Benign prostate hyperplasia (BPH) is a well-recognised men's health issue, although other important medicinal conditions should not be overlooked. Prostatitis syndromes — inflammation of the prostate gland — in general are responsible for 2 million visits to physicians per year in the United States, and prostate cancer is the second leading cause of death, accounting for 14 per cent of all cancer fatalities in men.1,2,3
Erectile dysfunction also shares a prominent place in any discussion on men's health, what with the blockbuster popularity of Viagra and its competitors. Therefore, this article will cover a broad range of topical trends regarding the application of nutraceuticals for the enhancement of men's health beyond the traditional focus on saw palmetto for BPH.
The prostate gland surrounds the bladder and neck of the urethra and provides a large proportion of the seminal fluid for the transport of sperm. Diseases of the prostate are the most common form of urinary problems in men and are often related to inflammation of the prostate, which impairs urine flow and increases the risk of infection.
A move toward clarification and identification of non-cancerous prostate conditions has occurred because of the lack of structural and functional abnormalities in many prostate conditions. One such condition is non-bacterial prostatitis, defined as demonstrating no leucocytes in prostatic secretions.4
Because of a traditional antibiotic treatment approach to all categories of prostatitis (including repeated antibiotic dosing, even if the known pathogen cannot be identified), the acquisition of anti-microbial resistance and negative changes in the gastrointestinal flora have been identified.5 These adverse treatment events have lead to a search for safe and efficacious nutritional-based remedies of prostatitis that are not bacterial in origin and do not respond to antibiotic treatment. Cernilton (Cernitin pollen extract) is one such treatment clinically evaluated in the treatment of chronic nonbacterial prostatitis.6 Twenty-four patients were treated with 6mg/day for six weeks and assessed for related pain/discomfort and quality of life using the Japanese version of the National Institutes of Health Chronic Prostatitis Symptoms Index (NIH-CPSI). Following supplementation, all scores were significantly lower in comparison to placebo and may be related to the antioxidant properties of the cernitin extract.
In a previous study, similar work studied cernitin's influence on nonbacterial prostatitis as well as on prostatodynia.7 Also known as chronic pelvic pain syndrome (CPPS), it is used loosely to designate any unexplained complaints of chronic pelvic pain and characterised by a lack of inflammation.
In a 1989 trial, 15 patients diagnosed as suffering with nonbacterial prostatitis or prostatodynia took 6mg cernitin pollen extract for one to 18 months. Of the 15 patients, only two failed to respond, with 13 showing lasting symptom relief or marked improvement. Although the mechanism of action is poorly understood, it is thought to be linked to both anti-androgenic and anti-inflammatory properties.
Quercetin belongs to a group of plant pigments called bioflavonoids that are largely responsible for the colours of many fruits. Because of the many therapeutic claims made in open-label trials, researchers from the Institute of Male Urology, California, ran a randomised, double-blind, placebo-controlled trial.8 Thirteen men with CPPS received either placebo or the bioflavonoid quercetin at a dose of 500mg twice daily for one month. Twenty percent of patients taking placebo and 67 per cent of supplementing patients had an improvement of at least 25 per cent in the Chronic Prostatitis Symptoms score. The use of quercetin was well tolerated in all subjects and provides significant improvement in prostate-related conditions.
Prostatic and gonadal cancer
As mentioned previously, carcinoma of the prostate is one of the most common forms of malignant disease in both Europe and the United States. The tumour is rare under the age of 50 with peak incidence occurring between the ages of 60 and 85 years and on the increase.
Lycopene found in food intakes has been shown to decrease the incidence of prostate cancers.9,10 A carotenoid highly concentrated in tomatoes, it has been shown to outperform a number of other carotenoids as well as some vitamins, such as vitamin E, in several antioxidant systems.11 Carotenoids have been hypothesis to exhibit anti-carcinogenic activities, most likely a result of a combination of cell-signalling mechanisms. These mechanisms have been suggested as modulation of differentiation, induction of apoptosis (programmed cell death) and stimulation of the immune system.12
A recent study examined the effects of tomato sauce on apoptotic cell death in BPH and carcinomas.13 Researchers had previously shown that tomato sauce extract consumed for three weeks decreased prostate specific antigen,14 a marker used to assess efficacy. The aim of this study was to further this work and assess directly the influence of tomato sauce (lycopene) on apoptotic cell death in patients diagnosed with BPH and prostate carcinomas. Thirty-two patients supplemented their diets with pasta sauce entrées (equivalent to 30mg lycopene per day) for three weeks prior to prostatectomy. Although supplementation increased the values of apoptotic cells in both BPH and carcinoma groups (circa 1.4 fold), and the large variability within the samples, no differences were evident in comparison to non-sauce-consuming controls.
Because patients did not receive pure lycopene, it is unknown whether the apoptotic effect was purely a product of lycopene consumption or whether other nutrients such as carotenoids, phytoene, photofluene or beta-carotene influenced morphological and/or histological markers of tumourigenesis. Antioxidants have been postulated that activation of anti-apoptotic mechanisms, such as NF-kappaB, surviving, and Bcl-2, is postulated to give cancers a growth advantage.15,16 New research from the University of Utah published this year has investigated the application of a combination therapy (vitamins C and E) on human prostate cancer growth.17 The aim of the trial was to study a combination of antioxidants as a means of enhancing apoptosis by suppressing inhibitors of apoptosis, such as survivin protein. Although a cell culture study, it does seem to indicate that the combination of antioxidants was more effective in inducing apoptosis and suppressing human prostate cancer cells than either alone. Further studies will no doubt aid in clarifying if there is any potential as a treatment in the prevention of human prostate cancers.
According to the National Institutes of Health, male infertility is involved in approximately 40 per cent of the 2.6 million infertile married couples in the United States. One half of these men experience irreversible infertility and cannot father children, and a small number of these cases are caused by a treatable medical condition,18 increased levels of occupational toxins,19 obesity20 and more commonly smoking.21 The nutraceutical industry has taken note, and research output for an effective treatment has increased substantially, particularly over the past three years.
Overproduction of reactive oxygen species (ROS) in the male genital tract can be generated by infiltrating white blood cells or spermatozoa and is one of the main causes of defective sperm function. Prostato-vesticulo-epididymitis (PVE) is associated with sexual gland post-inflammation damage as described by the biochemical markers above. Furthermore, compared to patients with prostatitis or prostato-vesticulitis, PVE has the lowest bacteriological cure rate (52 per cent). Previous studies have shown even following three courses of antibiotics, there remains evidence of infertility, dyspermia and ROS overproduction.22 Therefore, the search for pharmacologically active molecules that could provide anti-infectious and antioxidant properties may provide an effective treatment strategy in patients.23
Carnitine or acetyl-carnitine complexes appear to be reparable antioxidative nutrients applicable for post-inflammatory damage. Carnitine seems to influence cellular repair through the removal of toxic acetyl-coenzyme A and/or the replacement of fatty acids in phospholipid membranes.24
The influence of carnitine ingestion in the presence of pro-oxidant factors in abacterial PVE infertile patients was assessed in one study. Thirty-four patients with normal (group A) seminal white blood cell concentrations and 20 abnormal patients (group B) received 1g L-carnitine and 0.5g acetyl-carnitine two times per day for three months.25 Following a three-month washout, ROS production was decreased, sperm forward motility, and, more importantly, spontaneous pregnancy was significantly higher in group A than group B (11.7 per cent or four out of 34, compared to zero).
Although the percentage of viable spermatozoa was increased in group B, for patients with abnormal white blood cell concentrations, carnitine treatments were only effective in treating abacterial PVE and elevated ROS production when seminal white blood cell concentration is normal, based on pregnancy outcome.
Folate, which is mainly present in green leafy vegetables, is essential for DNA, transfer RNA and protein synthesis. Because DNA synthesis is a main part of spermatogenesis, folate is probably important to this process.
Because of these factors, researchers from the Netherlands have studied the effects of folic acid and zinc sulfate treatment on semen variables in fertile and subfertile men (those with suboptimal sperm qualities).31 One hundred and three subfertile and 108 fertile men were randomly assigned to receive one of four treatments for 26 weeks. A daily dose of 66mg zinc sulfate and 5mg folic acid were divided between the four groups, which consisted of folic acid and placebo (group 1), zinc sulfate and placebo (group 2), zinc sulfate and folic acid (group 3), and a placebo (group 4).
Of the subjects who completed the study, subfertile men demonstrated a significant 74 per cent increase in total normal sperm count and a minor 4 per cent increase of abnormal spermatozoa compared to placebo. A similar trend was observed in fertile men. These findings emphasise the importance of two micronutrients on spermatogenesis. However, whether the improvement in sperm concentration observed after administration of folic acid and zinc will lead to an increase in pregnancy rates remains to be established. Nevertheless, these findings suggest new avenues of future fertility research and treatment.
An alternative Viagra
The annual cost of erectile dysfunction (ED) in the United States, as estimated from the number of physician-related visits in 1985, was $146 million. This is largely due to the rapid escalation of the incidence of complete ED (5-15 per cent) between the ages of 40-70 years32 and of moderate ED from 17-34 percent within the same age range. From this data, an estimated 30 million men in the US are affected by some degree of ED.33 Researchers speculate that as the global population ages, the prevalence of ED will more than double within the next 25 years, affecting more than 330 million men worldwide.34 As such, the natural products industry has commercialised a selection of botanical and nutraceutical interventions to meet the market demand.
L-arginine is the body's natural substrate for the production of nitric oxide (NO), and impaired penile endothelial L-arginine NO activity appears to play a role in the pathogenesis of ED.35 Although the majority of studies using L-arginine to treat ED show positive treatment results,36 it is possible that other nitrogen-donating amino acids and peptides may be even more effective in generating NO.
Although there is much evidence to show L-arginine is an effective treatment for NO-related ED,37 little evidence indicates that arginine is the natural substrate for generating nitric oxide synthase (NOS) enzyme activity. Researchers from London's Imperial College School of Medicine investigated tissue sections bathed in a selection of amino acids and peptides on NOS activity including: carnosine, arginine, carnosine and arginine, histidine and histidine plus arginine.38
Peptides can influence NOS activity: 5mM carnosine increased NOS activity 29.2 per cent higher than that achieved by 5mM L-arginine. Of interest, the increase in NOS achieved by arginine can be achieved with five times less carnosine. The combination of these two potent NOS regulators demonstrated a 106 per cent increase in NOS activity. It is also interesting to note histidine alone increases NOS 46 per cent more than an equivalent concentration of carnosine.
Since it had been established that NOS existed and could utilise arginine to generate nitric oxide and is an effective treatment for ED, all subsequent studies on NOS used arginine for this purpose. The present data indicates that carnosine may be the natural, and far more effective, substrate for this purpose; moreover, it is more widely distributed in the human body than is free arginine.38 Therefore, the use of an arginine/histidine mixture may be the new NO-releasing combination for companies to pursue.
Icariin is a flavonoid isolated from the plant Epimedii herba, which is a traditional herb believed to enhance sexual function.39,40 Previous studies have indicated that icariin relaxed corpus cavernosum (CC) and significantly increased cGMP mediated nitric oxide release, suggesting a direct mechanism to enhance penile erection and ameliorate ED symptoms.41,42 A recent study aimed to further clarify the therapeutic mechanisms behind icariin,43 and the results indicated icarrin is a specific inhibitor of phosphodiesterase, a molecule that degrades cGMP (increased cGMP causes relaxation and vasodilation of the CC, causing erection). The authors of the paper concluded that icariin may be developed into an orally effective agent for treating ED. Pycnogenol is an extract of French maritime pine bark (Pinus pinaster), consisting of a mixture of active phytochemicals including procyanidins, catechin, taxifolin and large amount of phenolic acids.44 Pycnogenol has previously been shown to stimulate NOS for enhancing NO production.45
A study on 40 men 40-45 years old with confirmed organic ED were supplemented for three months with 0.57g L-arginine, three times daily (month one); 0.57g L-arginine, three times daily, plus 40 mg/twice daily pycnogenol (month two); and 0.57g L-arginine, three times daily, with pycnogenol increased to 40mg/three times daily (month three).46 By the end of month three, 92.5 per cent of patients recovered normal erectile function, showing a significant improvement in sexual function in men with ED.
Many other nutrients are suggested to increase sexual drive and/or influence erectile dysfunction: horny goat weed, yohimbine, maca, Panax ginseng and ginkgo. However, little clinical data supports many of these claims. Further solid research study designs are needed to evaluate clinical outcomes for ED, reproductive wellness (increased pregnancy rate), and prostate health (decreased incidence or increased survival rate).
As research begins to decipher the most beneficial and effective ingredients to treat these health issues, and male-specific marketing improves, it is likely that the men's health market will become a highly competitive category, reaching the staggering potential already devoted to women.
Mark J Tallon, PhD, is chief science officer of UK consultancy Oxygenics. www.oxygenix.com
All correspondence will be forwarded to the author.
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