Molecular Mechanisms of Nutritional Interventions and Supplements for the Management of Sexual Dysfunction and Benign Prostatic Hyperplasia

Molecular Mechanisms of Nutritional Interventions and Supplements for the Management of Sexual Disfunction and Benign Prostatic Hyperplasia presents the epidemiologic data linking diet with BPH and ED, along with a deep explanation on why nutritional approaches and different macronutrients may modify the pathogenesis of the disease. Coverage includes the relevance/epidemiology of the disease, pathophysiological events causing the disease, available therapeutic options, molecular mechanisms of action of available treatments, epidemiological and intervention studies suggesting the benefit of diet as therapeutic option for BPH and ED, and potential mechanisms of action of nutritional based approaches as treatment for BPH and ED.

By combining medicine, diet and lifestyle options, this title provides a truly multidisciplinary approach to BPH and ED, making it a unique resource for those treating BPH and an irreplaceable reference guide for those in research.

• Provides a comprehensive review of lifestyle factors and their contributions to BPH and ED pathogenesis
• Includes a comprehensive review on the effect of different dietary patterns on BPH and ED pathogenesis and whether dietary modifications may be a viable treatment option
• Reviews herbal supplements, vitamins and minerals commonly used to treat BPH and ED, with an emphasis on safety and efficacy
• Describes lifestyle interventions that have been demonstrated to confer benefits to patients with BPH and ED

• Language: English
• Publisher: Academic Press
• Release date: Aug 7, 2021
• ISBN: 9780128226025

Book preview

Chapter 1

Introduction to benign prostatic hyperplasia

Julia Klein, Michelina D. Stoddard and Bilal Chughtai,    Department of Urology, Weill Cornell Medical College, New York, NY, United States

Abstract

This chapter introduces the epidemiology, risk factors, and pathophysiology of benign prostatic hyperplasia (BPH) in adult men. It starts by introducing the magnitude of BPH in the American population and presenting an overview of how BPH leads to bothersome lower urinary tract symptoms (LUTS) in many affected men. It then discusses the epidemiology of the condition and literature-supported risk factors. Next, our current understanding of the pathophysiological mechanisms that contribute to BPH is explored. The workup involved in making a diagnosis of BPH is briefly explained, followed by a broad discussion of treatment options, including medical and surgical options. Finally, an introduction to the relationship between BPH and diet is presented. By the end of the chapter, several key topics critical to understanding the scope of BPH are explained.

Keywords

Benign prostatic hyperplasia; BPH; prostate enlargement; lower urinary tract symptoms; LUTS; inflammation; metabolic syndrome

Introduction and epidemiology

Benign prostatic hyperplasia (BPH) is a common condition that affects a large number of older adult men in their lifetime. It is the second most common condition managed by urologists after urinary tract infection (UTI), representing 23% of all urology office visits [1,2]. It is known to have a high burden on quality of life, scoring similar to asthma and epilepsy on health-related quality-of-life measures [3].

BPH is a histological diagnosis indicated by the presence of stromal and epithelial hyperplasia in the transition zone of the prostate. The incidence of BPH is known to increase with age. One study by Berry et al. determined that BPH affects roughly 8% of men aged 31–40, 50% of men aged 51–60, and 90% of men over the age of 81 [4]. BPH results in benign prostatic enlargement, which causes compression of the urethra and impairment in urinary flow, also known as bladder outlet obstruction (BOO). BOO can lead to clinically significant lower urinary tract symptoms (LUTS) that are often associated with BPH. BPH is one of the most common causes of LUTS in men. LUTS are broadly classified into three categories: urinary storage or irritative symptoms (e.g., nocturia, frequency), voiding or obstructive symptoms (e.g., dysuria, weak urinary stream, urinary hesitancy), and postvoiding symptoms (postvoiding dribbling, sensation of incomplete voiding).

Several longitudinal cohort studies have been conducted to determine the overall incidence of BPH/LUTS, but these rates vary widely by study according to their disease definition and population studied. The Prostate Cancer Prevention Trial, which included 5667 men older than 55 years, determined the incidence rate to be 34.4 cases per 1000 person-years, while the Olmsted County study reported an incidence of 8.54 per 1000 men [5,6].

In epidemiological studies estimating the prevalence of BPH/LUTS, LUTS due to BPH affects greater than 20% of American men aged 30–79, accounting for approximately 15 million men [7,8]. There are racial variations: Hispanic men have the highest prevalence of BPH, followed by Black, White, and Asian men [5,9]. While the underlying cause of racial variation in BPH prevalence is not well understood, it is thought that it may be related to genetic and environmental differences. Some studies report that Japanese, Chinese, and Indian men have significantly lower prostate volumes than American or Australian men [10,11].

Risk factors

Many modifiable and nonmodifiable risk factors have been identified as contributors to increased risk and progression of BPH/LUTS. One well-known nonmodifiable risk factor for BPH/LUTS is age. Prostate volume is known to increase with age. Results from the Baltimore Longitudinal Study of Aging indicated that annual median rate of prostate volume change was 2.5% or 0.6 cc per year [12]. Although prostate growth is not directly related to the severity of LUTS, the incidence and prevalence of LUTS increases with age [13]. Genetic susceptibility is also considered a nonmodifiable risk factor for BPH. Early studies show that familial BPH (defined as three or more family members with BPH, including the patient) is associated with a larger prostate size and earlier age at the time of diagnosis [14]. Twin studies have supported that heritability contributes to the severity of BPH, with one study reporting that genetic factors accounted for 72% of the risk of high-moderate and severe LUTS [15]. More recently, efforts have been undertaken to identify specific genetic variants and single nucleotide polymorphisms (SNPs) that may confer an increased risk of BPH/LUTS. SNPs in the androgen receptor, cytokines, steroid metabolism, nitric oxide (NO) level, vitamin D level, and ∝1-adrenoceptor genes have all been considered in genome-wide association studies [16]. Multiple researchers have successfully identified SNPs at 2q31, 5p15, 6q22, 9q33.2, and Xp11 as possible candidates, although no clear genetic markers have been concretely identified [17,18].

Hormonal imbalances such as low testosterone and high estrogen levels have been implicated as potential risk factors for the development of BPH/LUTS. However, the role of androgen signaling in BPH is poorly understood, and researchers have yet to identify a consistent relationship between androgen levels and BPH risk [19]. Some evidence supports increased levels of estrogen as a possible contributor to BPH. One study identified free estradiol as a risk factor of BPH, and another study reported an association between estradiol levels and LUTS [20,21]. However, in the Prostate Cancer Prevention Trial, results suggested that high testosterone levels were associated with a reduced risk of developing BPH, and thus hormonal imbalance as a risk factor of BPH is still debated [22].

Metabolic syndrome is an important risk factor for BPH and includes obesity, insulin resistance, dyslipidemia, glucose intolerance, and hypertension. While metabolic syndrome and obesity are inextricably linked, growing evidence indicates that the other features of metabolic syndrome independently contribute to the risk of developing BPH/LUTS. The Boston Area Community Health (BACH) Study showed that men with mild-to-severe LUTS were at significantly increased odds of having metabolic syndrome in a large population-level study, particularly in men younger than 60 [23].

Multiple studies have shown that total prostate volume and total prostate volume growth are significantly higher in BPH patients with metabolic syndrome, noninsulin-dependent diabetes mellitus, hypertension, dyslipidemia, low high-density lipoprotein (HDL) cholesterol, and high fasting plasma insulin level than in BPH patients without these conditions [24–26]. Furthermore, one study calculated the annual BPH growth rate to be increased by 47% in men with diabetes, 36% in men with obesity, 31% in men with low HDL, 28% in men with insulin resistance, and 17% in men with hypertension [27]. A meta-analysis of recent literature on this topic also demonstrated that men with metabolic syndrome have significantly larger prostate volume. However, they did not see a difference in International Prostate Symptom Score (IPSS) scores between men with and without metabolic syndrome [28]. The effect of metabolic syndrome on the pathophysiology and development of BPH is not fully understood. However, a number of factors, including increased autonomic tone, insulin resistance, activation of the Rho kinase system, and a chronic low-grade proinflammatory state, have been considered as possible mechanisms for the increased risk of BPH/LUTS [29,30].

An important component of metabolic syndrome, obesity has been identified as an independent, modifiable risk factor for BPH. Several studies reviewed by Parsons et al. [31] have shown that measures of adiposity, including body weight, body mass index, and waist circumference are all positively associated with prostate volume. In the Prostate Cancer Prevention Trial, a waist-to-hip ratio increase of 0.05 was associated with a 10% increased risk of total and severe BPH [5]. Collectively, research on this topic strongly suggests that obesity may promote prostate growth and increase the likelihood of developing associated LUTS, supporting obesity is a risk factor for BPH/LUTS [31,32]. Many studies lend support to the hypothesis that physical activity reduces the risk of BPH/LUTS. One meta-analysis of 11 studies reported relative risk reductions of as much as 25% with moderate-to-vigorous physical activity compared to a sedentary lifestyle [33]. This supports the possibility of exercise as a method of risk reduction.

Other comorbid conditions have also been associated with an increased risk of BPH/LUTS. Large population-level studies indicate that arthritis, asthma, chronic anxiety, depression, diabetes, heart disease, hypertension, irritable bowel syndrome, neurological conditions, sleep apnea, and prostatitis have been associated with the development of LUTS [34,35]. However, the relationships between these conditions and BPH/LUTS fall beyond the scope of this chapter.

Pathophysiology of BPH

BPH describes proliferation of the periurethral and transition zones of the prostate; however, the precise pathophysiology is not well understood at this time. There is extensive literature to support that prostate volume and incidence of BPH are correlated with age, but prostatic enlargement is highly variable and complex [36]. In one study of 464 men aged 40–80 in Olmsted County, Minnesota, prostate volume was age dependent and ranged from 20 to 60 g [37]. Other studies suggest that prostate size remains constant unless BPH is developed later in adulthood, reporting that the average prostate volume with autopsy evidence of BPH averaged 33±16 g [4]. Interestingly, however, multiple studies have reported that prostate volume, peak urinary flow rate (Qmax), and symptom scores are not significantly correlated in men with BPH, suggesting that there is more to the physiological explanation of how BPH causes LUTS than prostatic enlargement [38,39]. As discussed earlier, it has been suggested that BPH causes BOO and LUTS by two mechanisms: (1) static obstruction due to prostatic enlargement causing encroachment on the prostatic urethra and bladder outlet and (2) dynamic obstruction due to prostate smooth muscle tension [37,40].

Research indicates that BPH involves the proliferation of both stromal and epithelial components of the prostate; however, it appears to have more to do with stromal proliferation than epithelial proliferation, and it has been consistently demonstrated that the stromal-to-epithelial ratio is higher in men with BOO than in men without [36,40–43].

Several mechanisms for how and why prostatic proliferation occurs have been proposed. The primary mechanism relates to androgen regulation. Under normal conditions, 5-α reductase converts testosterone to dihydrotestosterone (DHT), the principal androgen of the prostate. DHT and testosterone levels are low in the prepubertal period but rise during the postpubertal period. DHT is responsible for promoting stromal tissue proliferation, while both DHT and DHT-dependent growth factors mediate cell signaling between the stromal and epithelial components [44]. Research suggests that the development of BPH is likely related to a disruption in the DHT-mediated balance between cell proliferation and cell death [45,46]. One study using rats showed that only 2.1% of prostate cells die on a daily basis when there is sufficient testosterone to maintain the prostate gland, but this increased 10-fold in rats that had only 10% of the original amount of testosterone 3 days after castration, supporting the role of androgens in BPH pathophysiology [46,47].

Acute and chronic inflammation may also play a key role in the pathophysiology of BPH. Although there is a known relationship between inflammation and obesity/metabolic syndrome that may contribute to BPH in men affected by these conditions, there is also evidence of a heightened inflammatory state in hyperplastic prostates of men without metabolic syndrome. Prostate biopsies and histological samples obtained from prostate surgeries exhibit inflammation on histology and overexpression of inflammatory cytokines [47–52]. Specifically, it appears that the chronic inflammatory state in BPH is characterized by an infiltration of activated T cells and macrophages [53–56]. These inflammatory cells produce various cytokines and growth factors, including interleukin (IL)-2 and interferon-γ, which cause the proliferation of stromal and epithelial cells of the prostate [51].

A state of active inflammation causes oxidative stress and prostatic tissue damage via the production of free radicals such as NO [57,58]. NO and chronic inflammation both upregulate cyclooxygenase activity, especially cyclooxygenase-2 (COX-2), leading to an increase in proinflammatory prostaglandins that promote hyperplasia of prostatic cells [57,59]. Interestingly, one prospective randomized controlled trial enrolling 80 patients evaluated the COX-2 selective blocker celecoxib versus placebo for a 1-month treatment of BPH patients complaining of nocturia. Their results indicated that IPSS scores significantly improved from 18.2±3.4 to 15.5±4.2 in the celecoxib group (P<.0001); however, IPPS scores in the control group only decreased from 18.4±3.1 to 18±3.9 (P>.05), revealing a statistically significant difference between the two groups (P<.0001) [60].

While the relationship between inflammation and BPH is consistently demonstrated, the precise trigger leading to an inflammatory state is not entirely clear, and several triggers have been postulated. Viral or bacterial infection may incite inflammation, triggering the development of BPH. There is histological evidence of bacterial and viral strains in prostate biopsies of BPH, promoting the production of the proinflammatory cytokines and chemokines involved in stromal hyperplasia and prostatic cell growth [57]. Another possibility is a genetic trigger and subsequent downregulation of the macrophage inhibitory cytokine-1 gene. This ultimately leads to inflammatory infiltration of prostatic tissue, causing gland destruction followed by stromal proliferation [61]. Local hypoxia is known to trigger the activation of transcription factor hypoxia-inducible factor 1 (HIF-1) in stromal cells and initiation of increased growth factor production [62]. Growth factors such as vascular endothelial growth factor (VEGF), fibroblastic growth factor (FGF-2), FGF-7, tumor growth factor-beta (TGF-B), and cytokines like IL-8 are associated with the HIF-1 transcription factor and trigger prostatic growth [63,64].

Despite the need for more research, it is evident that there are multiple triggers of a chronic inflammatory state, which may play a role in the development of BPH. It has been suggested that inflammation serves as a stimulus for nonmalignant pathway of prostate hyperplasia where other factors such as oxidative stress, cytokines, and hypoxia contribute [65].

It is also important to consider the pathophysiology of the dynamic component of BPH, increased smooth muscle tone. Increases in smooth muscle tone and contraction appear to be related to an abundance of adrenergic innervation of the prostate via α-1A adrenoceptors [66]. These receptors exist primarily in the stromal tissue of the prostate, which is the suspected primary source of proliferating tissue in BPH [67–70]. It has been reported that there are 35% more binding sites for α-1A adrenoceptors in BPH compared to non-BPH men [71]. Many studies support that noradrenergic stimulation of these receptors induces prostatic smooth muscle contraction, leading to urethral constriction and resistance and LUTS [45]. Other studies in rats have shown that increased noradrenergic stimulation results in increased voiding episodes, suggesting that norepinephrine and increased noradrenergic innervation may underlie voiding dysfunction [72]. Interestingly, studies have shown that these intracellular and extracellular changes in smooth muscle cells that contribute to detrusor overactivity and decreased bladder compliance are adaptive and persist even after surgical intervention for obstructive symptoms due to BPH [45,73–75].

Overall, the pathophysiology of BPH is most likely multifactorial in nature. As discussed, the development and progression of BPH may involve a number of contributing mechanisms including, but not limited to, androgen regulation, chronic inflammation, oxidative stress, genetics, recurrent infections, and metabolic syndrome, ultimately producing the combination of prostatic enlargement and LUTS diagnosed as BPH.

Diagnosis and workup

A diagnosis of BPH with LUTS can be made by the presence of urinary storage, voiding and postvoiding symptoms that are not attributable to any other known possible cause. The diagnosis can be made without a prostate biopsy, and often this is not required unless there is a concern for prostate cancer.

The initial workup for LUTS should follow the American Urological Association and European Association of Urology guidelines [76–78]. The initial intake should include a full medical history and physical examination, including a digital rectal examination. The history is important in identifying any key risk factors or lifestyle factors that may increase the likelihood of BPH, characterizing urinary storage, voiding and postvoiding symptoms that may be present, and recognizing any alarm symptoms indicative of prostate cancer or other conditions that may necessitate urology referral. Validated, widely used symptom score questionnaires such as the self-administered American Urological Association Symptom Index (AUA-SI) should also be used to classify symptoms at each visit [79]. Urinalysis should be performed to rule out any other causes of similar symptoms, such as renal dysfunction or UTI. Postvoid residual urine (PVR) measurements, uroflowmetry, pressure flow studies, and urodynamic testing are commonly considered to evaluate severity in the early phases of a BPH workup prior to any treatment intervention. Other diagnostic methods such as frequency charts and renal function assessments including serum creatinine and estimated glomerular filtration rate may be considered when appropriate.

In more severe cases where BPH is bothersome to the patient and surgical intervention is considered, prostate imaging may be considered, especially prior to surgical intervention. Studies have shown that both prostate-specific antigen and digital rectal examination may not enable reliable estimation of prostate size, warranting prostate imaging [80].

Management of BPH

While BPH without LUTS does not necessitate treatment, the development of LUTS is quite bothersome for patients who present for options are often discussed between the patient and their healthcare provider when bothersome LUTS are present. Treatment options range from observation to medical therapy and surgical intervention. These are reviewed here briefly, as this is beyond the scope of the chapter. The treatment of BPH requires active management of 12.2 million patients each year, with roughly 35% managed with observation, 54.8% managed with medication, and 1.1% managed with surgery [2]. Measures of the prostate volume are also frequently considered when evaluating treatment options and goals [45]. The goals of BPH treatment are to reduce LUTS, delay the progression of BPH, and improve quality of life.

Typically, treatment begins with a watchful waiting period for patients with low IPSS and AUA-SI scores and no major complications or quality-of-life interference. This typically involves education about BPH, periodic monitoring, and lifestyle and behavioral modifications [77]. These include decreasing fluid intake at night or when leaving the house, decreasing caffeine intake, decreasing alcohol intake, smoking cessation, altering the timing of diuretic medications, using double-voiding techniques, urethral milking, and bladder retraining [81–83].

Medical therapy, either monotherapy or combined therapy, is the next intervention. There are several categories of medical treatment, each targeting specific pathophysiological mechanisms. Alpha-blockers (αBs), such as tamsulosin and silodosin, work by inhibiting smooth muscle contraction, resulting in easier passage of urine across the prostatic urethra and increased urinary flow rates. Symptomatic improvement with these medications may occur within hours to days, although the full effect profile takes a few weeks to develop [84]. Overall, they exhibit a minimal adverse effect profile and good efficacy, making them the first-line drug treatment choice [77].

5-Alpha reductase inhibitors (5-αRIs), such as finasteride and dutasteride, block the conversation of testosterone to DHT and induce epithelial cell apoptosis, ultimately leading to prostate volume reduction, symptom improvement, and an increase in maximum urinary flow rate [85,86]. Finasteride has been shown to significantly reduce the risk of acute urinary retention and the need for subsequent surgical intervention [87–89]. Unfortunately, however, clinical effects compared to placebo usually require a minimum of 6–12 months of treatment, and overall efficacy depends on prostate volume at baseline [77]. Consequently, this class of medications is best used for patients with larger prostates.

Phosphodiesterase-5 inhibitors (PDE5-Is), like tadalafil, are a mainstay of treatment for LUTS due to BPH. However, their precise mechanism of action is not well understood. PDE5-Is are believed to cause smooth muscle relaxation of the bladder neck, urethra, and prostate via NO, and increase lower urinary tract blood perfusion, thereby reducing bladder dysfunction and urethral contractions and improving voiding symptoms [90–93]. This class of medications has direct antiinflammatory effects by inducing high levels of cyclic GMP [94].

Meta-analyses indicate that PDE5-I use is associated with significant improvement of IPSS values, but not maximum urinary flow rate, suggesting that it may be better utilized in combination with other therapies [95].

Muscarinic receptor antagonists, including oxybutynin, solifenacin, tolterodine, have also been used as a medical therapy choice for LUTS due to BPH. These medications antagonize muscarinic activation, therefore impeding detrusor contraction and relieving symptoms related to urinary urgency and frequency. The TIMES study determined that tolterodine was effective in reducing urgency incontinence; however, it was not effective in improving IPSS scores, prompting a need for further research on this medication class [96]. Currently, this drug is best used in men with LUTS, predominantly consisting of overactive bladder (OAB) symptoms and low postvoid residual volumes [77]. β-3 adrenergic receptor agonists like mirabegron lead to detrusor relaxation, relieving OAB.

Given the growing evidence in support of the relationship between inflammation and BPH, the use of nonsteroidal antiinflammatory medications (NSAIDs) has been considered in the prevention and treatment of BPH. These studies, however, have led to conflicting results. In the Olmsted cohort, men who took NSAIDs daily had decreased risks of moderate to severe urologic symptoms, low maximum urinary flow rate, and high prostate volume by 35%, 50%, and 50%, respectively [97]. Other cohorts, such as the Prostate Cancer Prevention Trial, did not demonstrate that NSAID use has any protective role in the development of BPH or associated outcomes [98,99].

Combination therapy of the aforementioned drug classes is often used. Combinations include αBs and 5-αRIs, αBs, and antimuscarinics, and PDE5-Is with αBs. In one large systematic review and meta-analysis of 66 randomized controlled trials that included 29,384 participants, the combination of αBs and 5-αRIs was the best treatment for increasing the maximum urinary flow rate. The same study also determined that the combination of PDE5-Is and αBs appears to improve maximum urinary flow rate and improve IPSS scores [90]. Another study found that treatment with the specific combination of doxazosin, an α-B, with finasteride, a 5-αRI, led to significant improvement in symptom scores and reduction in long-term risk of acute urinary retention that were superior to either medication alone [100].

Surgery is typically reserved for those who fail or refuse medical therapy or who develop severe or concerning BPH-related complications, including renal insufficiency, refractory urinary retention, recurrent UTIs, recurrent bladder stones, or gross hematuria [78]. Chughtai et al. [45] classified surgical options into three main categories: (1) compression of prostatic tissue, (2) debulking of the adenoma, and (3) complete removal of adenoma.

The prostatic urethral lift (PUL) is a minimally invasive, tissue-sparing procedure utilizing implants that displace the lateral lobes of the prostate to relieve prostatic urethral obstruction and improve LUTS. Five-year results from the L.I.F.T. study of 206 men with prostate volumes below 80 g indicated improvement of IPSS by 36% and quality of life by 50% [101]. Recent studies on PUL have found similar improvements in IPSS scores, quality-of-life scores, BPH Impact Index scores, and Qmax while preserving sexual function