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February 1999

LE Magazine February 1999


Phytotherapy for Enlarged Prostate
The research, and testimony, can be persuasive in favor of natural therapies

Saw palmetto versus prostate enlargement

Saw palmetto in men with lower urinary tract symptoms: Effects on urodynamic parameters and voiding symptoms Urology (1998 Jun) 51(6):1003-7

Methods: Fifty men with previously untreated LUTS and a minimum International Prostate Symptom Score (IPSS) of 10 or greater were treated with a commercially available form of saw palmetto (160 mg twice per day) for six months. The initial evaluation included measurement of peak urinary flow rate, postvoid residual urine volume, pressure-flow study, and serum prostate-specific antigen (PSA) level. Patients completed an IPSS, serum PSA was determined, and flow rate was measured every two months during the course of the study. A urodynamic evaluation was repeated at the completion of the six-month trial.

Results: The mean IPSS (+/-SD) improved from 19.5+/- 5.5 to 12.5+/-7.0 (P<0.001) among the 46 men who completed the study. Significant improvement in the symptom score was noted after treatment with saw palmetto for two months. An improvement in symptom score of 50% or greater after treatment with saw palmetto for two, four and six months was noted in 21% (10 of 48), 30% (14 of 47), and 46% (21 of 46) of patients, respectively. There was no significant change in peak urinary flow rate, postvoid residual urine volume, or detrusor pressure at peak flow among patients completing the study. No significant change in mean serum PSA level was noted.

Conclusions: Saw palmetto is a well-tolerated agent that may significantly improve lower urinary tract symptoms in men with BPH. However, we were unable to demonstrate any significant improvement in objective measures of bladder outlet obstruction. Placebo-controlled trials of saw palmetto are needed to evaluate the true effectiveness of this compound.

SHBG and androgen

Sex hormone-binding globulin mediates prostate androgen receptor action via a novel signaling pathway. Ding VD Moller DE Feeney WP Didolkar V Nakhla AM Rhodes L Rosner W Smith RG Endocrinology (1998 Jan) 139(1):213-8

Estradiol (E2) and 5alpha-androstan-3alpha,17beta-diol (3alpha-diol) have been implicated in prostate hyperplasia in man and dogs, but neither of these steroids binds to androgen receptors (ARs). Recently, we reported that E2 and 3alpha-diol stimulated generation of intracellular cAMP via binding to a complex of sex hormone-binding globulin (SHBG) and its receptor (R(SHBG)) on prostate cells.

We speculated that this pathway, involving steroids normally found in the prostate, was involved in the indirect activation of ARs. Using the dog as a model to test this hypothesis in normal prostate, we investigated whether E2, 3alpha-diol, and SHBG stimulated the production of the androgen-responsive protein, arginine esterase (AE), the canine equivalent of human prostate-specific antigen. In cultured dog prostate tissue preincubated with SHBG, E2 and 3alpha- diol stimulated AE activity. These effects were blocked by hydroxyflutamide, an AR antagonist, and by 2-methoxyestradiol, a competitive inhibitor of E2 and 3alpha-diol binding to SHBG. In the absence of exogenous steroids and SHBG, AE also was significantly increased by treatment with forskolin or 8-Bromoadenosine-cAMP. These observations support the hypothesis that in normal prostate, E2 and 3alpha-diol can amplify or substitute for androgens, with regard to activation of the AR via the R(SHBG) by a signal transduction pathway involving cAMP. Because both E2 and 3alpha-diol are involved in the pathogenesis of benign prostatic hyperplasia in dogs and implicated in benign prostatic hyperplasia in man, antagonism of the prostatic SHBG pathway may offer a novel and attractive therapeutic target.

Nettle vs. BPH

The inhibiting effects of Urtica dioica root extracts on experimentally induced prostatic hyperplasia in the mouse. Lichius JJ Muth C
Planta Med (1997 Aug) 63(4):307-10

Extracts of stinging nettle roots (Urtica dioica L. Urticaceae) are used in the treatment of benign prostatic hyperplasia (BPH). We established a BPH-model by directly implanting an urogenital sinus (UGS) into the ventral prostate gland of an adult mouse. Five differently prepared stinging nettle root extracts were tested in this model. The 20% methanolic extract was the most effective with a 51.4% inhibition of induced growth.

Estrogen and SHBG

Roles of estrogen and SHBG in prostate physiology. Farnsworth WE
Prostate (1996 Jan) 28(1):17-23

Heretofore, the function of estrogen in the prostate, other than as an antiandrogen, has been unclear. In this review of a growing fund of knowledge about both estrogen and the plasma protein, sex hormone- binding globulin (SHBG), or testosterone-estradiol binding globulin (TeBG), the hypothesis is proposed that estrogen, mediated by SHBG, participates with androgen in setting the pace of prostatic growth and function. It is suggested that the estrogen not only directs stromal proliferation and secretion, but also, through IGF-I, conditions the response of the epithelium to androgen.

Benign prostatic hyperplasia

Phytotherapy of benign prostatic hyperplasia
Urologe A (1997 Jan) 36(1):10-7

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.

DHEA and the elderly

Effects of dehydroepiandrosterone replacement in elderly men on event-related potentials, memory, and well-being
J Gerontol A Biol Sci Med Sci (1998 Sep) 53(5):M385-90

Background: In humans, concentrations of the adrenal steroid hormone dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA/S) decline with age. Results from studies in rodents have suggested that DHEA administration can improve memory performance as well as neuronal plasticity. However, a first study from our laboratory could not demonstrate beneficial effects of DHEA substitution on cognitive performance and well-being in elderly subjects. To further evaluate whether DHEA replacement has effects on the central nervous system, an experiment using event-related potentials (ERPs) was conducted.

Methods: In this placebo-controlled crossover study, 17 elderly men (mean age, 71.1 +/- 1.7 years; range 59-81 years) took placebo or DHEA (50 mg/day) for two weeks (double blind). After each treatment period subjects participated in an auditory oddball paradigm with three oddball blocks. In the first two blocks, subjects had to count the rare tone silently, whereas in the third block they had to press a button. In addition, memory tests assessing visual, spatial, and semantic memory as well as questionnaires on psychological and physical well-being were presented.

Results: Baseline DHEA/S levels were lower compared with young adults. After two-week DHEA replacement, DHEA/S levels rose fivefold to levels observed in young men. DHEA substitution modulated the P3 component of the ERPs, which reflects information updating in short-term memory. P3 amplitude was increased after DHEA administration, and only selectively in the second oddball block. DHEA did not influence P3 latency. Moreover, DHEA did not enhance memory or mood.

Conclusions: A two-week DHEA replacement in elderly men results in changes in electrophysiological indices of central nervous system stimulus processing if the task is performed repeatedly. However, these effects do not appear to be strong enough to improve memory or mood.

Effects of DHEA on body fat

DHEA treatment reduces fat accumulation and protects against insulin resistance in male rats
J Gerontol A Biol Sci Med Sci (1998 Jan) 53(1):B19-24

The purpose of this study was to determine whether administration of dehydroepiandrosterone (DHEA) protects male rats against the accumulation of body fat the development of insulin resistance with advancing age. We found that supplementation of the diet with 0.3% DHEA between the ages of 5 months and approximately 25 months resulted in a significantly lower final body weight (DHEA, 593 +/- 18 grams versus control, 668 +/- 12 grams, p < 0.02), despite no decrease in food intake. Lean body mass was unaffected by the DHEA, and the lower body weight was due to a approximately 25% reduction in body fat. The rate of glucose disposal during a euglycemic, hyperinsulinemic clamp was 30% higher in the DHEA group than in the sedentary controls due to a greater insulin responsiveness. The DHEA administration was as effective in reducing body fat content and maintaining insulin responsiveness as exercise in the form of voluntary wheel running. The DHEA had no significant effect on muscle GLUT4 content. A preliminary experiment provided evidence suggesting that muscle insulin signaling, as reflected in binding of phosphatidylinositol 3- kinase to the insulin receptor substrate-1, was enhanced in the DHEA-treated and wheel-running groups as compared to controls. These results provide evidence that DHEA, like exercise, protects against excess fat accumulation and development of insulin resistance in rats.

Steroids and DHEA

Panhypopituitarism as a model to study the metabolism of dehydroepiandrosterone (DHEA) in humans
J Clin Endocrinol Metab (1997 Aug) 82(8):2578-85

The physiological importance and therapeutical interest of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA/S) are still controversial. Panhypopituitarism is characterized by the absence of secretion of adrenal and gonadal steroids and thus the production of their metabolites. The conversion of DHEA given orally into delta 5 derivatives, androgens, androgen metabolites, and estrogens was studied in 10 patients with complete panhypopituitarism. Sex steroid therapy was withdrawn for at least two months. Each patient received, at one-month intervals and in a random order two single oral doses of DHEA (50 mg and 200 mg) and placebo. During each treatment, urine samples were collected for 24 hours, and blood samples were drawn at hourly intervals for eight hours. In patients with pituitary deficiency, plasma DHEA and DHEA/S were not detectable and increased, with the 50 mg dose, up to levels observed in young adults. The administration of 200 mg of DHEA induced an increase of both steroids to supraphysiological plasma levels. A small increase of delta 5-androstenediol was observed. In contrast, the increase of plasma delta 4-androstenedione was important and dose dependent. DHEA was also converted into the potent sex steroid testosterone (T). The administration of a 50 mg dose of DHEA restored plasma T to levels similar to those observed in young women. The 200 mg dose induced an important increase of plasma T, slightly below the levels observed in normal men. The increase of plasma dihydrotestosterone levels was small at both doses of DHEA, in contrast with the large conversion of DHEA into androsterone glucuronide and androstanediol glucuronide. Finally, DHEA administration induced a significant and dose dependent increase of plasma estrogens and particularly of estradiol.

In conclusion, this short term study demonstrates that: 1) panhypopituitarism is a model of interest to study the metabolism of DHEA; 2) in the absence of pituitary hormones and of adrenal and gonadal steroids, DHEA given orally is mainly converted into delta 4 derivatives, which in turn are strongly metabolized into 5 alpha- 3 keto-reduced steroids; and 3) a significant increase of sex active hormones was observed in plasma after 200 and even 50 mg of DHEA. Thus, biotransformation of DHEA into potent androgens and estrogens may explain several of the reported beneficial actions of this steroid in aging people.

Physical well-being, cognition

Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men
J Clin Endocrinol Metab (1997 Jul) 82(7):2363-7

The levels of dehydroepiandrosterone (DHEA) and its sulfate ester DHEA/S decrease with age after a peak around 25 years. Animal studies as well as the first studies in humans have generated the idea that DHEA replacement in elderly subjects may have beneficial effects on well-being and cognitive functions. In the present experiment 40 healthy elderly men and women (mean age, 69 years) participated in a double blind, placebo-controlled DHEA substitution study. For 2 weeks subjects took 50 mg DHEA daily, followed by a 2-week wash-out period and a 2-week placebo period. The treatment sequence was randomized in a cross-over design. After 2 weeks of DHEA or placebo, psychological and physical well-being as well as cognitive performance were assessed using several questionnaires and neuropsychological tests. All subjects had low DHEA/S baseline levels. DHEA substitution led to a 5-fold increase in DHEA/S levels in women (from 0.67 +/- 0.1 to 4.1 +/- 0.4 micrograms/mL; P <0.001) and men (from 0.85 +/- 0.1 to 4.5 +/- 0.4 micrograms/mL; P < 0.001). DHEA, androstenedione, and testosterone levels also increased significantly in both sexes (all P < 0.001). No significant changes were observed in insulin-like growth factor I or insulin-like growth factor-binding protein-3 levels. DHEA replacement had no strong beneficial effect on any of the measured psychological or cognitive parameters. Only women tended to report an increase in well-being (P = 0.11) and mood (P = 0.10), as assessed with questionnaires. They also showed better performance in one of six cognitive tests (picture memory) after DHEA. However, after Bonferroni alpha adjustment, this difference was no longer significant. No such trend was observed in men (P > 0.20). Likewise, no beneficial effects of DHEA substitution could be observed in any of the other tests of the neuropsychological test battery in either sex (all P >0.20). In conclusion, the present data do not support the idea of strong beneficial effects of a physiological DHEA substitution on well-being or cognitive performance in healthy elderly individuals.

Smoking, alcohol and stomach carcinoma

The influence of cigarette smoking, alcohol, and green tea consumption on the risk of carcinoma of the cardia and distal stomach in Shanghai, China
Cancer (1996 Jun 15) 77(12):2449-57

Background: The divergent incidence patterns of gastric cardia and distal stomach cancer may suggest different etiologies. This study examined the role of cigarette smoking, alcohol drinking, and green tea consumption as risk factors for carcinoma by anatomic subsite of stomach. Methods: Newly-diagnosed stomach carcinoma patients (n = 1124) and frequency-matched population controls (n = 1451) were interviewed in person. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models.

Results: Excess risks associated with cigarette smoking and alcohol consumption were observed largely among men. The adjusted ORs for all stomach cancer combined were 1.35 (CI: 1.06-1.71) for current smokers, and 1.26 (CI: 0.86-1.84) for ex-smokers. For tumors of the distal stomach, statistically significant positive dose-response trends were found for the number of cigarettes smoked per day, the duration and pack-years of smoking, and inverse trends for years of stopped smoking. For tumors of the gastric cardia, however, a monotonic association was found only for the number of cigarettes smoked per day (P=0.06). Alcohol consumption was not related to the risk of cardia cancer, while a moderate excess risk of distal stomach cancer (OR: 1.55; CI:1.07-2.26) was observed among heavy alcohol drinkers. Green tea drinking was inversely associated with risk of stomach cancer arising from either subsite, with ORs of 0.77 (CI:0.52-1.13) among female heavy drinkers, and 0.76 (CI: 0.55-1.27) among male heavy drinkers.

Conclusions: Our findings provide further evidence that cigarette smoking and, possibly, alcohol consumption increase the risk of stomach carcinoma, notably of the distal segment. An inverse association with green tea drinking was also observed.

Protective ginger and atherosclerosis

The protective action of ethanolic ginger (Zingiber officinale) extract in cholesterol fed rabbits
J Ethnopharmacol (1998 Jun) 61(2):167-71

The effects of ethanolic extract of ginger (200 mg/kg, p.o.) were studied in cholesterol fed rabbits. The marked rise in serum and tissue cholesterol, serum triglycerides, serum lipoproteins and phospholipids that followed 10 weeks of cholesterol feeding, was significantly reduced by the ethanolic ginger extract and results were compared with gemfibrozil, a standard orally effective hypolipidemic drug. The severity of aortic atherosclerosis as judged by gross grading was more marked in pathogenic, i.e. the hypercholesterolemic group, while animals receiving ginger extract along with cholesterol showed a lower degree of atherosclerosis. The results indicate that ginger is definitely an antihyperlipidemic agent.

Vitamin E as an anti-aging therapy

Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomized controlled trial [see comments]. Meydani SN Meydani M Blumberg JB Leka LS Siber G Loszewski R Thompson C Pedrosa MC Diamond RD Stollar BD
JAMA (1997 May 7) 277(17):1380-6ISSN: 0098-7484

Objective: To determine whether long-term supplementation with vitamin E enhances in vivo, clinically relevant measures of cell- mediatedimmunity in healthy elderly subjects. Design: Randomized, double-blind, placebo controlled intervention study.

Setting and Participants: A total of 88 free-living, healthy subjects at least 65 years of age. Intervention: Subjects were randomly assigned to a placebo group or to groups consuming 60, 200, or 800 mg/d of vitamin E for 235 days.

Results: Supplementation with vitamin E for 4 months improved certain clinically relevant indexes of cell-mediated immunity in healthy elderly. Subjects consuming 200 mg/d of vitamin E had a 65% increase in DTH and a 6-fold increase in antibody titer to hepatitis B compared with placebo (17% and 3-fold, respectively), 60-mg/d (41% and 3-fold, respectively), and 800-mg/d (49% and 2.5-fold, respectively) groups. The 200-mg/d group also had a significant increase in antibody titer to tetanus vaccine. Subjects in the upper tertile of serum alpha-tocopherol (vitamin E) concentration (>48.4 micromol/L [2.08 mg/dL]) after supplementation had higher antibody response to hepatitis B and DTH. Vitamin E supplementation had no effect on antibody titer to diphtheria and did not affect immunoglobulin levels or levels of T and B cells. No significant effect of vitamin E supplementation on autoantibody levels was observed.