Chapter 6
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Herbal Drugs in the Treatment of Benign Prostatic Hyperplasia
H. Schilcher Alfred Neumann Anger 17, D-81737 München-Perlach, Germany
The natural history of benign prostate hyperplasia (BPH) is a slow enlargement of fibromuscular and epithelial structures within the gland, eventually leading to obstructive urinary symptoms experienced to some extent by most men over the age of 50. Its etiology and pathogenesis have not yet been clearly defined. Therefore, the therapy strategy is controversial. Besides the transurethral resection of the prostate, medical treatments, including alpha-receptor blocking agents, 5-alpha-reductase inhibitors, and phytomedicines, are becoming more and more important world-wide. Herbal remedies, such as Cucurbitae peponis semen, Serenoae repentis fructus, Urticae radix, and other herbal drugs, have a long tradition for successful treatment of BPH in Europe, although no exact mechanism of action nor precise classification of the active compounds are known. However, in the past decade many clinical and pharmacological studies have confirmed the empirical observations, thereby advancing these traditionally used phytomedicines to rational drugs. Benign prostatic hyperplasia (BPH) is one of the most common causes of urination problems in men, manifesting itself as hesitancy, incomplete voiding of the bladder, terminal dribbling, urgency, frequency, and nocturia. Pronounced BPH is found in 25% of men 40 to 50 years of age and in nearly 80% of men over 70 years of age. Despite the considerable importance of the clinical picture, particularly for general practitioners and urologists, the etiology and pathogenesis of BPH remain unclear (7). The ongoing controversy concerning therapeutic strategy is therefore entirely understandable. Many urologists believe that treatment should not target BPH as such but only the associated symptoms, especially the distressing obstructive and irritative urination symptoms (2). Provided that the patient receives regular medical attention, the symptoms are not life-threatening, but they can substantially diminish the patient's quality of life. The strategy of "watchful waiting" until surgery becomes necessary is understandably
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©1998 American Chemical Society
In Phytomedicines of Europe; Lawson, L., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
63 rejected by most patients. The approximately D M 250 million (wholesale price) spent by Germans on prostate remedies in 1995 is certainly not to be seen as a "financed luxury". Surgical treatment remains the gold standard in urology because, in a scientific sense, it is still the only proven causal therapy (3). Nevertheless, there is a growing interest worldwide in conservative pharmacological measures for the patient's sake, even though uncertainty about the underlying mechanisms of action is still a source of scientific contention.
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Etiology and Pathogenesis of BPH / Problems Finding Medications According to the current state of medical knowledge, prostatic hyperplasia is due mainly to increased proliferation of the stromal components (supportive tissue) of the prostate. To a far lesser extent, glandular hypertrophy also occurs (i). Histologically, marked growth of the muscular stroma is seen. Despite numerous experimental studies, it is still unclear how this leads to palpable and easily diagnosed hyperplasia, and this lack of knowledge makes any causal therapy extremely difficult The recent finding that there is often no direct correlation between prostate size and symptom intensity further complicates the rational search for suitable drugs. And last but not least, the aforementioned symptoms, which are of primary concern to the patient, may also be due to concurrent abacterial prostatitis with relatively little hypertrophy of the prostate. Of the five hypotheses advanced to explain the development of hyperplasia (4) (Table I), only two are mentioned here, since they are most amenable to experimental investigation, and since the prostate drugs used—whether synthetic or of plant origin—have a regulating effect on the postulated causes. The first is synthesis of dihvdro-testosterone (DHT) from testosterone, the second a shift of the androgenestrogen ratio due to increased synthesis of 176-estradiol, likewise from testosterone.
Table I. The pathogenic background of BPH. The development of benign prostatic hyperplasia is a multifactorial process and the pathogenic mechanism is triggered by various hormones and mediators, • Increased concentration of 1. SHBG (Sexual hormone binding globulin) • Increased enzymatic activity of 2. 5oc-Reductase: Testosterone - » Dihydrotestosterone 3. Aromatase : Testosterone - » Estrogen • Increased concentration of 4. Cholesterol (a precursor of testosterone and its metabolites) • Increased concentration of 5. Prostaglandins and leukotrienes (edema and inflammation mediators)
In Phytomedicines of Europe; Lawson, L., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.
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64 Table n. Pharmacological Treatment of BPH with Synthetic Drugs Relaxation of smooth (Xi Blockers Selective blockade of (alfuzosin and noradrenergic a! receptors in the muscles in the bladder neck and prostate. terazosin) prostate, trigonum vesicae, and Improvement of urethra. obstructive and especially Blockade of noradrenergic (Xi irritative symptoms. receptors not only in the vascular system but also in other extraprostatic tissues. Finasteride Remission of hyperplasia. Competitive inhibition of 5aThe reduction of the reductase and thus reduction of prostate volume by plasma DHT levels. approx. 20% does not necessarily correlate with the intended improvement of symptoms. Aromatase Delay of hyperplasia. Prevention of the age-related inhibitors Improvement of urinary shift of the androgen-estrogen flow. ratio, i.e. inhibition of 17-pestradiol (E2) synthesis. Antiestrogens Delay of hyperplasia. Delay of the age-related shift of Improvement of urinary the androgen-estrogen ratio in favor of the androgen fraction. flow.
Pharmacological Approaches Table II gives a general overview of the synthetic prostate drugs, which account for about 19% of prostate medications currently sold in Germany. By relaxing the smooth muscles of the prostate and bladder neck, alpha-adrenoceptor blockers (alfuzosin and terazosin) bring about an improvement in the "dynamic component", i.e. the obstructive and especially the irritative symptoms. Of course the side effects and the cost of treatment (DM 1.50 per day) must also be considered. Although finasteride has been tested in clinical studies with the longest observation times and leads to the greatest remission of hyperplasia of all the prostate drugs (
