European Phytotherapy: Pharmacological Effects of Saw Palmetto and Urtica Extracts for Benign Prostatic Hyperplasia

European Phytotherapy: Pharmacological Effects of Saw Palmetto and Urtica Extracts for Benign Prostatic Hyperplasia

Reference: Urologe 34 ( 2): 90-95, 1994.

Summary: Extracts of saw palmetto berries (Serona repens fructus) and stinging nettle roots (Urticae radix) are used in the treatment of benign prostatic hyperplasia (BPH). The use of these plant preparations, originally and largely based on empirical medicine, has achieved a solid scientific basis in recent years thanks to extensive experimental investigations. It is the aim of this paper to present the wide-ranging pharmacological profile of these extracts.

In the advanced stages of BPH, transurethral resection of the enlarged prostate gland is considered to be the therapy of choice. The risk of side effects through invasive treatment methods, however, is not acceptable for many patients with mild BPH, thus explaining the large demand for other forms of therapy. In Germany, conservative treatment of BPH is based to a large extent on the use of pharmaceuticals of plant origin.( 1, 27) Derived from empirical medicine, the use of these plant preparations has received scientific support over recent years as a result of experimental study. New experimental results are principally available for lipophilic extracts from the fruits of the american dwarf or saw palmetto (Serenoa repens, formerly Sabal serrulata) as well as for aqueous/alcoholic extracts from the roots of the stinging nettle (Urtica dioica). In the present study, the pharmacological effects of the ethanolic saw palmetto extract WS 1473 and the aqueous/alcoholic extract WS 1031 from stinging nettle roots are described.(*)

The Pathogenesis of BPH

The etiology and pathogenesis of BPH has remained unclear up to the present. As causes for nodular prosthetic hyperplasia, a large number of factors and theories are under discussion. In the development of BPH, a major part is attributed to the sexual hormones in particular. Other concepts start by assuming a resurgence of embryonal properties, or represent the opinion that different growth factors are produced in the prostate under the influence of sexual hormones which are responsible for the disease. According to the primal cell theory, an increase in the number of hypothetic primal cells and/or clonal increase and conversion of these cells into so called amplifier and transit cells is increased in the case of BPH.( 2, 14)

Basically, BPH can only develop in the presence of male sexual hormones. BPH is practically never observed in men who have subjected themselves to castration before their fortieth year or in whom no or only an insuffient formation of hormones occurs in the gonads due to a functional insuffiency of the pituitary gland. In the same way, the normal development of the prostate and the formation of hyperplastic changes is completely absent in cases of congenital defect or an absence of androgen receptors. As, in addition, the incidence of BPH increases with age, it is thus age alone plus a testicular androgen production which are considered to be certain risk factors for the development of a prostatic hypoplasia.( 10, 33)

The Importance of Androgens for the Pathogenesis of BPH

Testosterone is the most important circulating male sex hormone in human beings. It exerts biological effects either directly or indirectly after conversion into the two most important metabolites, dihydrotestosterone (DHT) and estradiol. The metabolization of testosterone into DHT and 17-à-estradiol is catalysed by the two enzymes 5-à-reductase and/or aromatase. Details on the different effects of testosterone and DHT during and after puberty have principally been obtained from investigations in males with a genetically produced deficit in 5-à-reductase (Table 1). In spite of a normal testosterone production and clinically normal external genitals, the prostate is underdeveloped or completely absent in these patients. ( 10, 33) Clinical and experimental indications speaking in favor of a participation of DHT in the pathogenesis of BPH have been listed together in Table 2.

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On the basis of what has just been described, there has been no lack of attempts to treat BPH by withdrawing androgens. On account of the severe side-effects connected with the general loss of male sex hormones, considerably more favourable results are expected through selective 5-à-reductase inhibitors.

Sultan, et al. first reported on the inhibitory effects of an lilophilic extract obtained from saw palmetto fruit via hexane extraction on the activity of 5-à-reductase in human preputial fibroblasts.( 31) Since then, this effect has also been confirmed for an ethanolic and CO( 2) extract.( 6, 9) We tested the influence of the saw palmetto extract WS 1473 on the enzyme activity of 5-à-reductase in a large-particle cellular fraction from the ventral prostate of the rat, and determined a semi-maximum inhibitory concentration of 71 æg/ml. There were no major differences between this extract and a hexane extract. In the investigation of the individual components, a clear assignment of the 5-à-reductase inhibitory effect to a specific ingredient was, however, not possible. We therefore suspect the presence of previously unidentified 5-à-reductase inhibitors in the saw palmetto extract WS 1473, or else the previously found active ingredients must have pronounced synergistic properties. Sitosterin, the phytosterol that is often touted as being connected with the clinical efficacy of saw palmetto extracts, was found to be inactive in our investigations. In the same way, the urtica extract WS 1031 showed no influence on the conversion of testosterone into DHT.

A number of publications report on a specific and competetive inhibition of the binding of the synthetic androgen, methyltrienole, to the cytostolic androgen receptors in the prostate of the rat, as well as a displacement of DHT at nuclear and cytostolic androgen receptors in human preputial fibroblasts due to hexane-soluble active components in saw palmetto.( 7, 30, 31) In agreement with two other work groups, we have been able to demonstrate practically no receptor-blocking effect for the saw palmetto extract WS 1473 in concentrations causing a complete inhibition of 5-à-reductase.( 6, 9) We consider the only moderately pronounced receptor antagonism of saw palmetto WS 1473 to be an advantage, as testosterone-dependent biological processes are virtually unaffected by the largely selective inhibition of 5-à-reductase (compare Table 1).

The Importance of Estrogens for the Pathogenesis of BPH

Initiated by the morphological investigations of McNeal, BPH has been considered more and more to be a disease of the stroma over recent years. ( 23) According to this concept, the prostate is divided into a large peripheral zone and a small centrally positioned zone, both of which together make up approximately 95% of the glandular volume. The remaining 5% are occupied by the so called transition zone, surrounding the urethra in the proximal part of its prostatic section. It is assumed that the stroma of this transitional zone sets off BPH by stimulating the periurethral glands to growth. Whereas the prostatic epithelia and prostate stroma are considered to be an androgen-dependent tissue, the stroma also appears to react to estrogens.( 16) Table 3 provides a list of arguments in favor of a participation of estrogens in the pathogenesis of BPH.

The arguments listed speak in favor of the possibility of treating BPH by withdrawing estrogens. Apart from using antiestrogens, we have also used the application of aromatase inhibitors. Indications for an influence on estrogen metabolism by an alcoholic extract of stinging nettle root was first obtained in a clinical study, in which the serum concentrations of estradiol and estrone decreased significantly after twelve weeks of treatment with 600 milligrams extract twice daily.( 4) It has been possible to demonstrate in vitro in the meantime that this effect is possibly based on an inhibition of the aromatase.( 15) With the help of chromatographic separation processes, 9-hydroxy-10-trans-12-cisoctadecadienic acid was found to be the active principle. This compound is presumably not produced until after extraction by autoxidation or under the influence of lipoxygenases from linoleic acid.

Using placenta microsomes as a source of aromatase, we have also been able to confirm an inhibitory influence of the urtica extract WS 1031 in vitro on the aromatization of androstenedione. Surprisingly, when compared with the dry urtica extract, the saw palmetto extract WS 1473 produced a considerably more pronounced inhibition of the aromatase. The combination of both extracts showed, in addition to this, a clear additive effect (Fig. 1). In accordance with the generally accepted assessment criteria for plant-based combination agents, the combination of these two extracts in one preparation is thus to be assessed as clearly positive.( 20)

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Animal Experiments

Besides humans, the dog and the lion are the only known species which spontaneously develop BPH with increasing age. Due to the restricted transferability of investigations carried out in dogs to human beings, there is a large demand for alternative animal experimental models.( 29) One interesting in vivo system has been available for a number of years due to the transplantation of human prostate tissue to the hairless mouse. On account of a congenital thymus aplasia, nude mice do not reject tissue transfered from other species. Under synchronous substitution with DHT and estrodiol, normal human prostate tissue exhibits the typical histological picture of a BPH two months after the subcutaneous transfer to male mice. Through a single oral administration of a 150 æl saw palmetto extract WS 1473 per week, it was possible to inhibit completely the increase in size of the prostate transplant produced by hormone substitution.( 25) As based on the hypothesis of a reactivation of embryonal properties in the origin of BPH mentioned at the beginning of this article, it has been shown in the mouse that the mesenchyma of the fetal urogenital sinus (fetal prostatic stroma) is able to regulate the development of the epithelium.( 8) After the implantation of fetal urogenital sinus in the prostate glands of fully grown syngenetic mice, a prostate hypoplasia develops which, in its histological structure, shows great similarity to human BPH. ( 24) In cooperation with Dr. Chung of the M.D. Anderson Cancer Center at the University of Texas in Houston, we have investigated whether Prostagutt(R) forte inhibits the development of this process or causes a reversal of already initiated pathological changes. The most prominent finding was a significant, dose-dependent decrease of the DNA content in the pseudosurgically treated prostate lobes of the Prostagutt(R) forte treated animals (Fig. 2). In the same way as in other tissues, the DNA content in the prostate is accepted as an indirect measure for the cell count. In the rat, it was possible to demonstrate a direct correlation between the DNA content and the DHT concentration in the prostate.( 17) We thus interpreted the results to the effect that Prostagutt(R) forte produced a reduction of DHT concentration in the prostate.

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Similar to investigations with a hexane extract, we were also able to show the antiandrogenic effects of the alcoholic saw palmetto extract WS 1473 in rats which had been castrated and received testosterone substitution.( 30) Treatment with the hexane extract had no influence on the anabolic activities of testosterone nor on the weight of the thymus, spleen and adrenal gland. In the same way, no estrogenic or gestagenic properties could be demonstrated, and no neuroendocrine reverse coupling mechanisms were influenced.( 30)

(*) The saw palmetto extract WS 1473 is contained in Prostagutt(R) mono. The combination product Prostagutt(R) forte contains as additional active content the stinging nettle root extract WS 1031. Manufacturer: Dr. Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany.

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Other Pharmacological Effects of Saw Palmetto and/or Urtica Extracts

Due to congestion of secretions, BPH is frequently accompanied by a nonbacterial prostatitis characterized by lymphocytic/plasma cellular infiltrates.( 21) The anti-inflammatory properties of plant-based urologics are therefore constantly linked with the clinical efficacy of these preparations. Antiedematous and antiphlogistic activities have also been demonstrated for saw palmetto and urtica extracts.( 5, 13, 21, 34)

A few years ago, a group of isolectins was isolated from stinging nettle roots as pharmacologically interesting active substances.( 26) Lectins are proteins which bind specifically to sugar residues. Thanks to this property, lectins are in a position to precipitate complex carbohydrates, to agglutinize platelets, or to stimulate lymphocytes to proliferate. Urtica lectins only possess slight hemagglutinating activities, but effect a manifest activation of murine or human T-lymphocytes.( 19, 34) We have been able to confirm the stimulating effect on the proliferation of lymphocytes in the mouse for the urtica extract WS 1031. At a concentration of 50 æg/ml, this effect was at its maximum.

Summary

Benign prostatatic hyperplasia is considered to be an endocrinopathia of elderly males initiated by readjustments in the hormone system as age increases. Androgens are basically necessary to maintain the size and function of the prostate gland, although they are connected with the hyperplastic growth of this gland. DHT, which is produced from testosterone under the influence of 5-à-reductase is the biologically most important androgen in the prostate. An inhibition of this enzyme is therefore considered to be an effective measure in the treatment of BPH. The fundamental correctness of this concept has recently been confirmed in a comprehensive clinical study with the reductase inhibitor finasteride.( 11) The improvement of clinical symptoms was, however, only weak in extent. Apart from the slight influence on subjective conditions, the increase in urine flow rate by 1.6 or 1.4 ml/s remained clearly behind expectations. ( 18)

As hyperplastic prostate tissue contains stromal, estrogen-sensitive components in addition to glandular ones, the combination of estrogen and DHT inhibition is now being viewed as an ideal therapy of BPH. ( 12, 22) This treatment concept is realised through a combination of saw palmetto and stinging nettle root extract. As BPH is frequently associated with a nonbacterial prostatitis, the antiphlogistic and antiedematous active components of the extracts provide additional benefits. The combination of saw palmetto extract WS 1473 and urtica extract WS 1031 is characterized by good tolerance and a low incidence of side-effects, thus fulfilling all requirements necessary for long-term use in mild to moderate BPH( 28)

Conclusion

Saw palmetto and urtica extracts (e.g. Prostagutt(R) mono and Prostagutt(R) forte) are notable for their wide pharmacological range of action. Through inhibition of 5-à-reductase and aromatase, metabolic routes for the formation of pathogenetically important testosterone metabolites dihydrotestosterone and estrogen are inhibited. These activities are complemented by antiphlogistic and antiedematous, as well as immunomodulatory properties. Combined with good tolerance and a low risk of adverse reactions, both preparations fulfill all prerequirements for a rational therapy of BPH in Stages I and II.
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