Benign prostatic hypertrophy

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Chapter 26 Benign prostatic hypertrophy

Kieran Cooley, ND, MSc

AETIOLOGY AND EPIDEMIOLOGY

While benign prostatic hypertrophy of the prostate (BPH) (or more accurately benign prostatic hyperplasia) and erectile dysfunction (ED) are typically seen in the ageing male, these can occur at any age. Current understanding of the disease involves imbalanced states of androgens (particularly dihydrotestosterone [DHT]), oestrogens, insulin and insulin-like growth factor (IGF), and detrusor dysfunction of the bladder neck.¹ The chief complaint of patients with BPH is urinary frequency, urgency, nocturia, decreased and intermittent force of stream and the sensation of incomplete emptying of the bladder, although these symptoms are neither specific or necessary for the diagnosis of BPH and do not correlate with the extent or degree of hypertrophy of the prostate.¹ One study suggests that 20% of men in their 40s and 90% of men in their 70s have varying degrees of BPH,² although incidence rates for age groups vary depending on population demographics (some suggest 50% of men older than 60, and 80% of men over 80 years).³ Increasing age is the predominant factor associated with prevalence of BPH. Likewise, the incidence and prevalence of ED are also linked to age, with United States of America data suggesting a tripling of the incidence occurring between the ages of 40 and 70 years, and up to 66% of men having suffered from some erectile dysfunction (mild to complete) by the age of 70 years.⁴ Worldwide estimates suggest up to 330 million men could be affected by this disorder,⁵ although criticism exists pertaining to the over-medicalisation and resulting prescription rates for drugs providing only symptomatic relief for some age-associated disorders like ED.⁶ Conversely, both ED and BPH may suffer from under-diagnosis due to the symptomatic nature and psychological stigma associated with each of these diseases.⁷

Previously, diagnosis of BPH was thought to involve solely lower urinary tract symptoms (LUTS) syndrome; however, recent evidence suggests that LUTS is often due to anatomical disorders (detrusor muscle dysfunction)⁹ and that symptoms of BPH do not correlate well with prostate size. However, an enlarged prostate could contribute to detrusor dysfunction and urinary retention, often termed ‘LUTS-BPH’. Clinicians should note that not all men with BPH have LUT symptoms and LUTS is not specific or exclusive to BPH.

There is little certainty surrounding the exact pathogenesis of BPH. It is characterised by periurethral prostate tissue proliferation, which is indicated by an increase in the number (not size) of epithelial and stromal cells.¹⁰ This has been posited to be a relatively normal (or at least highly pervasive) process of ageing, often linked to the prostate tissue response to increase in androgens (dihydrotestosterone [DHT]) that occurs in the ageing male. Environmental exposure to hormone disruptors like xenoestrogens may result in a cascade of events that influence the development of dysfunctional regulation of testosterone, 17β-oestradiol and DHT (see Figure 26.1).¹⁰ The enzymes aromatase and 5-alpha reductase are involved in hormone regulation and these are often targets of both conventional as well as naturopathic treatment. Other evidence suggests that increased exposure to growth factors (insulin and insulin-like growth factor (IGF)) initiates the onset of hyperproliferation, ultimately leading to decreased urinary and vascular flow and an increased risk for ED, LUTS, prostatitis and prostate cancer, all of which can be associated disorders.¹ As the prostate enlarges, it causes discomfort in the groin and increased pressure on the bladder, leading to variable urine flow rates, frequent urination, nocturia and a sense of incomplete voiding. With chronicity or severity of enlargement, blockage of the urethra can occur, increasing the risk for urinary tract infections, bladder stones and possible kidney damage.

Figure 26.1 Hormonal factors in BPH

Source: Rakel D, ed. Integrative medicine. 2nd edn. Philadelphia: Saunders, 2007.

In 2001 a landmark paper suggested a link between ED, BPH, cardiovascular disease and depression in the ageing male,¹¹ supporting earlier suggestions linking some of these disorders to vascular function.¹² Since then, further evidence has confirmed a strong correlation among these disorders, with significantly higher prevalence rates of any of the listed conditions when a comorbidity from any of the other disorders exists. The correlation is particularly strong between BPH and ED, possibly due to a shared vasculogenic pathophysiology, revolving around atherosclerosis and endothelial dysfunction or injury, in production of nitric oxide (NO).¹³ Other factors associated with cardiovascular disease and/or depression (such as central obesity, increased circulating levels of insulin, diabetes, decreased physical activity, hypertension and increased oxidative stress) are also implicated in the state that promotes the hyperproliferationof prostatic tissue and decreased functioning of circuitry relating to achieving an erection.^14,¹⁵

RISK FACTORS ^1,^3,¹⁶

Several factors may promote BPH/LUTS, whereas other influences may have a protective effect (see Figure 26.2). The following is a list of potential risk factors and indicators of BPH:

• Urethral structure as a result of recurrent urinary tract infection, bladder infection or trauma or bladder neck contractions (congenital or acquired) can induce LUTS and stimulate the onset of hyperproliferation.

• Comorbid conditions such as cardiovascular disease, erectile dysfunction and depression are also implicated in increased incidence or potential for earlier onset of BPH.

• Increased serum prostate-specific antigen (PSA) can be indicative of BPH, but it is neither sensitive nor specific to BPH although monitoring change in this marker over time gives some small clinically relevant indication of prostate status or change. Suggested PSA levels that may indicate a hyperproliferative prostate are > 1.6 ng/mL for men in their 50s, > 2.0 ng/mL for men in their 60s and > 2.3 ng/mL for men in their 70s.

• A positive digital rectal exam is the strongest indicator of BPH and regular screening is recommended in men over 50 years old or those exhibiting symptoms.

Figure 26.2 Factors affecting BPH or LUTS

CONVENTIONAL TREATMENT

Conventional treatment of BPH varies often begins with ‘watchful waiting’ if the symptoms are mild. Alpha-blockers (alfuzosin and tamsulosin) are often selected for decreasing sympathetic tone with minimal change in blood pressure to give LUT symptom relief and are often employed in those without significantly raised levels of PSA.^1,16 5-alpha reductase inhibitors (finasteride or dutasteride) inhibit the conversion of testosterone to DHT and are the most frequently prescribed treatment, sometimes in conjunction with alpha-blockers with greater success. If symptoms are severe, there is a long history of smoking or risk factors for cancer, or PSA levels are relatively high, surgical removal of the prostate (transurethral resection of the prostate or TURP) may be indicated.

KEY TREATMENT PROTOCOLS

A comprehensive strategy addressing cardiovascular risk and reduction of inflammation is required to address the underlying vascular cause. Additional strategies to provide symptomatic relief from LUTS are necessary for short-term management of this debilitating disorder. The initial approach in treating this disorder is always to assess the lifestyle of the patient and recommend judicious and achievable adjustments when required.

NATUROPATHIC TREATMENT AIMS

• Address risk factors including achievement of healthy weight and increased physical activity.

• Regulate hormones, particularly through aromatase and 5-alpha reductase as well as environmental sources of hormones.

• Address symptom relief and quality-of-life issues.

• Protect endothelial function through decreasing inflammation, improving NO production.

• Address latent, recurrent or chronic infection and sources of oxidative stress.

Lifestyle and exercise modification

As mentioned above, lifestyle modification is an important protocol in treating BPH and ED. Observational studies indicate that there is a positive association between abdominal obesity and BPH,^17,¹⁸ and an inverse association between physical activity and BPH.^19,²⁰ Diets high in fats or in calories may encourage abdominal obesity and sympathetic nervous system activity, both of which can increase the risk of BPH. Sympathetic nervous system activation (which is the ‘fight or flight’ arm of the autonomic nervous system) may cause the prostate smooth muscle to contract, resulting in a worsening of lower urinary tract symptoms. Studies suggest that there is no increased risk of BPH with higher caloric intake when accompanied by increased physical activity.¹⁸ With respect to ED, weight loss, physical activity, smoking cessation and decreased sympathetic activity (relaxation) have also been suggested as beneficial treatments.²¹ Dietary sources of caffeine and other diuretics should be reduced, and fluid intake monitored to reduce nocturia and urinary output to the bladder from the kidneys.

Three potential mechanisms for physical activity and decreased risk for BPH and ED may be proposed:

1. It may increase blood flow to the area, allowing the body to remove wastes efficiently.

2. It may decrease sympathetic stress responses, thus relaxing prostatic tissue.

3. It may reduce excess abdominal weight, increasing overall lower body pressure, thus relaxing the prostate and rectal region and improving blood flow into and out of the area.

Nutritional hormonal modulation (5-alpha reductase, aromatase, dihydrotestosterone and oestrogen)

Clinicians should consider dietary strategies to modulate hormones, hydroxylation of DHT and maintain healthy cholesterol and cardiovascular states; these strategies include avoiding sources of pesticides,²² increasing fruit consumption, increasing the intake of zinc and essential fatty acid, decreasing butter consumption, avoiding margarine,²³ decreasing coffee consumption²⁴ and keeping cholesterol levels below 200 mg/dL.²⁵

Inconclusive evidence exists regarding protein intake and BPH. Some research demonstrates that a high-protein diet (total calories made up of 44% protein, 35% carbohydrate and 21% fat) can inhibit 5-alpha reductase, while a low-protein diet (10% protein, 70% carbohydrate and 20% fat) may stimulate the enzyme.²⁶ Contrary to this evidence, a large 8-year observational study of 3523 men with BPH suggests that total protein intake is positively associated with BPH, with the association being slightly stronger for animal protein intake than for vegetable protein intake.¹⁸ A second epidemiological study based in China also revealed a correlation between higher animal intake and the incidence of BPH (91.1% in those eating high animal diets as opposed to 11.8% in those not eating animal protein).²⁷

Authors of these studies suggest that a high protein intake may result in a greater osmolar load, which may be one possible mechanism for its detrimental effects on symptoms of BPH. This will increase urinary output and thus impose undue extra burden on an already partially obstructed or strained elimination system.¹⁸ Consistent with an anti-inflammatory approach, a diet high in quality, plant-derived and coldwater fish-based protein sources in moderate amounts seems prudent, given the current evidence.

Zinc supplementation has reduced the size of the prostate (confirmed by rectal palpation, radiography and endoscopy) and reduced overall symptomatology in the majority of patients with BPH in studies conducted in the 1970s as well as recently.²⁸ The clinical efficacy of zinc is probably due to its critical involvement in many aspects of androgen metabolism. High amounts of oestrogen can inhibit intestinal uptake of zinc, whereas elevated androgens increase absorption. Because oestrogen levels are increased in men with BPH, zinc uptake may be low, suggesting a higher functional need for this nutrient and begging the need for additional supplementation.^29,³⁰ However, one case-control study suggested a positive association between zinc levels and BPH.³¹ This deviation from other research may be partially explained by dietary confounding factors.

The relationship between zinc levels and 5-alpha reductase activity in hyperplastic prostates is inconsistent; however, zinc has been shown to inhibit the activity of 5-alpha reductase, and decreases the conversion of testosterone to DHT.³²^–³⁵ Zinc can also inhibit specific binding of androgens to the cytosol and nuclear androgen receptors present in high amounts in prostatic tissue.³² These mechanisms suggest that zinc has more of a preventative role by maintaining a nutritional status that discourages prostate hypertrophy. No interventional studies investigating the use of zinc for BPH exist, although observational studies suggest it has a safe and effective role in diminishing the size of the prostate, particularly for prostate cancer, although one study suggests it can increase urinary symptoms.³⁶^–⁴⁰

Zinc is also involved in the regulation of prolactin secretion, leading to increased uptake of testosterone and subsequent rise in DHT in the prostate.⁴¹^–⁴³ Natural (from beer, stress and tryptophan)^44,⁴⁵ and pharmaceutical prolactin antagonists (bromocriptine)⁴⁶ have been shown to reduce many of the symptoms of prostatic hyperplasia. However, this strategy can have severe side effects, particularly pertaining to cardiovascular and neurological systems, including severe changes in mood.^47,⁴⁶

A 100 g serving of soybeans or soy products contains 90 mg of beta-sitosterol, which has been shown to decrease cholesterol; this is a potential mechanism for soy’s effect on BPH. The cholesterol-lowering effects of phytosterols are well documented,^48,⁴⁹ while also showing an effect on treating BPH.⁹ One double-blind study⁵⁰ in 200 men using beta-sitosterol (20 mg) or placebo three times daily demonstrated an increase in the maximum urine flow rate from a baseline of 9.9 mL/s to 15.2 mL/s and a decrease in mean residual urinary volume of 30.4 mL from 65.8 mL in the beta-sitosterol group. No changes were observed in the placebo group. An increased consumption of soy and soy foods is associated with a decrease in the risk of prostate cancer,^51,⁵² which is associated with the incidence of BPH. Phytoestrogens in soy (isoflavonoids, genistein and daidzein), as well as Trifolium pratense are implicated due to their effect on oestrogen receptors^51,⁵³ and inhibition of 5-alpha reductase.⁵⁴ Other sources of beta-sitosterols such as Hypoxis hemerocallidea may also be of benefit, although many of these studies are lacking in the rigour of reporting including dose and method of extraction as well as adverse-event reporting.⁵⁵ Clinical use of these substances may be most appropriate for men with BPH in the ‘watchful waiting’ stage of the condition⁵⁶ with clinically effecting doses of beta-sitosterol ranging from 60–130 mg daily.^57,⁵⁸

One study ⁵⁹ suggested that 60 mg twice daily of the dried, ground flowers of Opuntia spp. over 2 to 6 months was effective at reducing urinary urgency and the sensation of a full bladder, although this remains to be repeated in other studies and stands as preliminary evidence.

The diet should be as free as possible from environmental toxins such as pesticides and other contaminants because many of these compounds (such as dioxin, polyhalogenated biphenyls, hexachlorobenzene and dibenzofurans) increase 5-alpha reduction of steroids.²⁶ Diethylstilbestrol produces changes in rat prostates histologically similar to BPH.⁶⁰ While cadmium is a known antagonist of zinc and can influence testosterone levels through effects on the activity of 5-alpha reductase, its concentration in, and effects on, the prostate are unclear. Several studies have produced conflicting results.^61,⁶²

Herbal hormonal modulation (5-alpha reductase, aromatase, dihydrotestosterone and oestrogen)

During the 1990s, botanical medicine in Germany and Australia were considered ‘first-line’ treatments for BPH and accounted for greater than 90% of all drugs in the medical management of BPH.⁶³ In Italy, plant extracts accounted for roughly 50% of all medications prescribed for BPH, while alpha-blockers and 5-alpha reductase inhibitors account for only 5.1% and 4.8%, respectively.⁶⁴

Clinical success with any of the botanical treatments of BPH may be determined by the degree of obstruction as indicated by the residual urine content.^1,²² For mild LUTS symptoms and residual urine levels less than 50 mL, the results are usually excellent. For levels between 50 and 100 mL, the results are usually quite good. Residual urine levels greater than 100 mL will be more difficult to produce significant improvements in the customary 4- to 6-week period without co-management using other therapies including pharmaceuticals, and with botanical medicine adding little to the overall reduction in symptoms within a 4–6 week period. One small (n = 40) but well-designed clinic-based research study investigating the open use of phytotherapy for LUTS/BPH demonstrated a statistically significant superiority of phytotherapy use (as both adjuvant to pharmacological treatment or as a stand-alone) over use of alpha-blockers to reduce urinary retention, and improve erectile and ejaculatory dysfunction.⁶⁵ Adulteration and/or contamination in herbal products for erectile dysfunction is relatively widespread^66,⁶⁷ particularly in ‘commercial’ natural health products in some countries. As with usual prescriptions, clinicians should ensure that patients are accessing high quality products.

The liposterolic extract of the fruit of Serenoa repens, native to Florida in the USA, has been shown to significantly improve the signs and symptoms of BPH in numerous clinical studies. The mechanism of action is postulated to be related to inhibition of DHT binding to both the cytosolic and the nuclear androgen receptors, inhibition of 5-alpha reductase, interference with intraprostatic oestrogen receptors and an anti-inflammatory effect.¹⁰ As a result of this multitude of effects, positive results have been produced in numerous double-blind clinical studies. However, different extracts of S. repens (permixon) may have more of an anti-inflammatory mechanism of action in modulating BPH;^63,⁶⁶^–⁷⁰ clinicians should be mindful of these differences in therapeutic action from the myriad of extraction methods used in natural health products and the multifaceted effects of herbal medicines, particularly S. repens.⁶⁸

Synthesis research, including systematic reviews of clinical trials, has previously reported excellent results using S. repens.^71,⁷² One examination of 21 randomised, controlled trials involving a total of 3139 men (including 18 double-blind trials) demonstrated that men treated with S. repens experienced decreased urinary tract symptom scores, less nocturia, better urinary tract symptom self-rating scores and peak urine flow improvements compared with men receiving placebo.⁷¹ This analysis also showed that, matched up with men receiving the DHT inhibitor finasteride (Proscar), men treated with S. repens had similar improvements in urinary tract symptom scores and peak urine. A related review also reported that adverse effects due to S. repens were mild and infrequent with erectile dysfunction appearing more frequently with finasteride (4.9%) than with S. repens (1.1%).⁷² However, a recent update to this Cochrane review, which included nine new studies comparing S. repens to either placebo or finasteride, demonstrated no significant benefit for treating any symptoms of BPH except nocturia.⁷³ The large variability in patient population, severity of disease and extraction or source of S. repens, as demonstrated by a lack of heterogeneity between studies and wide confidence intervals for outcomes, highlights some of the challenges in herbal medicine research when applying research results to individuals. At the same time, these results indicate that clinical success in using serenoa for BPH is variable, with the greatest likelihood for improvement occurring in men with mild to moderate symptoms receiving treatment within the first 4–6 weeks of onset.

Overall, it can be stated that some men with mild to moderate BPH experience some improvement in symptoms during the first 4 to 6 weeks of therapy using S. repens. All major symptoms of BPH are improved, especially nocturia. And despite an efficacy profile similar to finasteride for mild to moderate severity, serenoa has a lower risk profile and is less expensive.⁷⁴ The most common side effect is gastrointestinal distress, and this is easily remedied by taking S. repens with food.

Cernilton®, a proprietary combination of water-soluble and acetone-soluble extract of Secale cereale, has been used to treat prostatitis and BPH for years in Europe.^75,⁷⁶ Several short clinical studies and one systematic review suggest it to be beneficial in the treatment of BPH,⁷⁷^–⁸³ with patients reporting moderate improvement. Patients who respond typically have reductions of nocturia and diurnal frequency of around 70%, as well as significant reductions in residual urine volume. The extract has been shown to exert some anti-inflammatory action and produce a contractile effect on the bladder while simultaneously relaxing the urethra.⁸⁴

In one study, the clinical efficacy of Cernilton® in the treatment of symptomatic BPH was examined over a 1-year period.⁷⁶ Seventy-nine males of an average age of 68 years (range 62 to 89), with a mean baseline prostatic volume of 33.2 cm², were administered 63 mg Cernilton® pollen extract twice daily for 12 weeks. Average urine maximum flow rate increased from 5.1 to 6 mL/s. Average flow rate increased from 9.3 to 11 mL/s. Residual urine volume decreased from 54.2 mL to less than 30 mL. Urgency and discomfort improved by 76.9% with dysuria, incomplete emptying, intermittency, delayed or prolonged voiding all having 60–70% improvement. Nocturia improved by 56.8%. Overall, 85% of the test subjects experienced benefit, 11% reporting ‘excellent’, 39% reporting ‘good’, 35% reporting ‘satisfactory’ and 15% reporting ‘poor’ as a description of their outcome.

A systematic review conducted in 2000 compiling two placebo-controlled studies, two comparative trials (both lasting 12 to 24 weeks) and three double-blind studies of 444 men showed that, although Cernilton® did not improve urinary flow rates, residual volume or prostate size compared with placebo or the comparative study agents, it did improve self-rated urinary symptom scores and reduced nocturia compared with placebo.⁸¹ Again, this review highlights some of the variability in evidence for the use of this herbal extract with the chances of clinical success in using this as a stand-alone treatment remaining unclear.

Extracts from the bark of Pygeum africanum used in research studies are fat-soluble sterols and fatty acids. Virtually all of the research on pygeum has featured a pygeum extract standardised to contain 14% triterpenes including beta-sitosterol and 0.5% n-docosanol. The suggested therapeutic action has been suggested to be due, in part, to the inhibition of growth factors EGF, bFGF and IGF-I, which are responsible for the prostatic overgrowth.^85,⁸⁶

Clinical trials totalling more than 600 patients have demonstrated pygeum extract to be effective in reducing the symptoms and clinical signs of BPH, especially in early cases.^86,⁸⁷ The research studies suggest pygeum having a superiority in objective parameters, especially urine flow rate and residual urine content, over saw palmetto. However, as the two extracts have somewhat overlapping mechanisms of actions, they can be used in combination.

Lepidium meyenii (maca) is a root belonging to the brassica family traditionally known for its aphrodisiac properties in both men and women.⁸⁸ A recent randomised, double-blind placebo-controlled trial demonstrated a subjective improvement on the International Index of Erectile Function (IIEF-5) and Satisfaction Profile (SAT-P) using 2400 mg/day of dry extract of maca compared to placebo.⁸⁹ Although both groups improved significantly from baseline self-rated psychological performance scores, there was a statistically significant superiority in the maca group in physical and social performance. This represents a small but statistically significant clinical effect from using this dose of maca in men with mild erectile dysfunction. Two other randomised, placebo-controlled studies with limited information suggest that 1.5 and 3 g/day dose of maca can improve erectile dysfunction without altering testosterone levels in men with this disorder.^90,⁹¹ Further research is necessary to better determine the mechanism of action, the clinical relevance and optimal dose and constituents in maca for use in erectile dysfunction. No clinical evidence exists for the use of maca for treating BPH.

Extracts of Urtica dioica have also been shown to be effective in the treatment of BPH, although less research evidence exists compared to other botanical medicines. A number of long-term, double-blind studies have shown it to be more effective than a placebo, with no adverse effects reported.^92,⁹³ A randomised, multicentre, double-blind study in 431 patients using extracts of both serenoa and U. dioica found clinical benefit equal to that of finasteride,⁹⁴ with a larger, second study lasting 24 weeks confirming its benefit in reducing residual urine and improving peak flow.⁹² A similar therapeutic action between urtica and serenoa extracts appears to exist in that each interact with binding of DHT to cytosolic and nuclear receptors.⁹⁵ Other in vitro studies also show that lignans found in U. dioica may modulate hormonal effects due to their affinity for sex hormone-binding globulin.⁹⁶

In vitro studies of Epilobium spp. suggest steroid receptor and aromatase inhibition activity as well as potent cyclo-oxygenase-2 (COX-2) and antioxidant potential, so this herb could theoretically be used in BPH.^97,⁹⁸ Other cell-line research supports this and elucidates the antihyperplastic and potential anticancer action of Epilobium parviflorum extract (oenothein B) as a potent inhibitor of DNA synthesis in a human prostate cell line. Aqueous extracts have also demonstrated plausible COX-2 action,⁹⁹ although ethanolic extracts appear to have the most potential inhibitory action on this enzyme linked to inflammatory pathways.¹⁰⁰ These results have yet to be duplicated in clinical trials.

Inflammation

While limited, some studies suggest that the inflammatory process including the production of cytokines (interleukin 1 and 6, and tissue necrosis factor alpha) increases prostatic tissue proliferation.^63,⁷⁵ Other research links the presence of platelet-derived growth factor (PDGF) (produced during the inflammatory processes) and androgens with the incidence of BPH and hyperproliferation of prostate cells.^101,¹⁰² In these studies, DHT failed to produce a mitogenic response in prostate cells without the presence of PDGF.

In a large, Italian, case-control study essential fatty acids (EFA) consisting of linoleic, linolenic and arachidonic acids have resulted in significant improvement for many BPH patients.¹⁰³ All 19 subjects in an uncontrolled study showed diminution of residual urine, with 12 of the 19 having no residual urine by the end of several weeks of treatment. Prostatic and seminal lipid levels and ratios are often abnormal,¹⁰⁴ and supplementation may be addressing an underlying EFA deficiency. Cell-line research suggests differences in essential fatty acid composition in hyperplastic or cancerous prostate cells.^105,¹⁰⁶ Because of concern regarding increased oxidation of unsaturated acids,¹⁸ a basic antioxidant regimen should be employed when taking EFAs.

The role of tomatoes, tomato sauce and lycopene in BPH is not clear; however, epidemiological and population-based studies suggest that their consumption is linked to decreased incidence of BPH,¹⁰⁶ a reduction in PSA levels,¹⁰⁷ and decreased progression of BPH to prostate cancer.¹⁰⁹ The therapeutic action of lycopene in this disorder may be due to its potent antioxidant properties.

Sympathetic nervous system hyperactivity

Reduction of urethral stricture and relaxation of smooth muscles is aided by parasympathetic stimulation or parasympathetic mimetic agents.¹¹⁰ Reduction in sympathetic nervous activity and/or parasympathetic stimulation may aid in LUTS symptom relief, as evidenced by some studies suggesting that a combination of glycine, alanine and glutamic acid (in the form of two 6-grain capsules administered three times daily for 2 weeks and one capsule three times daily thereafter) relieved many BPH symptoms. Nocturia was relieved or reduced in 95%, urgency reduced in 81%, frequency reduced in 73% and delayed micturition alleviated in 70% in one study¹¹¹ with similar results reported in other controlled studies.¹¹² The mechanism of action is unknown. These amino acids may act as inhibitory neurotransmitters, providing symptom relief and reducing the feelings of a full bladder, or providing an overall nervine function that can positively affect urine flow in men suffering from BPH.¹¹³

While no clinical evidence supports the use of hops (Humulus lupulus), the antiproliferative effects of flavonoids on prostate cancer cell lines, as well as its nervine and parasympathetic action, may warrant further research and clinical benefit.^68,¹¹⁴ Other nervine and antispasmodic botanical medicines may have a potential supportive role in managing BPH; examples are Scutellaria lateriflora and Passiflora incarnata. However, no studies have presently been conducted to assess this potential.

Vascular functioning

Chronic ischaemia can result in thickening of the prostate and growth of tissue in response to an altered endothelial growth factor resulting from the diminished blood supply.¹¹⁵ Atherosclerosis and diminished blood supply appear to be potential root causes in BPH and ED. Improving vascular function via herbal and nutrient interventions (discussed in the ED section), managing cholesterol and moderating alcohol consumption, in addition to dietary strategies to address cardiovascular risk, will possibly prove beneficial (see Section 3 on the cardiovascular system).

In addition to epidemiological studies suggesting a relationship between higher cholesterol levels and cardiovascular disease with higher incidence of BPH and ED, the breakdown products of cholesterol itself can also be cytotoxic and carcinogenic and have been shown to accumulate in hyperplastic or cancerous prostate tissue.¹⁰⁴

Hypocholesterolaemic (statin) drugs have been shown to have a favourable influence on BPH possibly by limiting subsequent formation of epoxycholesterols (metabolic by-products of cholesterol).¹¹⁶ As discussed above, the regulation of cardiovascular risk factors (such as elevated LDL and total cholesterol) and decreased HDL may help in the holistic prevention and treatment of BPH.

Although only beer has been associated with increasing prolactin levels, higher overall alcohol intake may be associated with BPH. In a large Hawaiian study involving 6581 men, an alcohol intake of at least 740 mL/month was directly correlated with the diagnosis of BPH,³¹ with a stronger association for beer, wine and sake compared with distilled spirits. While this indicates a relationship in incidence, a smaller study suggested that men waiting for TURP surgery were more likely to avoid the surgical procedure (having remission of symptoms) with higher consumption of alcohol.²⁴ This study also described the correlation of higher rates of BPH in men with coronary disease. Although these studies are apparently contradictory in relationship to alcohol, it is possible that in men at higher risk for coronary artery disease due to higher levels of low-density lipoproteins, alcohol may play an overall protective role by reducing these lipoproteins.

INTEGRATIVE MEDICAL CONSIDERATIONS

The severity of the symptoms will dictate whether surgery or catheterisation is necessary for acute urinary obstruction. Counselling may be necessary to address the psychological issues of sexual dysfunction. Progression of BPH to prostate cancer is of concern and should be monitored appropriately using regular DRE with possible PSA testing. Acupuncture and moxibustion can increase blood flow, and some studies have provided evidence that it may be considered as a viable adjunctive treatment,¹³³^–¹³⁵ particularly when combined with hypnotherapy.¹³⁶ Numerous studies on the effect of acupuncture on urinary frequency have been conducted; however, no studies exist on the use of acupuncture for BPH specifically, and many of these studies involve ageing women.¹³⁷^–¹⁴¹ Other studies suggest trigger point release therapy and relaxation as being beneficial for addressing ED and BPH, particularly if chronic pelvic pain is involved.¹⁴² Counselling and psychiatry may be beneficial for addressing the psychological roots or manifestations of ED and the symptoms of BPH. Pelvic floor (kegal) exercises have been shown to be beneficial in up to 35% of ED patients^143,¹⁴⁴ with some potential shown for their ability to improve urinary function.¹⁴⁵

Figure 26.3 Naturopathic treatment decision tree—benign prostatic hypertrophy

ERECTILE DYSFUNCTION

Overview

• Erectile dysfunction is classified as organic (circulatory or a side effect of medication, particularly anti-depressant or neurogenic) or psychological.¹¹⁷

• Significant psychosomatic or mind/body connections affect this disorder.¹¹⁸

• Normal erectile function involves a balance between excitatory and inhibitory psychological, vascular and neural responses,^12,¹¹⁹ involves release of nitric oxide (NO) gas into the endothelial cells of the penis and causes the subsequent relaxation of smooth muscle cells lining the corpus cavernosum so that there is increased blood to flow into the organ and retention of blood in the spongy erectile tissue.

• Parasympathethic nervous activity and conversion of guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP) by the enzyme guanylate cyclase.⁸ An erection subsides when cGMP is hydrolysed by phosphodiesterase type 5 enzymes (PDE5), causing smooth muscle contraction and emptying of the corpus cavernosum.

• Screening and diagnostic evaluation should include a complete patient history to identify the presence of comorbid conditions, particularly diabetes, dyslipidaemia and hypertension ¹¹⁹ as well as assessment of any neurological or circulatory obstacles to proper innervation of the pelvic area.

Conventional treatments

Conventional treatments focus on providing symptomatic relief through pharmacological substances (phosphodiesterase type-5 (PDE-5) inhibitors such as sildenafil or tadalafil) as first-line therapy, removing causative agents (the side effects of beta-adrenergic blockers, antidepressants or spironolactone), and counselling.^13,¹²¹

CAM treatments

Arginine

Three small, pilot, randomised, controlled studies provided relative support for the clinical effectiveness of L-arginine in doses ranging from 1500 mg—5 g/day used over a 2–6-week period for ED.¹²²^–¹²⁴ While the study¹²³ using 1500 mg/day for 2 weeks did not demonstrate a significant benefit over placebo, the other two studies demonstrated a 20–40% self-reported improvement in symptoms of ED. It is unclear whether foods rich in L-arginine such as legumes, whole grains and nuts consumed in moderate-to-large amounts would have a similar effect. Other studies using L-arginine in combination with other natural substances such as pycnogenol¹²⁵ or yohimbine¹²⁶ generally supported the notion that L-arginine can have some positive effect on the symptoms of erectile dysfunction; however, further research is necessary.

Herbs

Panax ginseng has the most promising evidence for safe and effective treatment of ED, with 900 mg/day for 8 weeks showing clinical and physiological effectiveness in up to 60% of men with ED.^8,¹²⁷ Yohimbine (5.4 mg t.i.d. for 8 weeks) also shows promising results, although significant side effects associated with its therapeutic action as an alpha-2-adrenergic receptor make it a less desirable treatment option.¹²⁸ Based on vasodilatory actions, Ginkgo biloba may benefit some men where penile blood flow is impaired (however, the clinical evidence is mixed).^129,¹³⁰ Tribulus terrestris may be a viable option to treat ED, via increasing the release of nitric oxide from the endothelium and nitrergic nerve endings in penile tissue (clinical studies have not yet, however, confirmed its efficacy).^131,¹³²

Example treatment

Urinalysis was performed to rule out urinary tract infection and patient was advised that the urogenital health of his partner is necessary for a healthy sexual relationship. Patient was advised to increase physical activity, including a mix of aerobic and anaerobic activity for at least 30 minutes three times per week to address mood, weight loss, blood flow and cardiovascular risk. The treatment rationale was aimed at regulating androgens and addressing inflammation using an aggressive dose of Serenoa repens, Cernilton®, Pygeum africanum and zinc, address urinary tract symptoms using stinging nettle, and 1 tablespoon of flaxseed oil two times/day to address inflammation and cardiovascular risk markers. Dietary advice was given, including consumption of a diet high in soluble fibre to help address cardiovascular risk and regulate weight, consume 100 g of soy products (soybeans or tofu) each day to assist hormone regulation, and increase fruit consumption to facilitate hydroxylation and elimination of DHT. Other prescriptive options include increased consumption of pumpkin seeds, which are sources of essential fatty acids and zinc. Limit alcohol consumption, particularly beer. Regulation of androgens and hormones may take up to 2 months and patients may need additional or integrative support to manage symptoms while addressing the root cause. Acute catheterisation if urine outflow is sufficiently obstructed, or co-management using alpha-blockers to address symptoms that significantly affect quality of life (nocturia and urinary frequency), may be necessary.

Herbal prescription

Urtica dioica (radix) 1:2	35 mL
Epilobium spp. 1:2	35 mL
Pygeum africanum 1:2	30 mL
5 mL t.d.s.	100 mL

Serenoa repens tablets 160 mg b.d.

Flower pollen extract (e.g. Cernilton®) 63 mg two or three times/day

Nutritional prescription

Flaxseed oil 1 tbsp two times/day

Zinc amino acid chelate 50 mg/day

High-fibre diet including 100 g of soy products each day

Expected outcomes and follow-up protocols

If PSA levels are used as one means of monitoring prostate health, this test should be done once every 6 months (especially if there is a significantly enlarged prostate on digital rectal exam). Reassessment of symptoms of BPH should occur every 6 weeks if moderate, and at least every 4 weeks if severe. Patients should keep a diary of daily trips

Table 26.1 Review of the major evidence

to the toilet, fluid intake and attempts to collect urine output, as a means of assessing the effectiveness of treatment as well as whether adjunctive or emergency care is warranted.

Improvements to ED may take time, particularly if there is a strong psychological component, and a discussion with the patient that encourages realistic expectations for changes but that adds no undue pressure should take place. Individual or couples counselling may be warranted. If the root cause of BPH and ED is likely to be vascular in origin, and there are no signs or diagnostic tests indicating hypertension, infection, hormone abnormalities or inflammation, 3 g/day of L-arginine could improve ED as well as circulation. If no improvements occur within 3 months, other therapeutic options include removal of the potential sources of inflammation in the diet, supplementation using glycine, alanine and glutamic acid (6 g/day), and the use of herbal medicines such as Epilobium spp. for BPH and Ginkgo biloba or Tribulus terrestris for ED.

KEY POINTS

• BPH shares many properties with cardiovascular, erectile dysfunction, depression and urinary tract infection disorders.

• The holistic treatment approach should look beyond hormonal regulation and include therapies to reduce inflammation, reduce oxidative stress and improve nitric oxide production.

• BPH is predominantly an androgen-mediated disorder. Factors that decrease the production of dihydrotestosterone should be included in most treatment protocols.

• Counselling to address issues of ageing, mood and sexual health may be important in moderating quality of life and the mental/emotional aspects of these diseases.