The therapeutic uses of Urtica in benign prostatic hyperplasia

2015

The use of stinging nettle (Urtica dioica L.) root extracts in the therapy of benign prostatic hyperplasia has a rather short tradition. The basis is a report by a German physician about the use of tea in the treatment of urinary tract disorders.

Biochemical models

Inhibition of 5α-reductase

Testosterone is transformed by 5α-reductase into dihydrotestosterone (DHT). DHT is the active androgen in the prostate (dihydrotestosterone hypothesis). Androgen deprivation has been shown to decrease the size of the prostate. Nettle root extracts come off badly in studies of their effect on 5α-reductase. Respective studies were made of 60% ethanolic extract and a 20% methanolic extract, both of which turned out to be ineffective. The study made by Rhodes and coworkers, however, is not without certain shortcomings. For instance, it compares data in mg/ml and not on the basis of daily doses, without taking into account that the daily dose shows distinct differences between finasterid and plant preparations (finasterid 1–5 mg/day; bazoton 600 mg of 20% methanolic extract, corresponding to 6,300 mg of drug per day). In addition to inaccuracies regarding the botanical names there is no consideration of the excipient. In spite of such criticism it remains a fact that an activity of the extracts cannot be explained as a consequence of an inhibited 5α-reductase.

Inhibition of aromatase

With increasing age the balance of androgen/estrogen in the serum and in the prostate shifts in favour of estrogens. By blocking the aromatase the growth of the prostate is influenced. Clinical studies provided an impulse for investigating the effect of plant extracts on aromatase (estrogen hypothesis). It was found that during a twelve-week-treatment with 2*600 mg of 20% methanolic nettle root extract, there was a significant reduction of estradiol and estrone in the serum. After a bioassay-guided isolation it was found that the extract contained a weak aromatase inhibitor (9-hydroxy-10,12-octadecadienacid).

Possibly this substance is only a pro-drug taking effect by way of a metabolic product, the 9-oxo-compound known to be an active aromatase inhibitor. It remains an open question whether or not the quantities contained in the extract are sufficient for a therapeutic effect or if an accumulation can be assumed, or else if other mechanisms are responsible for the therapeutic activity.

Interaction with sex hormone binding globulin (SHBG)

SHBG is biosynthesized in the liver and has two binding sites, one for sexual hormones and one for membrane receptors identified in the prostate tissue and the endometrium (mucous membrane of the uterus). The hypothesis is structured as follows: (1) Only free SHBG is bound to the membrane receptors. (2) A steroid is bound to the docked SHBG. (3) This causes an increase of intracellular cAMP. Hryb et al. and Rosner found that a hot water extract of the nettle root (rich in polysaccharides) dose-dependently inhibits the binding of SHBG to the membrane receptors. Urtica dioica agglutinin (UDA), stigmasta-4-en-3-on and a 70% ethanolic nettle root extract were not active in this system. Schöttner et al. was able to prove that a number of lignanes of nettle root are bound to the membrane receptors. Free SHBG is very important for the regulation of the plasma concentrations of free androgens and estrogens. Bauer reports on a clinical study in which a decrease of estradiol and estrone values as well as the SHBG concentrations were observed. Further research will be necessary to find out to what extent the clinical picture corresponds to the in vivo experiment.

Inhibition of leucocyte elastase

Human leucocyte elastase (HLE) is a sensitive and quantitative marker for clinically inconspicuous infections of the genital tract. HLE is a serine endopeptidase. It has a low substrate specificity and is counted among the destructive enzymes.

The human prostate is run through by smooth muscles. In the course of Benign Prostatic Hyperplasia (BPH) there is a distinct hyalinization of the periacinal connective tissue and a hyperelastosis. Progessively these may result in a degeneration and fragmentation of the elastic fibres. Apart from the enlargement of the prostate it is, among other things, the loss of elasticity which is responsible for the obstructive symptoms. The inhibition of the proteolytic activity of HLE might be a useful contribution to the elimination of the BPH symptoms. Nettle root extract (60% ethanolic extract) turned out to be highly active, resulting in a dose-dependent inhibition of the degeneration of peptide substrates by HLE.

Immunomodulatory activity

Hyperplastic prostate tissue has some particular characteristics: special, unique anti-genic structures and lower titers of certain specific prostate antigens (as compared with a normal prostate). This is why it seems to be useful to discuss an immunological therapeutic approach. An immunomodulating activity is attributed to lectin (UDA) as well as to the polysaccharide fraction.

Thus, Wagner et al. were able to show that aqueous extracts and polysaccharide fractions gained from them have a stimulating effect on T-lymphocyte proliferation (in vitro lymphocyte transformation test). This group was also able to show a stimulating effect of UDA on the lymphocyte proliferation.

Influencing complement activation

The complement system consists of about two dozen different serum proteins influencing each other like a cascade and is the most important effector system of inflammatory responses. Apart from the classical activation (immune reaction) the complement system can also be activated in an alternative way. This is why bacterial polysaccharides or proteolytic enzymes are able to activate the complement system. Polysaccharides gained from nettle root extracts were extremely effective as anti-complements both in the classical as well as the alternative approach.

Influencing growth factors

On the basis of the hypothesis of an epidermal-stromal interaction regulated by growth factors, investigations made by the team of Wagner analyzed in vitro the influence of UDA on receptors of growth factors. UDA is bound to the epidermal growth factor receptor (EGF-R) as well as to the fibroblast growth factor receptor FGF-R. Among the processes following the receptor binding there is an activated phytotyrosine kinase. This is inhibited by UDA. It should be noted that the occurrence of EGF-R in the basal cells of the prostate is a definite fact; however, only a few not very conclusive investigations have been made about its function in benign prostatic hyperplasia. The bFGF receptor was identified in the prostate stroma, but its role in the pathogenesis requires further research.

Interaction with Na+,K+ -ATPase

At the membrane-binding site of androgen a Na+,K+ -ATPase is located. By influenc-ing the enzyme a change of the metabolic energy of the cell is effected. Excess growth could be inhibited in this way. Hirano et al. investigated the inhibiting influence of hydrophobic components of the nettle root on the untreated human prostate Na+,K_ -ATPase. They showed that the inhibiting activity of the respective steroids (found in the nettle root, e.g. β-sitosterol) is in a concentration range of 10-3 to 10-6.

Cell cultures

Fibroblast cultures from ventral rat prostates were used to determine the effect of nettle root extract (20% methanolic extract). By means of a solution of the extract (concentration 0.01%) the number of cells could be lowered by 50%. No proof was furnished of either dosage dependance or androgen dependance. Explant samples of human prostate tissue cells were cultivated for some weeks. The morphology of the cells remained unchanged, the growth rate of the medicated group decreasing significantly as compared with the control group given no medication. Rausch et al. continued the studies undertaken by Enderle-Schmitt. They found that 20% methanolic nettle root extract inhibits the growth of explant cultures (human prostate tissue) by 20%, stigmastenon by 30–50%, and ceramide 50–80%. The 20% methanolic extract and the polysaccharide fraction of this extract were then examined in hPCPs and LNCaP cell culture lines. The cell cultures used for the experiments are representative of the organ to a certain extent; the stromal cell culture line (hPCPs) and the epithelial cell culture line (LNCaP). In these experiments a 20% methanolic extract and the polysaccharide fraction of this extract had only an inhibitory effect on the growth of epithelial cells (LNCaP).

Animal experiments

Natural BPH occurs in humans, whereas in the animal kingdom it is only found in apes, lions, and dogs. Thus it does not come as a suprise that animal experiments in basic research were mainly conducted with dogs. In this context it should be noted that the pattern of ailments is different in dogs and humans. Contrary to humans, dogs usually have defecation rather than miction disorders, which are rare. Moreover there are histological differences in the form the disease takes (diffuse, glandular and, to some extent, cystic hyperplasia). Other studies deal with the physiology of the prostate in rodents and their organ preparations.

The most important experiments are summed up as follows: A pilot study conducted by Daube investigated the therapeutical effect of 20% methanolic nettle root extracts on BPH on dogs. The prostate volume of ten medicated dogs showed an average decrease of 30% during a 100-day therapy. The volume was determined sono-graphically. Scapanini and Friesen made a study of the antiandrogenic effect of nettle root extracts on castrated rats with an implanted testosterone donator.

The implants were filled with increasing testosterone concentrations. On 11 days 20% methanolic nettle root extract was administered. By this therapy the weight increase of the prostate was significantly diminished compared with the control group. Similar experiments were made by Rhodes et al., who gave castrated young rats a daily dose of testosterone or DHT-propionate (i.p.). In these experiments a normal prostate was used, whose growth was induced by hormone shifting. Simultaneously, the rats were treated with a preparation containing a 20% methanolic nettle root extract; the dose administered was 1/5 the dose per kg for humans. There was no verifiable effect on prostate growth. Why such a low dose was chosen is hard to understand, because normally ten times the dose for humans is used in experiments with rats. The antiphlogistic activity of substances can be verified in the rat’s paw edema model. This measures the ability of a substance to reduce an edema caused by carragenan. The molecuar mechanism has not been completely understood, but a possible participation of lymphocytes and the complement system is under discussion. Willer was able to show that an orally applied raw fraction of polysaccharides from nettle roots achieved an inhibition of the induced growth by 36.8%. The hypothesis of embryonic re-awakening according to McNeal says that the mechanism of epithelio-stromal interaction during embryonic development, as described by Cunha and coworkers, is reactivated in benign prostatic hyperplasia, the stroma providing the impulse for glandular growth.

An in vivo model was developed that showed that the implantation of urogenital sinus tissue has a growth stimulating effect on the prostate of the mouse. In this model, a combination of nettle root extract (60% ethanolic extract) and saw palmeto extract (90% ethanolic extract) was tested in a first series of experiments. Medication took place from day 3 to 18 or from day 30 to day 45 after the operation. However, there were no ascertainable effects on the weight and the histological structures of the prostate. The same model was used with slightly different conditions (e.g. medication from day 1 to day 28) in another study.

Five different extracts prepared with solvents of increasing polarity (cyclohexane, ethyl acetate, 1-butanol, 20% methanol and water) were evaluated. Only the methanolic extract caused a significant growth inhibition of about 51%. Some compounds like UDA, polysaccarides, and secoisolariciresinol were considered to be active substances in this extract. In further experiments only the polysaccharide fraction of the methanolic extract showed a significant inhibiting activity.

Some of the growth factors, whose important function in the development of BPH has been mentioned before, can be deliberately changed in certain cells by molecular biological methods. Such methods, permitting a programmed change in the DNA, can also be used for the in vivo testing of new drugs. Modified urogenital sinus tissue, in this case induced TGFpJ1 overexpression, can be implanted into a mouse whose development is then studied. This model resembles the one developed by Otto et al. () in which human BPH tissue was implanted into the skin of a nude mouse whose growth rate was consequently observed. Nettle root extracts have not yet been studied on the basis of this model developed by Thompson, but the example suggests a direction of future work.

Urtica: Therapeutic studies

Clinical studies with nettle root extracts have been carried out since the late 1970s. As time went on, the demands made on the studies were more sharply defined. Consequently, recent studies are placebo-controlled and correspond to the standards set by the GCP and the I-PSS. Some clinical parameters and the subjective conditions of the patients (symptom score) improved during therapy with nettle root extract. A decreasing volume of the prostate has not been ascertained so far. It would be desirable to conduct further studies with a greater number of patients over a longer period. Such studies might help to bring out the differences between synthetic drugs and phytomedicines.

 

Selections from the book: “ Urtica. Therapeutic and nutritional aspects of stinging nettles”. Edited by Gulsel M. Kavalali. Series: “Medicinal and Aromatic Plants — Industrial Profiles”. 2003.