High Homocysteine Risks Extend Beyond Stroke and Heart Disease
Ward Dean, MD
Homocysteine is an amino acid that forms naturally in the body as a byproduct of the metabolism of methionine, an amino acid found in red meat. Elevated blood levels of homocysteine are now recognized as an important risk factor for heart disease, possibly surpassing other risk factors such as cholesterol, fibrinogen, C-Reactive Protein (CRP), smoking, age and gender.
Homocysteine Increases Cardiovascular Risk
More than twenty studies with over 2,000 subjects reveal “remarkably consistent” findings regarding the relationship between elevated homocysteine levels and cardiovascular diseases. Patients suffering from stroke and other cardiovascular diseases tend to have higher blood levels of homocysteine (hyperhomocysteinemia) than do subjects without disease. Importantly, even minor elevation of homocysteine levels can significantly increase the risk of stroke and heart disease.
A number of studies have shown that homocysteine increases platelet adhesion and coagulation abnormalities, resulting in increased arterial and venous clots, leading to strokes and heart attacks.1,2 One paper that reviewed eight studies totaling 2,400 patients revealed that risk of developing thrombosis (clots in blood vessels) was up to thirteen times greater in people with elevated homocysteine.3
When researchers conducted a meta-analysis of 35 studies they discovered consistently higher homocysteine levels in patients diagnosed with atherosclerotic diseases. In fact, those subjects diagnosed with atherosclerosis were shown to have homocysteine levels averaging 26 percent higher than those of healthy subjects.4
Another study by Dr. Jacob Selhub of Tufts University and associates involved more than 1,000 elderly people enrolled in the long-running Framingham Heart Study. The authors reported that individuals with the highest levels of homocysteine had twice the risk of a carotid artery blockage (stenosis) than people with the lowest levels. Moreover, their research revealed that patients with the greatest blockage also had the lowest intake of folic acid and vitamin B6.5
The Physicians’ Health Study, a Harvard-based study that tracked nearly 15,000 male physicians (aged 40-84 years) came to a similar conclusion. At the start of the study, none of the physicians had ever suffered a heart attack or stroke. During the course of the five year study 271 men subsequently suffered a heart attack. When researchers compared homocysteine levels of those suffering a heart attack with those who remained healthy, they discovered that the men with the highest homocysteine levels were three times as likely to experience a heart attack as those with the lowest homocysteine levels.6
These findings are supported by a recent prospective study of homocysteine and heart disease conducted in the United Kingdom. When the researchers compared blood collected from 21,520 people (aged 35-64 years) they found that men who had died from heart attacks had homocysteine levels that were significantly higher than men who did not die from heart attacks. Additionally, men with the highest levels of homocysteine faced up to four times the risk of suffering a fatal heart attack as those with the lowest levels. The investigation revealed a continuous dose-response relationship, with risk of heart attack increasing by 41 percent for each additional 5 mM/L increase in homocysteine levels.7
When Norwegian scientists followed 600 men diagnosed with coronary artery disease for up to six years they found that those with the highest homocysteine levels suffered the highest incidence of heart attacks. Higher homocysteine levels also correlated with poor prognosis for survival (Figs. 1 and 2). In their paper the Norwegian researchers concluded that blood homocysteine levels were the strongest predictor of death, surpassing all other study parameters, including cholesterol, triglycerides, apolipoprotein B, apolipoprotein A-I, and lipoprotein (a) [Lp(a)].8
Homocysteine Not Just Bad for the Heart and Arteries
Homocysteine has been implicated in a number of other serious and life-threatening illnesses as well, including kidney disease, psoriasis, acute lymphoblastic leukemia, hypothyroidism, rheumatoid arthritis, gout, depression, Systemic Lupus Erythematosus (SLE), HIV/AIDS, and cancer.9
High levels of homocysteine are even related to worsening cognitive performance (Fig. 3). In a group of 156 individuals who ranged in age from 60-91, none of whom had any overt memory-related problems, researchers found that those who had the highest levels of homocysteine had the poorest cognitive performance.10
Homocysteine and Aging
Not surprisingly, homocysteine blood levels have also been found to increase with age (Fig. 4).11,12 In this regard, the findings of scientists at the Georgetown School of Medicine are of particular interest. Dr. Dong Xu and colleagues examined the effects of homocysteine on the length of telomeres of endothelial cells. Telomeres are unique molecular “caps” found attached to the ends of chromosomes. Telomeres are known to protect the ends of the chromosome from degradation and are involved in the division (mitosis) of cells. Each time a cell divides the length of the telomeres is slightly shortened. In due time, after a number of cell division cycles (or “population doublings”) the telomeres reach a critical length marked by the cessation of cell division and potential death of the cell. Telomeres are thus believed to act as a cellular clock to regulate lifespan. Dr. Xu and colleagues found that homocysteine in cell cultures greatly increased the rate of telomere shortening (Fig. 5), leading the authors to conclude that “a link exists between chronic exposure to homocysteine and the rate of aging.”13
Causes of Elevated Homocysteine
Inadequate B6, B12, Folate: In adults elevated homocysteine levels are usually related to the inadequate intake of B vitamins, particularly folic acid, B6, B12, and betaine (trimethylglycine). The reason these nutrients are so important is that they all act as cofactors in the metabolism of homocysteine (Fig. 6). The conversion of homocysteine to cysteine—known as transsulfuration—requires an enzyme called cystathionine b-synthase (CBS) along with vitamin B6 as a cofactor. In the absence of vitamin B6, transsulfuration cannot proceed, and homocysteine begins to build up and damage blood vessels. The conversion of homocysteine back to methionine is called remethylation. Folic acid and vitamins B6 and B12 are required for this reaction. Betaine can also facilitate remethylation. When levels of these nutrients are low, remethylation cannot proceed efficiently, allowing homocysteine to accumulate.
Coffee: Several studies have indicated that coffee consumption appears to cause a dose-related increase in homocysteine. A large study (4,754 participants) by scientists from Johns Hopkins University found that the more coffee one consumes the higher ones’ homocysteine levels (Fig. 7). Although this may appear as bad news for coffee drinkers, a solution (other than giving up coffee) is offered later in this article.14
Niacin: Another cause of elevated homocysteine is high dose nicotinic acid (Vitamin B3). This is especially surprising given the proven track record for niacin’s ability to dramatically improve lipid profiles. Niacin is one of the most economical and effective ways to lower total cholesterol, triglycerides, and lipo-protein (a) [lp(a)], and to raise HDL (the “good” cholesterol). However, doses of niacin in excess of 1,000 mg have been shown to cause an increase in homocysteine.15 This increase may be offset by the benefits of niacin, and may be mitigated by the use of homocysteine-lowering substances described below.
Metformin: Another surprise is that the drug Metformin (Glucophage) has been shown in several studies to cause an increase in homocysteine.16-18 This at first appears to be a disturbing finding, as many people take Metformin for its broad range of potential anti-aging effects—especially its ability to restore insulin and cortisol receptor sensitivity. Metformin’s homocysteine-raising effects may be due to its known effect of causing a decrease in absorption of vitamin B12. As mentioned previously, vitamin B12 is required to convert homocysteine back into methionine (remethylation), so Metformin-related deficiency of vitamin B12 could explain the reported increase in homocysteine. Obviously, this effect can likely be countered by taking supplemental B12, sublingually or by injection.
Keeping Homocysteine Levels Low
Lifestyle Modification: Relatively straight-forward lifestyle changes can help to maintain favorable homocysteine levels, including exercise, avoiding alcohol, and eating a diet high in protein. Although a high protein diet might seem contradictory, since homocysteine is produced from an amino acid found in meat, data from a large study demonstrates that the more meat one consumes, the lower one’s blood homocysteine level (Fig. 8).19 Since hyperinsulinemia (elevated insulin) is also associated with higher levels of homocysteine, higher meat consumption probably results in a reduction in carbohydrate consumption, and a consequent reduction in insulin levels.
Folic Acid: Folic acid enhances the remethylation process that converts homocysteine into methionine, and thereby further reduces homocysteine levels. Doses of folic acid ranging from 800 mcg up to 5 mg/day have been recommended.20,21,22
Vitamin B6: Vitamin B6 (pyridoxine) has been safely used in doses ranging as high as 750 mg per day for up to 24 years by patients with elevated levels of homocysteine.21 This is a remarkable record of safety, considering reports of peripheral neuropathy at doses as low as 500 mg per day of B6. One possible explanation is that since the metabolism of some people diagnosed with hyperhomocysteinemia is so severely altered that, not only can they tolerate such high doses of B6, they may actually require them. More common recommendations for B6 range from 100-300 mg per day.22, 23
Vitamin B12 (cobalamin): Vitamin B12 is also a cofactor in the remethylation of homocysteine to methionine. Vitamin B12 is effective in doses up to 1 mg per day. In a small study from the Denver VA Medical Center, physicians treated ten patients with high homocysteine levels with weekly injections of 1 mg of vitamin B12 per week for 8 weeks, followed by monthly injections for the next four months. This single therapy led to dramatic drops in the homocysteine levels of all patients (Fig. 9).11
Betaine (TMG): Some people are deficient in enzymes required to facilitate transsulfuration or folate-based methylation. Such a deficiency can result in elevated homocysteine levels regardless of the presence of adequate levels of folate and/or vitamin B6. In such cases betaine (tri-methylglycine, or TMG) has been shown to be quite effective in reducing high homocysteine levels by enhancing the remethylation of homocysteine by a different pathway than vitamin B6.24,25,26 Betaine has been shown to be effective in doses of 6 to 9 grams daily.27 Although that seems like a lot, betaine is an inexpensive, pleasant tasting, fast-dissolving powder that mixes well in just about any beverage. For those who don’t want to give up their homocysteine-raising cups of coffee every day, I’ve found that a teaspoon of Betaine (about 5 grams) added to a cup of coffee actually improves the flavor.
Choline: Choline has also been reported to be helpful in reducing elevated homocysteine levels, when administered in doses in the range of two grams daily.28
SAMe: Elevated levels of homocysteine have been shown to be related to low levels of S-Adenosyl-Methionine (SAMe).29
Vitamins C and E: Italian scientists studied the effects of 800 IU of Vitamin E and 1 gram of vitamin E on 20 healthy men and women after experimentally induced hyperhomocysteinemia (elevated blood homocysteine) in the subjects. The researchers reported that “Pretreatment with antioxidant vitamin supplements normalized both the level of cardiovascular risk and the impairment of endothelial functions following acute hyperhomocystenemia.” It appears from this study that consumption of high amounts of antioxidant vitamins may be protective against elevated homocysteine levels.30
Summary
Elevated blood levels of homocysteine are clearly shown to increase risks of developing cardiovascular and other diseases. Research shows that increased intake of folic acid, betaine, vitamin B6, and vitamin B12 is associated with a decrease in homocysteine levels and a concomitant drop in risks of cardiovascular disease.
Given the deadly consequences of elevated homocysteine levels it is truly remarkable when one considers the ease with which these levels can be reduced and maintained within a safe range by simply taking folic acid (folate), vitamins B6 (pyridoxine) and B12, SAMe, Choline, betaine (TMG), and antioxidants.
References
1. Welch, G.N., Loscalzo, J. Homocysteine and atherothrombosis, New Engl J Med, 1998, 338: 1042-1050.
2. Ray, J.G. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease, Arch Intern Med, 1998: 158: 2101-2106.
3. Selhub J, D’Angelo A. Relationship between homocysteine and thrombotic disease [In Process Citation]. Am J Med Sci. 1998; 316:129-41.
4. Moghadasian M, McManus B, Frolich J. Homocyst(e)ine and coronary artery disease. Clinical evidence and genetic and metabolic background. Arch Intern Med. 1997; 157:2299-2308.
5. Selhub J, Jacques P, Bostom A, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995; 332:286-291
6. Stampfer, M., Malinow, M., Willett, W., et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in U.S. physicians. JAMA, 1992, 268: 877-881.
7. Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J, Scott JM. Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention. Arch Intern Med. 1998; 158:862-7.
8. Nygard, O., Nordrehaug, J.E., Refsum, H., et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. New Engl J Med, 1997, 337: 230-6.
9. Bolander-Gouaille, C. Focus on Homocysteine and the Vitamins Involved in its Metabolism. 2002, Springer, Paris.
10. Budge, M., Joohnston, C., Hogervorst, E., et al. Plasma total homocysteine and cognitive performance in a volunteer elderly population. Ann NY Acad Sci, Vol 903, 2000.
11. Pennypacker L.C., Allen, R.H., Kelly, J.P., Matthews, M., et al. High prevalence of cobalamin deficiency in elderly outpatients. J Am Geriatrics Soc, 1992, 40: 1197-1204.
12. Selhub J, Jacques P, Wilson P, Rush D, Rosenberg I. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993;270:2693-2698.
13. Xu, D., Neville, R., and Finkel, T. Homocysteine accelerates endothelial cell senescence. FEBS Letters, 2000, 470: 20-24.
14. Stolzenberg-Solomon, R.Z., Miller, E.R., Maguire, M.G., et al. Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population, Am J Clin Nutr, 1999, 69: 467-475.
15. Garg, R., Malinow, M., Pettinger, M, et al. Niacin treatment increases plasma homocyst(e)ine levels. Am Heart J, 1999, 138: 1082-7.
16. Carlsen, S. Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease. Scan J Clin Lab Invest, 1997, 57: 521-527.
17. Chango, A. Vitamin B12 status and homocysteine metabolism in type 2 diabetes mellitus on biguanide therapy. 4th Eur Symp, Innsbruck, 1996, 11.
18. Hoogeven, E.K. Does metformin increase the serum total homocysteine in insulin-dependent diabetes mellitus? J Inter Med., 197, 42, 389-394.
19. Stolzenberg-Solomon, R.Z., Miller, E.R., Maguire, M.G., et al. Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population, Am J Clin Nutr, 1999, 69: 467-475.
20. Wald, D.S., Bishop, L., Wald, N.J., et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch Int Med, 2001, 161: 695-700.
21. Glueck, C.J., Shaw, P., Lang, J.E., Tracy, T., Sieve-Smith, L., Wang, Y. Evidence that homocysteine is an independent risk factor for atherosclerosis in hyperlipidemic patients. Am J Cardiol, 1995, 75: 132-136.
22. Arnadottir, M., Brattistrom, O., Simonsen, H, et al, The effect of high-dose pyridoxine and folic acid supplementation on serum lipid and plasma homocysteine co in dialysis patients, Clin Nephrol, 1993, 40: 236-240.
23. Wilcken, D.E., and Wilcken, B. B vitamins and homocysteine in cardiovascular disease and aging. In: Towards Prolongation of the Healthy Life Span—Practical Approaches to Intervention, Ann NY Acad Sci, Vol 854, by Denham Harman, Robin Holliday, and Mohsen Meydani (eds),1998, 361-370.
24. Wilcken DE, Wilcken B, Dudman NP, Tyrrell PA. Homocystinuria: The effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med. 1983; 309:448-53.
25. Dudman NP, Guo XW, Gordon RB, Dawson PA, Wilcken DE. Human homocysteine catabolism: three major pathways and their relevance to development of arterial occlusive disease. J Nutr. 1996;126:1295S-300S.
26. Wilcken DE, Dudman NP, Tyrrell PA. Homocystinuria due to cystathionine beta-synthase deficiency_the effects of betaine treatment in pyridoxine-responsive patients. Metabolism. 1985; 34:1115-21.
27. Malinow, M.R. Hyperhomocys(e)inemia: a common and easily reversible risk factor for occlusive atherosclerosis. Circulation, 1990, 81: 2004-6.
28. Jancin, B. Amino acid defect causes 20% of atherosclerosis in CHD. Family Pract News, 1994, 15: 7.
29. Bolander-Gouaille, C. Focus on Homocysteine and the Vitamins Involved in its Metabolism. 2002, Springer, Paris.
30. Nappo, F., De Rosa, N., Marfella, R., et al. Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins. JAMA, 1999, 281: 2113-2118.
|
Larch Arabinogalactan
Unique Natural Prebiotic for Immune Support
Carolyn Perrini, CLS, CNC
Larch arabinogalactan is a well known source of dietary fiber that offers powerful therapeutic benefit as a prebiotic and as a modulator of the immune system. Of particular interest is its potential as an adjunctive supplement in the treatment of chronic diseases, including cancer.1
Arabinogalactan (AG) is a polysaccharide found in the cell walls of a wide variety of edible and non-edible, woody plants. The wood of the western larch tree (Larix occidentalis) provides a rich harvest of free arabinogalactan from its inner bark. This complex carbohydrate helps the tree recover from injury from lightning strikes, and protects against the freeze-thaw cycles experienced in the high altitudes of the Pacific and Inland Northwest where it grows.2
Polysaccharides are often found in many medicinal herbs used for immune enhancement, including Echinacea and Astragalus.3 AG is a fine, dry, off-white powder with a mildly sweet taste that mixes well with liquids. This safe and effective phytochemical is FDA approved for use as a dietary fiber and as a food additive. There are no known reports of toxicity. Credit for introducing larch AG into clinical practice goes to the distinguished naturopathic physician, Dr. Peter D’Adamo.
AG Supports Digestion
Larch AG acts as a food supply to friendly intestinal bacteria. Like the well-known fructooligosaccharides (FOS), AG is considered a “prebiotic.” The non-absorbed fiber is eagerly fermented by the distal gut microflora, resulting in an elevated production of short-chain fatty acids (SCFAs)—primarily butyrate, but also propionate. SCFAs are critically important to the health of the colon and are the principal energy source (butyrate) for the colonic epithelial cells.8,9 Many clinicians use prebiotics to prevent and treat intestinal conditions like diverticulosis, leaky-gut, irritable bowel syndrome (IBS) as well as inflammatory bowel diseases (IBD) like Crohn’s and ulcerative colitis.
Studies have shown that larch AG consumption reduces intestinal ammonia generation.5 Reducing ammonia is significant because even low ammonia levels can have damaging effects on intestinal colonic cells.6 AG may especially benefit patients with liver disease who are unable to detoxify ammonia, resulting in hepatic encephalopathy.4,6,7
AG Enhances Immunity
While larch AG is important for digestive health it has received even more attention for its ability to promote the health of the immune system. Larch AG seems to enhance immune response and may be termed a biological response modifier.10
Larch AG may be important in cancer treatment protocols due to its ability to block the metastasis of tumor cells to the liver, and to stimulate NK cell cytotoxicity.3 Tumor metastasis to the liver is more common than to other organ sites. AG has been shown to reduce tumor cell colonization and increase survival time of subjects with various cancers.12,13,14 Incidentally, modified citrus pectin has the same anti-metastatic mechanism of action as larch AG, but does not provide the immune-modulating effects.
NK cell activity is a functional marker for health. In one well-designed study, larch AG induced an increased release of interferon gamma (IFN gamma), tumor necrosis factor alpha, interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6). This resulted in activating two powerful cells of the immune system: macrophages and NK cells. It was found that the IFN gamma was most responsible for the observed enhancement of NK cytotoxicity.11
Reports in the medical literature link decreased NK cell activity to a variety of chronic diseases including chronic fatigue syndrome,15 viral hepatitis,16,17 HIV/AIDS,3 and autoimmune diseases such as multiple sclerosis.18 The ability of larch arabinogalactans to stimulate NK activity might be the reason for the significantly improved clinical outcome of these patients.
Other Indications
Larch AG has also been shown to decrease the frequency and severity of pediatric otitis media caused by gram negative rods (especially, Escherichia coli and Klebsiella sp.)3 (Note: Xylitol consumption also reduces the incidence of otitis media.)
Dosage
Larch arabinogalactan in powder form is typically dosed in teaspoons or tablespoons at a concentration of approximately 3 grams per teaspoon. The adult dosage is one to three teaspoons per day in divided doses. Because of its mild taste and excellent solubility in water or juice, it is easy to use with children. Clinical feedback suggests an occasional reaction of bloating and flatulence in less than three percent of individuals (mostly women). This side effect is probably due to the effect AG has on beneficially altering intestinal microflora and will often disappear after several days to one week.10
References
1. Adams MF, Ettling BV. Industrial Gums 2nd Edition; Academic Press 1973.
2. Chemstone. Theoretical Basis for Process Improvement with Chemstone OAE Technology.
3. D’Adamo P. Larch arabinogalactan is a novel immune modulator. Townsend Letter for Doctors and Patients 1996, July; 156: 42-46.
4. Vince AJ, McNeil NI, Wager JD, Wrong OM. The effect of lactulose, pectin, arabinogalactan, and cellulose on the production of organic acids and metabolism of ammonia by intestinal bacteria in a faecal incubation system. Br J Nutr 1990;63:17-26.
5. Englyst HN, Hay S, Macfarlane GT. Polysaccharide breakdown by mixed populations of human faecal bacteria. FEMS Microbiol Ecology 1987;95:163-171.
6. Robinson R, Feirtag J, Slavin J. Effects of dietary arabinogalactan on gastrointestinal and blood parameters in healthy human subjects. J Amer College of Nutrition 2001; 20: 279-285.
7. Crociani F, Alessandrini A, Mucci MM, Biavati B. Degradation of complex carbohydrates by Bifidobacterium spp. Int J Food Microbiol 1994; 24:199-210.
8. Roediger WE. Utilization of nutrients by isolated epithelial cells of the rat colon. Gastroenterology 1989; 83:424-429.
9.Tsao D, Shi Z, Wong A, Kim YS. Effect of sodium butyrate on carcinoembryonic antigen production by human colonic adenocarcinoma cells in culture. Cancer Res 1983;43:1217-1222.
10. Kelly GS. Larch arabinogalactan: Clinical relevance of a novel immune-enhancing polysaccharide. Alternative Med Rev 1994; 4(2):96-103.
11. Hauer J, Anderer FA. Mechanism of stimulation of human natural killer cytotoxicity by arabinogalactan from Larix occidentalis. Cancer Immunol Immunother 1993;36:237-244.
12. Hagmar B, Ryd W, Skomedal H. Arabinogalactan blockade of experimental metastases to liver by murine hepatoma. Invasion Metastasis 1991;11:348-355.
13. Beuth J, Ko HL, Schirrmacher V,et al. Inhibition of liver tumor cell colonization in two animal tumor models by lectin blocking with D-galactose or arabinogalactan. Clin Exp Metastasis 1988;6:115-120.
14. Beuth J, Ko HL, Oette K, et al. Inhibition of liver metastasis in mice by blocking hepatocyte lectins with arabinogalactan infusions and D-galactose. J Cancer Res Clin Oncol 1987;113:51-55.
15.Levine PH, Whiteside TL,Friberg D, et al. Dysfunction of natural killer cell activity in a family with chronic fatigue syndrome. Clin Immunol Immunopathol 1998;88:96-104.
16. Machado IV, Deibis L, Risquez E, et al. Immunoclinical, molecular, and immunopathologic approach to chronic viral hepatitis.Therapeutic considerations. GEN 1994;48:124-132. [article in spanish].
17. Corado J, Toro F, Rivera H, et al. Impairment of natural killer (NK) cytotoxicity activity in hepatitis C virus (HCV) infection. Clin Exp Immunol 1997;109:451-457.
18. Kastrukoff LF, Morgan NG, Zecchini D, et al. A role for natural killer cells in the immunopathogenesis of multiple sclerosis. J Neuroimmunol 1998;86:123-133.
|
Benign Prostatic Hypertrophy
Ward Dean, MD
Few men ever consider the walnut-sized fibrous gland located just below the bladder, until it starts to give them trouble. In fact, a 1995 survey in the London Times found that 89 percent of the men surveyed did not know where the prostate was located. After the age of 50, the prostate begins to hypertrophy, or increase in size. This is known as benign prostatic hypertrophy (BPH). The urethra (the tube that carries urine from the bladder) runs through the middle of the prostate. Consequently, when the prostate enlarges the urethra is compressed. (Fig. 1) This causes difficulty in urinating and requires many men to get up three or four times during the night to urinate. Other symptoms of BPH include hesitancy, dribbling, reduced force of the urinary stream, and occasional bleeding or infection. This condition may even proceed to the point of complete urinary obstruction.
Fifty to sixty percent of men between 40-60 years of age suffer from BPH, escalating to 75 percent of men by age 60 (Fig. 2).1 The projected annual cost of hospital care and surgical treatment for BPH in the United States is over $1 billion. In fact, this condition is so common that physicians routinely ask their over-50 male patients, not “whether” but “How many times do you have to get up at night to go to the bathroom?” I wonder how many men have seen the cartoon character “Calvin” on the back of a truck windshield urinating from one side of the vehicle to the other and said secretly to themselves, “I wish I could still do that?”
Causes of Prostatic Enlargement
Prostate hypertrophy and inflammation are believed to be due to the consequences of a number of age-related changes in the metabolism and levels of male steroid hormones.2 After the age of fifty, the level of free testosterone decreases, while levels of prolactin, estradiol, and sex hormone-binding globulin (SHBG) increase. Concen-trations of dihydrotestosterone (DHT)— the active metabolite of testosterone—in the prostate increase, and binding of DHT to prostate tissue increases. DHT stimulates the prostate cells to enlarge, resulting in the swollen gland.
5-alpha reductase is the enzyme that converts testosterone into DHT. Con-sequently, one approach to preventing BPH has been to use substances that inhibit this enzyme, thereby blocking the formation of DHT, and its prostate-enlarging effect. Estrogen also seems to play a role in BPH by inhibiting the breakdown and removal of testosterone and DHT. The increased ratio of plasma estrogen/testoster-one is due to the increased formation of estrogens formed by the conversion of androstenedione to estrone and estradiol by the enzyme, aromatase. Another approach to preventing or treating BPH is, therefore, to use aromatase inhibitors to prevent this estrogenic conversion.
Therapeutic Options for BPH
Until recently, outside of “watchful waiting,” surgery was about the only solution for this troublesome condition. Fortunately, less invasive and more physiological approaches to prevent and treat BPH are now available, based on our increased understanding of its causes. Clearly, a rational approach should include: (1) normalization of prostate nutrient levels; (2) restoration of steroid hormones to normal levels; (3) inhibition of excessive conversion of testosterone to DHT (dihydrotestosterone); (4) reduction of DHT receptor binding; and (5) reduction of prostatic inflammatory promoters such as prolactin.
Proscar® is a prescription drug which inhibits 5-alpha reductase. This drug has recently been introduced into the physician’s armamentarium for treatment of BPH. Use of Proscar results in a 20 percent decrease in prostate size in 50 percent of the men who are treated. Unfortunately, Proscar is fairly expensive, with the significant side effect of sexual dysfunction.2 Fortunately, however, there are nutritional alternatives which provide, without adverse effects, equivalent or greater benefits at reduced cost.
Saw Palmetto (Serenoa repens)
Extracts of saw palmetto berry are being used extensively throughout the world for the relief of BPH. Both the French and German governments approve lipo-philic extracts of saw palmetto berries for this purpose. Saw palmetto reduces prostate hypertrophy by blocking the conversion of testosterone to dihydrotestosterone by inhibiting 5-alpha reductase—just like its expensive prescription “cousin”—and by preventing the binding of DHT to androgen receptor cell sites. These actions increase the breakdown and excretion of DHT. Saw palmetto also interferes with the actions of inflammatory substances that contribute to prostate inflammation and reduces the pro-hypertrophic effects of estrogen and progesterone on the prostate.3-6
Positive results with saw palmetto have been confirmed in numerous open8-14 as well as double-blind, placebo-controlled clinical trials.15-19 All of these studies demonstrated statistically significant improvements in the symptoms of BPH, which included increased volume and rate of urine flow, alleviation of pain and night time urination, and reduced number of voidings per day. Overall, these studies showed a consistent benefit of saw palmetto extract, with virtually no side effects of any consequence. A striking characteristic of these studies is that most subjects experienced relief within days of beginning the therapy, with benefits continuing to improve over time — in many cases, as much as one year of continuing improvement! Most studies however, were terminated after 30, 60 or 90 days. “A striking characteristic of these studies is that most subjects experienced relief within days of beginning the therapy, with benefits continuing to improve over time, in many cases, as much as one year of continuing improvement!”
Most recently, University of Chicago researchers studied the effects of saw palmetto extract versus placebo on 85 men, 45 years of age or older.20 The researchers evaluated the subjects based upon three measurements: the International Prostate Symptom Score, a sexual function questionnaire, and the urinary flow rate. At the end of the study, the subjects treated with saw palmetto experienced significant improvement and reduction of symptoms such as frequent urination both during the night and day and interruptions in urination. The researchers stated that their study provides the most conclusive evidence to date that saw palmetto can benefit men with prostate problems.
Of particular interest was a study that compared Proscar with saw palmetto extract that found that saw palmetto had fewer side effects, provided an equivalent or greater benefit, and was a more affordable form of treatment.21,22 The optimum dose of saw palmetto in most clinical studies was 320 mg per day.
Pygeum Africanum
Extracts of the African herb Pygeum africanum have also shown impressive results in relieving symptoms of BPH. The action of pygeum extract in counteracting prostate hypertrophy is believed to be due to a number of mechanisms, which include its ability to: (1) inhibit the basic fibroblast growth factor induced cellular proliferation;23 (2) inhibit aromatase;24 (3) restore secretory activity of the prostatic epithelium;25 and (4) increase prostatic secretions.26
In one study, 18 patients with BPH or chronic prostatitis, many of whom also had sexual disturbances, received an extract of pygeum. After 60 days, all urinary parameters that were investigated were improved, and sexual disturbances were relieved.27 In a placebo-controlled French trial of 120 patients, the pygeum group experienced significant reductions in the number of urinations and more complete bladder emptying than the placebo group.28
An international, multi-center, double-blind, controlled trial of pygeum extract in 263 patients with BPH over a 60 day period showed improved urinary symptoms in 66 percent of the patients.29 Italian placebo-controlled studies confirmed these benefits.23-25 Most of the clinical studies with pygeum used dosages ranging from 75-150 mg per day.
Stinging Nettle (Urtica dioica)
Extracts of stinging nettle are used routinely in Europe to treat BPH. Stinging nettle shares several mechanisms with Pygeum and saw palmetto, but has several actions that are unique. The known mechanisms of stinging nettle on the prostate include its ability to: (1) inhibit aromatase;30 (2) reduce the binding activity of SHBG;31,32 (3) inhibit prostate membrane Na+, K+-ATPase activity;33 (4) block epidermal growth factor receptors;34 and (5) block 5-alpha reductase.35
Stinging nettle has been tested and found to be effective in BPH as a single nutrient,36-39 or in combination with Pygeum.40 Extracts of stinging nettle when used alone were superior to placebo, but efficacy was enhanced when combined with Pygeum. The dosages of stinging nettle in the clinical studies was 300 mg per day.
Beta-Sitosterol
Beta-sitosterol, one of the main subcomponents of a group of plant sterols known as phytosterols, is a white, waxy substance with a chemical structure very similar to that of cholesterol. Research into beta-sitosterol has shown beneficial effects against a wide variety of human ailments, including BPH. Beta-sitosterol is the key ingredient in a prescription formulation in Europe, Azuprostat-beta-sitosterol, which has been demonstrated to improve prostate symptom scores and quality of life, and reduce urine volume and residual urine levels. The research team reported that “beta-sitosterol itself is an effective option in the treatment of BPH.”41 Beta-sitosterol was also found to reduce the growth of human prostate cancer cells,42 and appears to be one of the key compounds in soybeans that suppresses carcinogenesis.43
Lycopene
More than 500 types of carotenoids exist in nature. The most common carotenoids include alpha carotene, beta carotene, lycopene, lutein, and beta cryptoxanthin.
In one study, a group of scientists evaluated prostate cancer risk in comparison to dietary intake of specific carotenoids. They found that of 43 fruits and vegetables examined, only tomato-based products (tomato sauce, tomatoes, and pizza—but not tomato juice) and strawberries were found to be protective against prostate cancer. The researchers attributed the protective effect of these tomato-based foods to their high lycopene content.
Lycopene is highly lipophilic (fat soluble) and requires fat for proper intestinal absorption. This is probably the reason for the lack of efficacy of tomato juice. Strawberries are not a good source of lycopene, and the reason for the protective effect of strawberries was not known. Thus, it would seem reasonable to include a high concentration of tomato-based foods (or a lycopene supplement) and strawberries in a prostate cancer preventive nutritional program.
Although researchers believed that tomato-based products may help prevent prostate cancer, they now have evidence that lycopene may also benefit patients already suffering from the disease. A study in the December 19, 2001 Journal of the National Cancer Institute, reported on 32 men with prostate cancer who were about to undergo radical prostatectomy.44 They began a three-week diet of pasta with tomato sauce—the equivalent of roughly 30 mg of lycopene daily—prior to their surgery. This resulted in markedly increased prostate lycopene concentrations, accompanied by a 21.3 percent reduction in leukocyte oxidative DNA damage. In addition, serum PSA levels (a marker for prostate cancer) dropped 17.5 percent, from a mean of 10.9 ng/mL before the diet to 8.7 ng/mL after the diet. Another impressive result of the study was the rate that DNA damage declined in the patients consuming diets high in lycopene. Oxi-dative DNA damage in prostate tissue from the men consuming high-lycopene diets was 28.3 percent less than in tissue samples from seven randomly selected prostate cancer patients not consuming a high-lycopene diet.
Most recently, Giovanucci reviewed eight epidemiological studies which reported that those with the highest tomato or lycopene consumption had a 30 percent to 40 percent reduction in prostate cancer risk.45 The largest study, in male health professionals, found that consumption of two to four servings of tomato sauce per week was associated with about a 35 percent reduction of total prostate cancer and a 50 percent reduction of advanced (extraprostatic) prostate cancer. In the largest study of blood lycopene levels, very similar risk reductions were observed for total and advanced prostate cancer. Those with the highest lycopene levels had the lowest incidence of prostate cancer.
Conclusion
Beta-sitosterol, and extracts from Saw palmetto, Pygeum africanum, and stinging nettle have all demonstrated efficacy when used in the treatment and prevention of benign prostatic hypertrophy (BPH). Because of their multiplicity of actions, it should be no surprise that when these phytonutrients are combined, they are even more effective than when used individually. Combined with the prostate-cancer-protecting carotenoid lycopene (and beta-sitosterol), men no longer need to consider the years over 50 as “The Prostatic Age.”
References
1. Denis, L.J. Quantification and incidence of benign prostatic hyperplasia. Drugs of Today, 1993, 29-30.
2. Horton R. Benign prostatic hyperplasia: A disorder of androgen metabolism in the male. J Am Geriatr Soc, 1984, 32:380-5.
3. Gormley, G.J., Stoner, E., Bruskewitz, R.C., Imperato-McGinley, J., et al. The effect of finasteride in men with benign prostatic hyperplasia. NEJM, 327: 17, 1185-91.
4. Briley, M., Carilla, E., and Fauran, F. Permixon, a new treatment for benign prostatic hyperplasia, acts directly at the cytosolic androgen receptor in rat prostate. Brit J Pharmacol, 1983, 79: 327.
5. Weisser, H., Tunn, S., Behnke, B., and Krieg, M. Effects of the Sabal serrulata Extract IDS 89 and its subfractions on 5 alpha reductase activity in human benign prostatic hyperplasia. The Prostate, 1996, 28: 300-306.
6. Breu, W., Hagenlocher, M., Redl, K., et al. Antiphlogistic activity of an extract from Sabal serrulata fruits prepared by supercritical carbon dioxide/In vitro inhibition of the cyclooxygenase and 5-lipoxygenase metabolism. Arzneim-Forsch, 1992, 42 (I):, 4, 547-551.
7. Brown, D.J. Saw palmetto: Herbal prescription for treatment of BPH. Drug Store News for the Pharmacist, 1995, April, 29-30.
8. Tripodi V, Giancaspro M, Pascarella M, et al. Treatment of prostatic hypertrophy with Serenoa repens extract. Med Praxis, 1983, 4:41-6.
9. Emili E, Lo Cigno M and Petrone U. Clinical trial of a new drug for treating hypertrophy of the prostate (Permixon). Urologia, 1983, 50:1042-8.
10. Cirillo-Marucco E1, Pagliarulo A, Tritto G, et al: Extract of Serenoa repens (Permixon) in the early treatment of prostatic hypertrophy. Urologia, 1983, 5:1269-77.
11. Greca P and Volpi R. Experience with a new drug in the medical treatment of prostatic adenoma. Urologia, 1985, 52:532-5.
12. Givia R. Radice GP and Galdini R. Advances m the phytotherapy of prostatic hypertrophy. Med Praxis, 1983, 4:143-8.
13. Crimi A and Russo A. Extract of Serenoa repens for the treatment of the functional disturbances of prostate hypertrophy. Med Praxus, 1983, 4:47-51.
14. Braekman, J. The extract of Serenoa repens in the treatment of benign prostatic hyperplasia: A multicenter open study. Current Therapeutic Research, 1994, 55: 7, 776-785.
15. Tasca A, Barulli M, Cavezzana A, d al: Treatment of obstructive syrnptomatology caused by prostatic adenoma with an extract of Serenoa repens. Double-blind clinical study vs. placebo. Minerva Urol Nefrol, 1985, 37:87-91,
16. Champault G. Bonnard AM, Cauquil J and Patel JC: Medical treatment of prostatic adenoma. Controlled trial: PA 109 vs placebo in 110 patients. Ann Urol, 1984,18:407-10.
17. Champlault G. Patel JC and Bonnard AM: A double-blind trial of an extract of the plant Serenoa repens in benign prostatic hyperplasia. Br J Clin Pharmacol, 198418:461-2.
18. Boccafoschi and Annoscia S: Comparison of Serenoa repent extract with placebo by controlled clinical trial in patients with prostatic adenomatosis. Urologia, 1983, 50:1257-68.
19. Cukier, P., et al. Permixon versus placebo. Results of a multi-center study. C R Ther Pharmacol Clin, 1985, 4/25: 15-21.
20. Gerber GS, Kuznetsov D, Johnson BC, Burstein JD. Randomized, double-blind, placebo-controlled trial of saw palmetto in men with lower urinary tract symptoms. Urology. 2001 Dec;58(6):960-4; discussion 964-5.
21. Cockett, A.T.K., Khoury, S., Aso, Y., Chatelain, C., et al. Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: A randomized international study of 1098 patients. Proceedings of the Third International Consultation on benign prostatic hyperplasia (BPH), Paris: SCI, 1996.
22. Denis, L.J. Editorial review of “Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: A randomized international study of 1098 patients.” The Prostate, 1996, 29: 241-242.
23. Bassi , P., et al. Standardized extract of Pygeum africanum in the treatment of benign orostatic hypertrophy. Controlled clinical study versus placebo. Minerva Urol Nefrol, 1987, 39 (1): 45-50.
24. Colpi G. Farina U. Study of the activity of chloroformic extract of Pygeum africanum bark in the treatment of urethral obstructive syndrome caused by non-cancerous prostapathy. Urologia, 1976, 43: 441-8.
25. Del Valio B. The use of a new drug in the treatment of chronic prostatitis. Minerva Urol, 1974, 26: 87-94.
26. Paubert-Braquet, M., Monboisse, J.C., Servent-Saez, N., et al. L’extrait de Pygeum africanum (Tadenantm) inhibie la proliferation des fibroblastes murins 3T3 par le basic Fibroblast Growth Factor. Biomed & Pharmacother, 1994, 48, Suppl 1: 435-475.
27. Carani C, Salvioli V, Scuteri A, et al: Urological and sexual evaluation of treatment of benign prostatic disease using Pygeum africanum at high doses. Arch Ital Urol Nefrol Androl , 1991, 63(3): 341-5.
28. Dufour, B., et al. Controlled study of the effects of Pygeum africanum extract on the functional symptoms of prostatic adenoma. Ann Urol (Paris), 1984, 18(3):193-95.
29. Barlet A, Albrecht, J., Aubert, A., et al. Efficacy of Pygeum africanum extract in the medical therapy of urination disorders due to benign prostatic hyperplasia: evaluation of objective and subjective parameters. A placebo controlled double-blind multicenter study. Wien Klin Wochenschr 102(22):667-73, 1990
30. Kraus, R., Spiteller, G., Bartsch, W. Octadecadiensaure, ein Aromatase-Hemmstoff aus dem Wurzelextrakt von Urtica doioica. Liebigs Ann Chem, 1991, 335-339.
31. Gansser, D., Spiteller, G. Aromatase inhibitors from Urtica dioica roots. Z. Naturforsch, 1995, 500: 98-104.
32. Schmidt K: Effect of radix urticae extract and its several secondary extracts on blood SHBG in benign prostate hyperplasia.] Fortschr Med, 1983, 101 (15): 713-16.
33. Clavert, A., Cranz, C., Riffaud, J.P., et al. Effets d’un extrait d’ecorce de Pygeum africanum (V1326) sue les secretions prostatiques du rat et de l’homme. Ann Urol, 1986, 20: 341-343.
34. Hirano, T., Homma, M., and Oka, K. Effects of stinging nettle root extracts and their steroidal components on the Na+, K+-ATPase of the benign prostatic hyperplasia. Planta Medica, 1994, 60: 30-33.
35. Wagner, H., Geiger, W.N., Boos, G, and Samtleben, R. Studies on the binding of Urtica dioica agglutinin (UDA) and other lectins in an in vitro epidermal growth factor receptor test. Phytomedicine, 1995, 4: 287-290.
36. Belaiche P: Lievoux O. Clinical studies on the palliative treatment of prostatic adenoma with extract of Urtica root. Phytother Res, 1991, 5:267-9.
37. Romics I. Observations with Bazoton in the management of prostatic hyperplasia. Int Urol Nephrol, 1987, 19(3):293-7.
38. Barsom S. Bettermann AA. Prostatic adenoma: Conservative therapy with Urtica extract. ZFA (Stuttgart), 1979, 55 (33): 1947-50.
39. Maar K: Regression of the symptoms of prostatic adenomas. Results of 7 months’ conservative treatment using ERU capsules. Fortschr Med , 1987, 105:18-20
40. Krzeski, T: Kazon, M., Borkowski, A., Witeska, A., Kuczera, J. Combined extracts of Urtica dioica and Pygeum africanum in the treatment of benign prostatic hyperplasia: Double blind comparison of two doses. Clin Therapeut, 1993, 15: 1012.
41. Klippel K. F., et al., A multicentric, placebo-controlled, double-blind clinical trial of beta-sitosterol (phytosterol) for the treatment of benign prostatic hyperplasia. German BPH-Phyto study group. Br J Urol 1997 Sep; 80(3): 427-32.
42. von Holtz RL, et. Al., beta-Sitosterol activates the sphingomyelin cycle and induces apoptosis in LNCaP human prostate cancer cells. Nutr Cancer 1998;32(1):8-12.
43. Kennedy AR, et al., The evidence for soybean products as cancer preventive agents. Journal of Nutrition 1995 Mar;125(3 Suppl):733S-743S.
44. Chen L, Stacewicz-Sapuntzakis M, Duncan C, Sharifi R, Ghosh L, Breemen RV R, Ashton D, Bowen PE. Oxidative DNA damage in prostate cancer patients consuming tomato sauce-based entrees as a whole-food intervention. J Natl Cancer Inst. 2001;93(24):1872-9.
45. Giovannucci E. A review of epidemiologic studies of tomatoes, lycopene, and prostate cancer. Exp Biol Med (Maywood). 2002 Nov;227(10):852-9.
|