Am J Health Syst Pharm. 2001;58(2) 

Introduction

Introduction

The bark of the African plum tree (Pygeum africanum, also known as Prunus africana) has been used traditionally for the discomfort of benign prostatic hypertrophy (BPH) by the Zulu people of Africa.[1] Other peoples of Africa and Madagascar use the bark for generalized urinary-tract troubles, fever, stomach ache, and "madness" and as an aphrodisiac.[2] The hydrocyanic acid content conveys a pleasant almond flavor, and milk-based infusions are sometimes substituted for almond milk (used for drinking and cooking).[2]

Use

Currently, pygeum extract is the most popular treatment for symptoms of BPH in France and is commonly used for this condition in Italy and the United States. Compared with many other popular botanical treatments, pygeum has been fairly well researched; however, it is not mentioned in the German Commission E monographs [3,4] or in several other common botanical medicine references.[5,6,7] Worldwide demand for pygeum extract has increased so much that in 1998 it was reported that the tree was a threatened species.[8] International trade in pygeum is now monitored under the Convention on International Trade in Endangered Species of Wild Fauna and Flora.[2]

Review of BPH

BPH is identified through biopsy in up to 80% of men over 60 years of age. Only half of men with symptoms of BPH ever seek medical treatment.[9] One survey found that 20% of men older than 60 had BPH symptoms equivalent to those of men undergoing prostate surgery.[10] The symptoms associated with enlargement of the prostate gland may be obstructive (decrease in the force of the urinary stream, difficulty in beginning or maintaining a urinary stream, inability to completely empty the bladder, and post-micturitional dribbling) or irritative (urgency and urge incontinence, dysuria, and increased frequency during the day and at night). Some obstructive symptoms tend to be a direct result of urethral constriction, while others result more from increased muscle excitability, leading to bladder instability, or weakening of the detrusor muscle. Growth of the prostate gland is thought to be affected by androgens, especially dihydrotes-tosterone.[11] Estradiol, synthesized from testosterone via the aromatase pathway, may also be implicated in initiating hyperplasia in the prostatic stroma and epithelium.[12]

Pharmacology

Like most botanicals, pygeum contains a wide range of constituents. Most of the bioactive substances in the bark are lipid-soluble compounds, including approximately 14% triterpenes (oleanolic, crataegolic, and ursolic acids), ferulic acid esters such as N-docosanol and N-tetracosanol, and phytosterols ( -sitosterol, -sitosterol, and campesterol).[2,13,14] Triterpenes have some anti-inflammatory activity. They inhibit enzymes involved in the destruction of connective tissue [14,15] and reduce intraprostatic prostaglandin formation.[16] Theoretically, phytosterols compete with androgen precursors and inhibit prostag-landin biosynthesis.[14] In animal studies, N-docosanol has been shown to decrease levels of testosterone, luteinizing hormone, and prolactin [13] ; however, one human study of pygeum extract did not find significant changes in testosterone, follicle-stimulating hormone, luteinizing hormone, or estrogens.[1] Other effects attributed to whole extracts of pygeum include normalization of glandular epithelium, an increase in prostatic secretions, estrogenic and antiestrogenic activity, and inhibition of fibroblast proliferation.[17,18]

Mechanism of Action

Many mechanisms may explain pygeum's effects on BPH. These include a slight decrease in levels of testosterone and prolactin (which stimulates intraprostatic dihydrotestosterone synthesis and testosterone uptake), a decrease in the excitability of the detrusor muscle, antiestrogenic effects (which may block the initiation of hyperplasia), a decrease in the proliferation of fibroblasts within the gland, and an increase in prostatic secretions (which may help to alleviate irritation within the urethra).[18,19] Pygeum inhibits 5 -reductase and binding of dihydrotestosterone to androgen receptors, although the inhibition is minimal and not clinically significant.[1] Pharmacokinetics. We found no information on the absorption, metabolism, or elimination of pygeum extract or of -sitosterol, one of the extract's primary components.

Clinical Studies

In clinical trials, five to six months of placebo treatment can improve BPH symptom scores by 30- 40%, a clinically significant response.[9] This placebo effect should be considered in interpreting the findings of open-label studies and in assessing their possible clinical signifance. However, the demonstrated magnitude of improvement with placebo cannot be compared directly with the results of a specific noncontrolled study to statistically confirm the efficacy of a treatment.

Various methods of measuring the response to therapy of BPH have been used. Homma et al.[20] determined that the combined use of four outcome measures -- the International Prostate Symptom Score (IPSS) (also known as the American Urological Association symptom index), the quality of life index from the IPSS (IPSS-QOL), the maximum urinary flow rate (MFR), and prostate volume -- are well correlated with clinical assessments of efficacy by physicians. Use of fewer than these four measures resulted in a much lower correlation with clinical judgment. Other indexes include the Madsen-Iverson and Boyarsky scoring systems and the Danish Prostate Symptom Score.[21,22]

A 1995 review of pygeum therapy for BPH listed 32 open-label studies in which global outcome or objective measures were used and 12 placebo-controlled trials, one of which used docosanol rather than a whole pygeum extract.[19] Since that review, two trials of pygeum extract,[23,24] two trials of -sitosterol [25,26] (with an 18-month follow-up for one 27), and one comparison between pygeum and a pollen extract 28 have been published.

The 1995 review, which included the experiences of 2262 patients, found that pygeum extract improved the symptoms and objective measures of BPH. The improvement was most probably due to combined effects on prostatic secretion, fibroblast proliferation, and detrusor muscle hypersensitivity. These results and the high tolerability of pygeum extract led the authors to conclude that pygeum should be reappraised as a treatment option and compared with standard treatments, such as 5 -reductase inhibitors.[19] One methodological advantage of this review is that the studies were examined in groups based on their design (e.g., double-blind and placebo-controlled studies, open-label comparisons, and double-blind studies with active-treatment controls).

The largest placebo-controlled trial to date was reported by Barlet and colleagues [29] in 1990. Although often cited in reviews, the original article was published in German, and it is unclear whether the reviewers were able to accurately assess the study's quality. We obtained an English translation of the original publication. The 60-day, randomized, double-blind trial examined the effects of pygeum extract (Tadenan) 50 mg twice daily versus placebo on symptoms and objective measures of BPH. The study enrolled 263 patients who were over 50 years old, had had symptoms of "stage 1" BPH for 6-48 months, and had quantifiable nocturia. Patients were excluded if they had other urinary-tract or prostate diseases or were using drugs (either concurrently or with-in the preceding six months) that would improve any BPH symptoms. After two months, differences between the groups were significant for all primary objective outcome measures. Urine volume increased 12% in the pygeum group versus 3.2% in the placebo group, residual urine volume decreased 24.5% in the pygeum group versus 3.5% in the placebo group, nocturnal micturitions fell from 2.9 to 2.0 in the pygeum group versus from 2.7 to 2.2 in the placebo group, and daytime micturitions fell from 7.2 to 5.8 in the pygeum group versus from 7.2 to 6.6 in the placebo group. MFR increased significantly from a baseline of 13.5 mL/sec to 15.7 mL/sec in the pygeum group and did not change significantly in the placebo group (14.0 mL/sec at baseline versus 14.6 mL/ sec at two months). Prostate volume, as estimated by digital rectal examination, did not change.

Improvement in or elimination of secondary subjective outcome measures of hesitancy, weak urine stream, night-time dribbling, and feeling of residual urine was reported by 55.8-62.0% of the patients in the pygeum group and 33.3- 43.2% of the placebo recipients. Intermittent urine stream, another secondary outcome measure, showed the least improvement (35.2% of pygeum recipients and 26.9% of placebo recipients). Both physicians and patients rated pygeum treatment as generally successful in 65.6% of cases, compared with success rates of 30.8% and 40.7% in the placebo group as rated by physicians and patients, respectively. Four patients in each group dropped out of the study. Diarrhea, constipation, dizziness, stomach pains, and blurred vision were reported for three pygeum-treated patients who withdrew. Mild, transient diarrhea was reported after the study by two other pygeum recipients and two patients in the placebo group. Laboratory test values showed no significant changes. The authors concluded that the risk-to-benefit ratio supports the use of pygeum extract for treating the symptoms of BPH. The objective outcome measures used in this trial are fairly standard for assessing the severity of BPH; however, symptoms were not assessed with a validated scale. All outcome measures were compared between the groups after treatment was completed. Change from baseline was statistically compared for MFR only. Information on the statistical power of the study was not provided. The fact that the inclusion criteria had specific requirements for only one objective symptom -- nocturia -- raises the question of whether the sample was representative of the population of patients with BPH. Although providing some solid information, the study cannot be considered definitive. Definitive results were also not provided by two more recent trials, since they did not have placebo or active-treatment controls. Breza and colleagues 24 used pygeum extract (Tadenan) 50 mg twice daily in an open-label, multicenter trial of two months' duration. Patients (n = 85) were men 50-75 years of age with at least a six-month history of urinary-tract problems and an IPSS of 12. The primary endpoint was mean change from baseline in IPSS at two months. Secondary endpoints included mean change from baseline in the frequency of nocturia and mean change from baseline in QOL score. Objective assessments included MFR, average flow rate and volume, residual volume, and prostate volume. The researchers found a significant decrease of 40% in mean IPSS and a significant increase of 31% in mean QOL score at two months. The mean frequency of nocturia decreased from 2.62 to 1.66 (p < 0.001).

The authors noted that the placebo effect could account for a 24% decrease in mean IPSS after two months of treatment.[9] Although the implication is that the additional 16% decrease in IPSS was attributable to the pharmacologic effects of pygeum, this conclusion is not necessarily valid in light of the lack of a placebo control in the study.

A double-blind, randomized study by Chatelain et al.[23] compared two dosage regimens of Tadenan-brand pygeum extract. Patients received 50 mg twice daily (n = 101) or 100 mg once daily (n = 108) for 2 months; 174 of these patients then participated in a 10-month open-label evaluation of 100 mg once daily. The primary outcome measure was change in IPSS, with a clinically important improvement defined as a decrease of 40% or more from baseline. Secondary outcome measures included nocturia, QOL score, prostate volume, and MFR. The therapeutic goal of 40% or more improvement in IPSS at two months was reached in 42.6% of the patients receiving 50 mg twice daily and 40.7% of those taking 100 mg once daily. During the 10- month open-label evaluation, 62.8% of the patients reached this goal. Mean IPSS at two months decreased by 38% and 35% in the 50-mg twice-daily group and the 100-mg once daily group, respectively. All changes in secondary outcome measures were similar between the groups at two months and were statistically and clinically different from baseline. Sexual function, assessed by questionnaire, was not significantly affected throughout the 12 months of the study. Mean prostate volume, assessed by transrectal ultrasonography, was reduced by 6.8% at 12 months. The authors concluded that there was no difference in efficacy between the two dosage regimens, that each provided a clinically important improvement in symptoms from baseline when the placebo effect was considered, and that pygeum extract is an acceptable treatment option for patients with mild to moderate symptoms of BPH. Although the applicability of this trial to clinical decision-making is minimal because of the lack of a placebo group, the results can be considered valid because the methodological limitations were minor.

In 1999 Wilt et al.[30] conducted a systematic review of studies of -sitosterol, a primary component of pygeum. Although -sitosterol improved objective and subjective symptoms, the studies' limitations did not allow a firm conclusion about efficacy.

Dosage

The recommended dosage of pygeum, on the basis of the clinical studies, is 100-200 mg of an extract standardized to a 14% content of sterols, including -sitosterol, usually given in two divided doses daily.[1,31] The maximum dosage used in trials to date has been 200 mg/day. The brand of extract most often used in clinical trials is Tadenan (Roussa-Pharma). Although not available on store shelves in the United States, Tadenan is available from Internet sources. Dried pygeum bark is occasionally available. It is used in dosages of 5-20 g twice daily.[1] However, the efficacy of the crude bark has not been studied, and the bark is not recommended.

Adverse Effects

Reported adverse effects associated with pygeum extract are rare. The most common effect (reported by up to 3% of patients in clinical trials) is gastrointestinal upset. Toxicity studies in animals have shown neither short-term effects at dosages of up to 6 g/ kg/day nor long-term effects at up to 600 mg/kg/day for 11 months.[13,31] Drug interactions and contraindications. No drug interactions involving pygeum or -sitosterol have been reported. No contraindications are known to exist.

Discussion

Studies of both good and poor quality have shown that pygeum decreases BPH symptoms more than placebo, but none of the trials to date provides conclusive evidence of efficacy. Patients with mild BPH (IPSS, 7) or moderate BPH (8-18) frequently choose "watchful waiting" or alternative therapies (including herbal therapies) over standard drug therapy or surgery. The very good tolerability of pygeum and the lack of toxicity support the use of pygeum extract as an adjunctive treatment for patients with mild to moderate symptomatic BPH. The minimal effect of pygeum on prostate volume suggests that it might not be as useful for patients with greatly enlarged prostates, whose symptoms are primarily obstructive. Patients who choose to try pygeum should be counseled that it is for mild to moderate symptoms of BPH, that they must first visit a physician to rule out prostate cancer, and that the recommended dosage is 100-200 mg of standardized extract given in one or two doses daily. Patients should also be informed that it may take several weeks for a benefit to be seen, that the treatment is symptomatic only and will not shrink the prostate gland, and that there may be gastrointestinal adverse effects.

The magnitude of benefit to be expected with pygeum must be further quantified in more rigorous trials. Well-designed trials comparing pygeum with standard therapies, such as 5 -reductase inhibitors and -adrenergic-receptor blockers, are essential before pygeum extract can be strongly recommended as a first-line treatment. Another question that remains to be answered is whether the use of pygeum extract in conjunction with saw palmetto extract, 5 -reductase inhibitors, or -adrenergic blockers has additive benefits in reducing BPH symptoms. Conclusion. Pygeum extract appears to have some efficacy in ameliorating the symptoms of mild to moderate BPH and has a low adverse-effect profile. More study is needed to determine whether pygeum's role should be more than adjunctive, however.

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