JOURNAL OF THE
INSTITUTE FOR TRADITIONAL MEDICINE
AND PREVENTIVE HEALTH CARE
Therapy for Benign Prostatic Hypertrophy
Web Posting Date: May 2002
Key medical terms: bph, prostate, prostatitis, dihydrotestosterone, 5-alpha reductase
Key Chinese medical references: lin syndromes, blood vitalizing therapy, damp-heat, kidney deficiency
Drugs: Finasterid, Doxazosin
Western herbs: saw palmetto, pygeum, pumpkin seeds, nettle root
Chinese herbs: vacarria, plantago seed, rehmannia
Chinese formulas: Guizhi Fuling Wan, Niu Che Shenqi Wan, Jingui Shenqi Wan, Tonglong Tang, Dahuang Mudan Tang
Chemical constituents: sterols, aucubin, iridoids, triterpenoids
SUMMARY: BPH (benign prostatic hypertrophy; an enlarged prostate) occurs with aging in most men and may be symptomatic, especially after age 60, with obstructed urinary flow. The disorder appears to be stimulated by dihydrotestosterone (DHT). Herbal medicines have been suggested as helpful for this condition, with particular attention to saw palmetto (Seranoa serrulata or Seranoa repens). Chinese herb formulas have been suggested to be helpful as well, including Rehmannia Eight Formula (Jingui Shenqi Wan) and its derivatives, as well as herbs specific for vitalizing blood (e.g., vaccaria) and for getting rid of damp-heat (e.g., plantago seed). Herbal products for BPH are readily available for over the counter purchase and Chinese herb therapies can be formulated for the individual by licensed acupuncturists and other prescribers. The dosage of saw palmetto extract used in clinical studies is 320-480 mg per day; pygeum extract is used in amounts of 100-200 mg/day. Treatment time is 45-90 days for symptom relief and 6 months for a complete therapeutic regimen.
Herbal Therapy for BPH
RECENT MEDICAL RESEARCH
Benign prostatic hyperplasia (BPH) is a common problem of aging for men. It has been proposed that the disorder has two phases, one that involves no clinical signs and the other that manifests as disorders of urination resulting from urinary tract obstruction by an enlarged prostate (1). In the first phase, there are microscopic changes within the prostate that may occur as early as the fourth decade of life and these may then be followed by macroscopic changes, namely enlargement of the prostate that typically begins during the fifth or sixth decade of life. However, clinical signs of the disorder occur only if the enlargement is substantial and becomes complicated by other disorders, such as prostatitis, or if the gland becomes hardened or deformed. The progression to clinical disease is most often seen after age 60. It is further suggested that while nearly all men will experience the microscopic changes in the prostate if they live long enough, only about half will experience prostate enlargement, and, of those, only about half will develop clinical symptoms. The question then arises: what causes the relatively common occurrence of prostate changes that lead to clinical disease?
Epidemiological studies have demonstrated that many of the same risk factors associated with cardiovascular diseases apply as risk factors for BPH. These risk factors include obesity, hypertension, and diabetes. The diabetes connection is considered especially strong; the risk is with non-insulin dependent diabetes mellitus (NIDDM), which often involves excessive insulin levels, a possible direct contributor to the growth of the prostate (2, 3). As with cardiovascular disease, both exercise and moderate alcohol consumption appear to be protective for BPH. The influence of cigarette smoking on BPH has been unclear: some studies indicate a protective effect (there is a protective effect of smoking for ulcerative colitis that is well-established, so this result is not to be rejected out of hand), but other studies indicate a negative impact, at least for heavy smokers (4, 5). Cigarette smoking has so many adverse health effects, that it should be discouraged regardless of its role in this particular ailment.
Hormones affect the development and progression of BPH. Men with liver cirrhosis have a lower incidence of BPH than those who have normal liver function, probably because the liver damage reduces the metabolism of hormones to compounds that adversely influence BPH. Not all hormonal influences on BPH have been determined, but sex hormones (estrogen, testosterone, prolactin) and insulin have been shown to have an effect thus far. In particular, it is thought that the conversion of testosterone to 5-alpha-dihydrotestosterone (DHT) may be a significant risk factor for BPH (6). The drug Finasteride suppresses DHT production by inhibiting the enzyme (5-alpha reductase) that converts testosterone to DHT, and this drug has been shown effective in reducing symptoms of BPH. DHT, produced in sebaceous glands, is also a contributor to male-pattern balding.
It is not known whether herbal, nutritional, or drug treatments for cardiovascular disease would also have a direct impact on BPH. However, the alpha-adrenoceptor agonist drug (Doxazosin) used for treating hypertension also appears to have therapeutic value for BPH (7). Certainly, lowering risk factors for cardiovascular disease would be important for everyone, including aging males with BPH.
Chinese medical literature has been relatively silent on the problem of BPH (8). Disorders of urination have been noted since ancient times, classified as "lin" syndromes, which involve obstruction of urinary flow. In descriptions of the lin syndromes, most times the obstruction of urination is described as accompanied by symptoms that are not characteristic of BPH, such as blood in the urine or passing of stones or cloudy urine. Therefore, while BPH may have been experienced and treated as one of the lin syndromes, it is unclear whether any of the therapies were specific for BPH.
In Japan, BPH has been described by medical doctors who prescribe herbal therapies (Kampo practitioners). These physicians rely on a relatively small set of formulas from which one or two are selected for administration according to differential diagnosis by constitutional factors. Dr. Toyohiko Kikutani described his knowledge of such treatment methods for prostate disorders and this information was relayed by Hong-yen Hsu of the Oriental Healing Arts Institute. According to Kikutani, the most commonly used formula for BPH is Rehmannia Eight Formula (Bawei Dihuang Wan, also called Jingui Shenqi Wan; see Appendix 1). This formula is commonly used for disorders of aging, and is also applied in Japan for treating hypertension.
The main alternatives to Rehmannia Eight Formula are prescriptions for blood stasis (impaired blood circulation, often associated with chronic inflammation or injury), such as Moutan and Persica Combination (Tonglong Tang) and Rhubarb and Moutan Combination (Dahuang Mudan Tang). These formulas include the tree peony, moutan, which is also an ingredient in Rehmannia Eight Formula. The primary descriptions for applications of these latter two formulas fit better with acute prostatitis rather than BPH, but this acute prostatitis may trigger the persistent clinical manifestation of a pre-clinical case of BPH. Sometimes the two approaches are combined: Dr. Domei Yakazu told of three patients receiving both Rehmannia Eight Formula and Moutan and Persica Combination. In an update by Dr. Hsu (9), he further mentioned combining Rehmannia Eight Formula with another blood vitalizing prescription, Cinnamon and Hoelen Formula (Guizhi Fuling Wan), and use of Achyranthes and Plantago Formula (Niu Che Shenqi Wan), which consists of achyranthes and plantago added to the base of Rehmannia Eight Formula. Achyranthes and Plantago Formula is also used in Kampo medicine to treat diabetes, including nephritic and neurological effects of the disease.
Modern journals of Chinese medicine remain relatively silent on the subject of BPH. For example, no articles on BPH treatment have appeared in the English language Journal of Traditional Chinese Medicine or Chinese Journal of Integrated Traditional and Western Medicine. By contrast, the Western literature has numerous reports on therapies for BPH based on herbs.
Chinese clinical researchers have addressed the problem of prostate disorders, but usually include a broad range of problems-dominated by acute prostatitis-in the study group, for which differential diagnosis is applied. Typical therapeutic categories are (10): qi and blood stasis (obstructed circulation), damp-heat accumulation (swelling and fluid accumulation), and kidney deficiency syndrome (problems of aging; weak function of the kidneys). The formulas administered vary considerably, but most formulations for treating qi and blood stasis include vacarria (wangbuliuxing); virtually all formulations for treating damp-heat and urinary obstruction include plantago seed (cheqianzi). Kidney deficiency formulations (subdivided into yin and yang deficiency categories) for prostate disorders usually incorporate herbs for treating blood stasis and damp-heat as secondary components (19).
It is possible that the microscopic changes in the prostate in the early development of the disease process are consistent with microcirculation changes that are normally treated with blood vitalizing herbs. Prostate enlargement is consistent with a damp-heat syndrome, since this syndrome is commonly associated with non-painful swelling in the lower abdomen. The final development of clinical symptoms of urination disorders corresponds closely with Chinese depictions of significant blood stasis and damp-heat coupled with weakening kidney qi. Thus, the three main diagnostic categories for prostate disorders described in the Chinese medical literature may have relevance to BPH in terms of its development over several decades, with a progression of each of the three syndromes. Based on such a scenario, the therapy for clinical BPH with Chinese herbs would involve a combination of treating kidney deficiency syndrome as a solution for the constitutional disorder associated with aging, along with blood vitalizing and damp-heat removing herbs as a treatment for the swollen prostate.
In accordance with traditional Chinese medicine doctrine, each patient should be treated on the basis of his actual syndrome rather than by a set formula. For example, yin deficiency fire (treated by modification of Zhi Bai Dihuang Wan) or spleen and lung qi deficiency (treated by modification of Buzhong Yiqi Tang) could each be factors contributing to urinary disorders such as those seen with BPH. Nonetheless, most cases of BPH in essentially healthy men are likely to correspond to the disorder categories generalized above. Although the Chinese herb formulas appear to have the potential to increase testosterone levels (see Appendix 2), this change may not be sufficient to adversely affect BPH, especially if the herbs can also suppress conversion of testosterone to DHT, as suggested for Western herbs used in treating BPH.
WESTERN HERBAL MEDICINE
The treatment of BPH became a medical issue during the same time that cardiovascular disease therapy came to the fore, mainly during the 1970s. In Germany, where herbal therapy (phytotherapy) was still pursued by the pharmaceutical industry, the use of herbs was investigated at the same time that other researchers pursued surgical and drug options.
Dr. Hildebert Wagner, one of the leading proponents of phytotherapy (working at the Institute for Pharmaceutical Biology at the University of Munich), proposed investigation of the active components in Sabal serrulata for BPH in 1981 (11). This herb, now referred to as Serenoa serrulata or, more commonly, as Serenoa repens, had been popular in the U.S. during the 19th century as a treatment for a variety of urino-genital disorders and had been mentioned as a treatment for prostate problems as early as 1899 (12). The fruit of the plant, a small palm called saw palmetto (palmetto is Spanish for small palm; it has sharp, saw-like leaves) that is abundant in Florida, was used as a food for farm and ranch animals and as a medicine for humans. Research into the effects of Serenoa in Germany, and subsequently in many other European countries, appeared to confirm a positive action on BPH, so that this became the principal use of the herb. By 1995, saw palmetto had become one of the 10 most extensively-used Western herbs, with almost all of the commercial supplies going into products for BPH. The fruit is rich in sterols, which appear to be the primary active constituents. Although various proposals have been made as to how the sterols might affect BPH, the mechanism of action is still not clearly established. It is thought that the sterols may have, as one mechanism of action, the inhibition of DHT production (15).
At the same time, other Western herbs were investigated, with most attention falling to pumpkin seeds (Cucurbita pepo), nettle root (Urtica dioica or Urtica urens), bee pollen (particularly that from the rye plant), African potato (tubers of Hypoxis rooperi), and the large high-altitude African tree Pygeum africanum, also known as Prunus africanum (13, 14). In most cases, but particularly with pumpkin seeds and African potato, the main active components are understood to be the sterols, such as beta-sitosterol, which has been used as a therapeutic agent for BPH by itself (18). Triterpenoids in pygeum have also been proposed to be active components, potentially having the action of reducing prostate swelling (17).
Among the Chinese herbs recommended for BPH, the iridoid glycosides may be the active components: these include aucubin from plantago seed, catalpol from rehmannia, and morroniside from cornus (an ingredient in the rehmannia formulas). Iridoids have not been found in the Western herbal therapies for BPH and represent a potential new area for future investigation. Iridoids are the recognized active constituents of the Western herb chaste tree berry, Vitex agnus costus, which has been shown to reduce prolactin levels in women (20); elevated prolactin may be a risk factor for prostate enlargement in men. Triterpenoids found in vaccaria and alisma (an ingredient in rehmannia formulas) could contribute to their therapeutic effects, in a manner similar to those suggested for pygeum.
Today, products for BPH remain one of the primary commercial successes in the field of herbal medicine. The herbs are sold either individually or in combination products with 2 or 3 of the ingredients. The two most commonly-used substances, both as single herbs or in combination products, are saw palmetto and pygeum. The National Institutes of Health (NIH) have taken note of this and proposed to fund a large study of saw palmetto and pygeum (see Appendix 3). The usual amount of saw palmetto provided in clinical studies is 320-480 mg of extract per day, in two divided doses (16). The usual amount of pygeum extract used in clinical trials is 100-200 mg/day (17). Treatment time is from 45 to 90 days to obtain significant improvement in symptoms; treatment time of 6 months has been reported to have a lasting effect for at least 18 months (18). Adverse effects of the herb therapies for BPH have not been reported.
APPENDIX 1. REHMANNIA EIGHT FORMULA AND ITS INGREDIENTS
Rehmannia Eight Formula is presented with some variations among the Chinese texts. The following is a representative formulation that can be used as a starting point for discussion of the ingredients and their effects:
The lead ingredient is cooked rehmannia, which is described in the Chinese tradition as a nutritive agent, alleviating dryness and promoting the functions of the liver and kidney systems (see Appendix 2 for further details). The remaining herbs of the formula can be understood as supporting the function of rehmannia. The small amounts of processed aconite and either cinnamon bark (rougui) or cinnamon twig (guizhi) serve as the hallmark of this particular rehmannia formula, one of numerous rehmannia-based combinations relied upon by Chinese doctors.
The characteristics of rehmannia, for which the processed form (shudi) is used here, are: rich and moist quality, sweet taste, and warming nature. Rehmannia would be too thick and rich to offer as a single herb: it is said to have a "cloying" quality (being very sweet and moist). Therefore, the herb is combined with others that can balance and harmonize its actions.
In particular, three of the herbs in this formula help to balance the rich, moist quality of rehmannia: alisma, hoelen, and dioscorea. These herbs:
Chinese doctors point to the role of alisma in dissolving greasiness, which is useful in countering the thick, moist quality of rehmannia; additionally, it removes (via urination) turbid materials that accumulate in the body. Dioscorea also helps the body to eliminate excess moisture, especially from the digestive tract (where diarrhea can occur if the moisture accumulates). Hoelen is depicted as absorbing moisture, like a sponge, from places of accumulation, to deposit it where it is needed (e.g., to areas that are dry or areas that will lead to its elimination).
The book Commonly Used Chinese Herb Formulas with Illustrations (21) gives a listing of the Kanpo applications for Rehmannia Eight Formula as follows:
The first three groups of indications are related to urinary system disorders (diabetes is included as a cause of frequent urination). In the original text presentations (Shanghan Lun and Jingui Yaolue), the principal applications of the formula were for syndromes that included urination disorders. The underlying causes of these urinary disorders were described in terms understood many centuries ago; today, it is believed that various diseases of the kidney, bladder, and prostate are responsible for most of the changes in urination.
For the most part, the other indications given for the formula (items 4-9) are more recent applications (developed during the past 50 years). Some of these indications can be predicted on the basis of the herb ingredients and Chinese medical theories. For example, the kidney system is said to control sexual function and influence the lower back and legs (e.g., symptoms of impotence, low back pain, sciatica, and knee swelling would often be interpreted as arising from dysfunction of the kidney system), thus helping to explain most of the items listed in 5 and 6. Disorders that typically arise as part of the aging process, such as the cardiovascular diseases (item 4), the eye disorders (item 7), and the dry skin problems (item 8), are addressed, according to Chinese doctrine, by nourishing the kidney and liver, as accomplished by the rehmannia-based formulas.
In the book, Kampo Treatment for Climacteric Disorders (22), Rehmannia Eight Formula is described as one for "conditions marked by degenerative changes and decline in functions, commonly associated with aging...." As a major indication, "limpness or pain in the lumbar region or knees" is cited, along with sensitivity to cold, abnormal urination, and a variety of symptoms such as impairment of vision or hearing, decline in mental abilities, dry itchy skin, and shortness of breath. The authors claim that the formula "can be more effective than conventional drug therapy in controlling and preventing complications of diabetes, such as peripheral neuropathy, nephropathy, and retinopathy." While the focus of their book is on climacteric syndrome (menopause), they also mention the "male menopause" conditions of impotence, prostatitis, and prostate hypertrophy as additional applications of the formula.
In the book 100 Famous and Effective Prescriptions of Ancient and Modern Times (23), which depicts the practices in mainland China, Rehmannia Eight Formula is said to have the following indications:
Insufficiency of kidney yang marked by lumbago, lassitude of the feet, cold feelings in the lower part of the body, cramping sensation in the lower abdomen, difficulty in urination or plenty of urination, impotence, pale and thick tongue proper, weak and fine pulse, as well as cough due to phlegm retention, diabetes, edema, chronic diarrhea...etc.
For modern indications, the book relates a list somewhat similar in nature, though shorter, than that given by Kanpo practitioners: chronic nephritis, hypertension, diabetes, prostatic hyperplasia, postpartum retention of urine, pulmonary emphysema, neurosis, menopausal syndrome, and senile cataract. The book goes on to mention two clinical trials of the formula, one for treatment of cataract and the other for dysuria (due to prostatic hyperplasia); both are claimed to show positive results.
APPENDIX 2. REHMANNIA ACTIVE INGREDIENTS
The main active constituents of rehmannia are iridoid glycosides. These are monoterpenes that have a glucose molecule attached. Catalpol was the first of these isolated from rehmannia (in 1969), and is the one present in largest amounts. There are more than a dozen iridoids that have been isolated from rehmannia, but the others are present in relatively minor quantities. In a study of several samples of rehmannia, it was found that catalpol makes up about 3-11% of the undried root content (depending on the growing conditions), with considerably less (about 1-2%) in the dried root: the drying process evidently destroys this component, converting it into another compound that may or may not be active.
The pharmacological action of catalpol and the other iridoids is not fully established, but it appears that their main function is to stimulate production of adrenal cortical hormones. These hormones have anti-inflammatory action (explaining the claimed benefits of rehmannia for asthma, skin diseases, and arthritis) and are involved in the production of sex hormones (explaining the claimed benefit of treating menopause, impotence, and other signs of hormone deficiency). It is possible that anti-inflammatory effects could explain its early use in mending injuries, and the androgens that the adrenal gland might yield could increase muscle mass. The adrenal steroids may then serve as precursors to production of sex hormones. Rehmannia Eight Formula was tested in aged rats. It was shown to increase estradiol level of the serum in female rats and to raise serum testosterone in male rats.
One of the iridoid glycosides that is found in small amounts in rehmannia and scrophularia is aucubin. It is very similar to catalpol and is also an active ingredient of the rarely used herb Acuba japonica, a close relative of cornus (which contains secoiridoid glycosides) that is used in many rehmannia formulas; aucubin is also present in the more commonly used plantago seed. Both aucubin (14) and geniposide (15) have been shown to have liver-protective actions.
APPENDIX 3. NIH ANNOUNCEMENT (January 16, 2002):
Alternative Therapies for Benign Prostate Symptoms-Clinical Trials Consortium
The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Center for Complementary and Alternative Medicine (NCCAM), and the Office of Dietary Supplements (ODS) invite cooperative agreement grant applications to establish a research consortium to conduct a randomized controlled clinical trial of Serenoa repens (saw palmetto) and Pygeum africanum in men with benign prostatic hyperplasia (BPH). The plan is to spend $29 million over the next seven years.
As the population ages the number of men with lower urinary tract symptoms indicative of BPH is expected to increase substantially. The segment of the United States population that utilizes alternative and complementary approaches to disease prevention and management is also increasing rapidly, including the use of phytotherapy to control the symptoms of BPH. The most common phytotherapeutic agent is Serenoa repens or saw palmetto. Pygeum africanum is also frequently used in this country for the same purpose. Little is known, however, about the long-term effects of these agents on the lower urinary tract symptoms experienced by men with BPH since rigorously conducted clinical trials for these agents have not been conducted.
In order to determine the effect of Serenoa repens and Pygeum africanum on the clinical progression of BPH the NIDDK and the NCCAM plan to establish a clinical trial consortium to conduct a large simple placebo-controlled clinical trial of these two agents comparing saw palmetto to placebo, and Pygeum to placebo. A secondary analysis will include head-to-head comparison of the two phytotherapy agents. The collaborative research group will consist of Clinical Evaluation and Treatment Centers (CETCs) to design and conduct the clinical trial and a single Data Coordinating Center (DCC) to collect, store, and analyze data generated by the CETCs.
More than one-half of the men 50 years of age or older have lower urinary tract symptoms associated with the development of benign prostatic hyperplasia (BPH). The condition accounts for at least 1.7 million office visits per year in the United States with estimated health care costs exceeding $4 billion a year. In addition, these symptoms have been shown to have a significant negative impact on patient-reported quality of life and psychological well-being. The use of alternative therapeutic agents to relieve the symptoms of BPH is increasing very rapidly. In 1996 extracts of the saw palmetto berry was the 9th most common herbal remedy sold in the U.S increasing to the 5th most common in 1997. It is anticipated that the use of alternative therapies for BPH will continue to increase substantially as the U.S. male population continues to age.
Despite the widespread use of phytotherapy for BPH in the United States, most physicians are reluctant to either discuss or recommend their use since only a modest number of published reports have appeared in the peer-reviewed medical literature about their efficacy. Moreover, very few have met rigorous standards for reporting the results of clinical trials. Nonetheless, the available literature supports the hypothesis that these compounds may have some beneficial effects on BPH symptoms. This is supported by a recent meta-analysis that suggests that Saw palmetto improves urinary flow-rate and nocturia in men with symptoms of BPH. However, there are no statistically significant reports of rigorously conducted clinical trials on the long-term effects (both beneficial and adverse) and on patient-reported outcomes.
The objective is to determine if Serenoa repens and Pygeum africanum prevent the clinical progression of BPH, as defined by the development of one of the following: acute urinary retention, renal insufficiency (due to BPH), recurrent urinary tract infections, incontinence, or an increase in the American Urological Association (AUA) symptom score index of four or more points. This definition of the clinical progression of BPH is identical to that used in a soon-to-be-completed clinical trial supported by the NIDDK, the Medical Therapy of Prostatic Symptoms (MTOPS) Trial. Results from the MTOPS Trial, in particular the event rate among the placebo group, will be made available to investigators participating in this consortium to assist in refinement of the trial design. The investigators participating in this consortium will design and conduct a large simple clinical trial. It is envisioned that the clinical trial will require a total of approximately 3,100 men with BPH who will be randomized over a two-year period. The clinical trial will be double-masked and placebo controlled. It is expected that each CETC will recruit and follow-up 300 men for the duration of the trial. Men will be followed for a minimum of four (4) years and a maximum of six (6) years post-randomization. Innovative methods will be required to implement this clinical trial including recruitment of a large number of men with symptoms of BPH, use of multiple strategies to promote long-term adherence to these agents, maintenance of high rates for clinic visits, and complete ascertainment of endpoints
For full details visit this NIH website: http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-02-026.html