride (Proscar) will be reported. Among all androgen metabolizing enzymes, within the human prostate 5 alpha-reductase is the most powerful one. Most of the androgen metabolizing enzymes undergo a significant age-dependent alteration. For distinct enzymes, the correlation with age is either negative (e.g. 5 alpha-reductase), or positive. Despite a complex pattern of age-dependent alterations, the dominance of 5 alpha-reductase among all androgen metabolizing enzymes is always maintained. This is underlined by a strong accordance between the age-dependent 5 alpha-reductase activity and the corresponding age-dependent endogenous DHT level. In epithelium, both the 5 alpha-reductase activity and the DHT level decrease with age, whereas in stroma not only the 5 alpha-reductase activity is rather constant over the whole age range but the DHT level as well. In contrast to the relatively unaltered DHT content in the stroma of the human prostate, the estrogen content follows an age-dependent increase. On the other side, in epithelium such a positive correlation between the estrogen level and age is not found. Thus, the age-dependent decrease of the DHT accumulation in epithelium and the concomitant increase of the estrogen accumulation in stroma will lead to a tremendous increase with age of the estrogen/androgen ratio in the human prostate. This could be of pathogenetic importance for BPH development if in fact a balanced androgen/estrogen synergism is necessary for the integrity of the normal human prostate. Finally, it is remarkable that the inhibition of 5 alpha-reductase activity by finasteride (Proscar) is significantly stronger in epithelium than in stroma. Therefore, it is conceivable that the global size-reduction of BPH under finasteride treatment is primarily due to the regression of BPH epithelium.

Pannek J, Marks LS, Pearson JD, Rittenhouse HG, Chan DW, Shery ED, Gormley GJ, Subong EN, Kelley CA, Stoner E, Partin AW
James Buchanan Brady Urological Institute and the Department of Clinical Chemistry, Johns Hopkins Medical Institution, Baltimore, Maryland, USA.
J Urol 1998 Feb;159(2):449-53

PURPOSE: Finasteride therapy for benign prostatic hyperplasia (BPH) results in a marked lowering of serum prostate specific antigen (PSA) levels. However, little is known about the effect of finasteride on unbound or free serum levels of PSA. Such information would be important since percent free PSA may substantially improve the cancer specificity of PSA testing. Thus, we prospectively studied the effect of finasteride therapy on total and free serum PSA levels.

MATERIALS AND METHODS: In a randomized, placebo controlled, double-blind trial 40 men with histologically confirmed BPH (age range 52 to 78 years) were treated with either 5 mg. finasteride daily (26 patients) for 9 months or placebo (14) for 6 months. Prostate volume was assessed by transrectal ultrasound. Serum levels of free and total PSA were measured from archived serum samples stored at -70C at baseline and for as long as 9 months of treatment.

RESULTS: In the finasteride group mean total PSA levels declined from 3.0 ng./ml. at baseline to 1.5 ng./ml. after 6 months of treatment (50% decrease, p <0.01). In the placebo group, with similar baseline levels, no significant change was observed. PSA density declined significantly in finasteride treated men (p <0.01) but not in men receiving placebo. The mean percent free PSA (13 to 17% at baseline) was not altered significantly by finasteride or placebo.

CONCLUSIONS: Total PSA serum levels decreased by an average of 50% during finasteride therapy but percent free PSA did not change significantly. This information is potentially useful in the interpretation of PSA data used for early detection of prostate cancer in men receiving finasteride. However, further studies are required to demonstrate the use of percent free PSA to detect the development of cancer.

Cote RJ, Skinner EC, Salem CE, Mertes SJ, Stanczyk FZ, Henderson BE, Pike MC, Ross RK
Department of Pathology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles 90033, USA.
Br J Cancer 1998 Aug;78(3):413-8

Prostate cancer is a disease associated with androgens. It has been hypothesized that reducing the conversion of testosterone (T) to dihydrotestosterone (DHT) in the prostate by the use of the drug finasteride, a 5alpha-reductase inhibitor, will reduce the incidence of prostate cancer. We investigated the chemopreventive potential of finasteride by evaluating its effect on the prostate gland of men with elevated serum prostate-specific antigen (PSA). Fifty-two men with elevated PSA and prostate sextant biopsies negative for cancer were randomized to receive finasteride 5 mg day(-1) (27 patients) or no medication (25 patients) for 12 months and were rebiopsied at 12 months. The biopsies were evaluated for the presence of cancer, the proportion of glandular and hyperplastic tissue, and the presence of high-grade prostatic intraepithelial neoplasia (PIN). Epithelial proliferation was assessed in the prestudy and 12-month biopsies by immunohistochemistry using antibody to proliferating cell nuclear antigen (PCNA). Serum blood samples were drawn at baseline and after 1, 3, 6 and 12 months of study. In the control group, serum levels of PSA and T were unchanged throughout the 12 months. In the finasteride group, PSA decreased 48% (P < 0.001), DHT decreased 67% (P < 0.001) and T increased 21% (P < 0.001). Histological evaluation of prestudy and 12-month biopsy specimens revealed that the finasteride group had a 30% reduction in the percentage of hyperplastic epithelial tissue (P = 0.002), although this decrease was not statistically significantly different between the finasteride and control groups (P = 0.11). In patients with PIN on prestudy biopsy, no change occurred in the PIN lesions with finasteride treatment. Finasteride also had no effect on the proliferation index of prostatic epithelial cells. Of the 27 patients treated with finasteride, eight (30%) had adenocarcinoma of the prostate detected on the 12-month biopsy, compared with one (4%) of the control patients (P = 0.025). In the treatment group, six cancers occurred in the eight patients with PIN on the prestudy biopsy; in the observation group no cancers were detected in the five patients with PIN on the prestudy biopsy (P = 0.021). Two cancers occurred in the 19 men in the treatment group with no evidence of PIN on the prestudy biopsy, compared with one cancer in the 20 men in the observation group with no evidence of PIN on the prestudy biopsy (P = 0.60). This study, using a novel model for evaluating short-term efficacy of chemopreventive or therapeutic agents in men at high risk of prostate cancer, provides little evidence that finasteride is an effective chemopreventive agent for prostate cancer in men with elevated PSA.

Gormley G.J.
Merck Research Laboratories, PO Box 2000,Rahway, NJ 07065-0914 United States
Biomedicine and Pharmacotherapy (France) 1995, 49/7-8 (319-324)

Finasteride is the first of a new class of 5alpha-reductase inhibitors which allows selective androgen deprivation affecting dihydrotestosterone (DHT) levels in target organs such as the prostate and scalp hair without effecting circulating levels of testosterone thus preserving the desired androgen mediated effects on muscle strength, bone density and sexual function. Finasteride has been demonstrated to produce significant effects in men with an enlarged prostate gland. The long-term data now emerging suggests that progression of benign prostatic hyperplasia (BPH) may be arrested providing additional long term benefits. Experimental uses in prostate cancer prevention and male pattern baldness offer new and exciting possibilities for this class of compounds.

Rhodes L.; Primka R.L.; Berman C.; Vergult G.; Gabriel M.; Pierre-Malice M.; Gibelin B.
RY80Y-140, Merck Sharp and Dohme Research Lab, POB 2000,Rahway, NJ 07065 United States
Prostate (United States) 1993, 22/1 (43-51)

Human prostate was used as a source of 5alpha reductase. Compounds were incubated with an enzyme preparation and (sup 3H)testosterone. (sup 3H)-dihydrotestosterone production was measured to calculate 5alpha reductase activity. IC$D5inf 0 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 5alpha reductase, while Permixon and Bazoton have neither antiandrogen nor 5alpha 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 5alpha 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 mug/ml). Based on these results, it is unlikely that these plant extracts would shrink the prostate by inhibiting androgen action or 5alpha reductase.

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