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Enlarged Prostate Linked To Metabolic Syndrome

Introduction

The increased life-expectancy in today's world has resulted in a rapid increase in the aging population, mostly occurring in the developing nations. This demographic trend has alternatively raised an increased focus on continuing health of these elderly patients as they appear more prone to certain diseases, in part as a consequence of aging. Nonetheless, this alongside has opened new areas of interest that deviates from the earlier known physio-pathological constructs related to "normal" consequences of the aging process.1   For instance, the common urological complaints of an elderly male are now seen more preventable than inevitable ailments of the elderly; influenced by several modifiable metabolic factors. Emerging data in this context suggests a hypothesis wherein metabolic syndrome and its components and accompanied prostate inflammation are commonly associated with urological disorders in the aging men.

Metabolic syndrome: a complex disorder

Metabolic syndrome is a complex disorder that has emerged as a worldwide epidemic, and might be more prevalent than clinically interpreted. As per the National Cholesterol Education Program's Adult Treatment Panel III report (ATP III), it is identified as a cluster of several abnormalities, including abdominal obesity, impaired glucose tolerance, dyslipidemia and hypertension, which increase the odds for cardiovascular disease (CVD) and type 2 diabetes, when occurring together (Table 1).2,5    Etiologically, metabolic syndrome seems to have three potential categories: obesity and disorders of adipose tissue; insulin resistance; and a constellation of independent factors (such as molecules of hepatic, vascular, and immunological origin) mediating specific components of this metabolic disease. However, there are other factors as well, such as aging, proinflammatory state and hormonal changes, which are implicated as important contributors.

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Understanding the emerging impact of metabolic syndrome on prostate health: why important?

A discussion on the impact of metabolic syndrome in aging men is important, particularly seeing its emerging association with urological diseases, which might be typically mediated through prostate pathology.6   The concept per se identifies metabolic syndrome as a new domain in patients with prostatic disorders, with possibility that benign prostatic hyperplasia (BPH) be regarded as a new aspect of metabolic syndrome. This translates into a clinical possibility that obese, dyslipidemic, and aged men will perhaps have a higher likelihood of having metabolic syndrome related derangements as determinant of their prostate enlargement.7   Therefore, it is rational that an understanding of the correlation of this syndrome with enlarged prostate will help in developing a more optimal approach for management, prevention, and treatment of these urologic diseases in a male patient.

Mechanisms linking metabolic syndrome and BPH

Despite BPH being an extremely common, chronic, progressive disease affecting aging men in its full clinical appearance, the pathogenetic correlation between BPH and metabolic syndrome is not exactly clear but emerging. And the two diseases appear to share several modifiable risk factors. Factors such as inadequate diet, lack of physical exercise, smoking and drinking behaviours, which are involved in metabolic syndrome, are emerging as important contributors to the development of BPH as well.1   Considering this comorbid trend, investigators have been exploring connections between BPH with clinically significant lower urinary tract symptoms (LUTS), the metabolic syndrome, prostate inflammation (a crucial component of BPH pathogenesis), alterations in cell signaling, and genetics; figure 1 proposes a graphical representation of the multifactorial pathogenesis of BPH/LUTS.1   The outcome is that numerous possible underlying mechanisms have been proposed, which most likely interact in the pathogenesis of this prostatic enlargement8,9  : inflammatory processes taking place predominantly in the stroma and inducing proliferation of all tissues within the transitional zone; an imbalance of androgens and estrogens and their receptors; and autosomal dominant inheritance. In addition, hyperinsulinemia and hypercholesterolemia act as direct promoters of the glandular growth. The detrusor muscle responds to the increased outflow resistance with muscular hypertrophy. Later on, decreased compliance of the bladder wall results in voiding difficulties, whilst electric instability of the hypertrophied detrusor muscle and increased recruiting of otherwise silent afferent fibres cause storage symptoms.8   This proposed pathway clearly suggests that BPH/LUTS - historically considered as a "normal" consequence of the aging process - shall now be countered more proactively as a preventable disorder of the elderly.

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Evidence for association between components of metabolic syndrome and BPH/LUTS

Obesity

Obesity is defined based on numerous anthropometric measures, including waist circumference, waist-to-hip ratio, and body mass index (BMI), and is been implicated in the etiology of prostatic growth due to its influence on metabolic and endocrine changes. It has been documented that in men abdominal obesity may increase the frequency and severity of urinary obstructive symptoms, and may increase the likelihood of them to undergo intervention for enlarged prostate.10,11     In a study, Giovannucciet al11   examined the data of 25,892 men who participated in the Health Professionals Follow-up Study and observed that patients with an obese waist circumference (>109 cm) had a 2.4-fold higher risk (p<0.001) of being surgically treated for BPH than their nonobese counterparts (waist circumference <89 cm).Per se, the waist-to-hip ratio can be an important independent predictor of BPH.

Dyslipidemia

Similar to obesity, the relationship also exists between BPH and dyslipidemia. Observation suggests that dyslipidemia may interact with other components of metabolic syndrome to increase the risk of BPH. In this context, numerous experimental evidences have documented significantly higher prostate weight in hyperlipidemic models than in controls. Besides, the relationship has also been documented in humans in epidemiological studies. In a study, Nandeesha et al12   observed that men with BPH had significantly higher total cholesterol and low-density lipoprotein (LDL)-cholesterol levels than did men without BPH. Likewise, high-density lipoprotein (HDL)-cholesterol was significantly lower in cases as compared to controls.

Hypertension

Several experimental models and epidemiological studies exist showing association of hypertension with BPH/LUTS. In a study, Josephet al13   reported that men with a history of hypertension had higher risk of moderate-to-severe LUTS, including obstructive and irritative symptoms, compared to their counterparts without a history of hypertension. Similarly, Rohrmann Set al14  , in the Third National Health and Nutrition Examination Survey (NHANES III), found hypertension to be positively associated with LUTS. Men with a history of hypertension had significantly higher odds of LUTS than did their counterparts without such a history.

Insulin resistance and hyperinsulinemia

Insulin resistance is an important component of metabolic syndrome that individually and through interaction with other components may affect prostatic growth. This decreased responsiveness of insulin-sensitive tissues towards insulin results in β-cells secreting more insulin, thereby leading to hyperinsulinemia. This hyperinsulinemia has been observed as an important mediator to influence the development of BPH/LUTS. Hammaresten and Hogstedt15   evaluated the relationship between fasting plasma insulin and BPH to test the hypothesis of hyperinsulinemia as a causal factor for the development of BPH. The authors found faster rate of median annual growth of BPH in men with a high than in those with a low fasting plasma insulin level (p = 0.019). When patients were divided into quartiles, the median annual BPH growth rate increased statistically significantly with increasing fasting plasma insulin levels. When performing a multivariate analysis using the total prostate gland volume as dependent variable, fasting plasma insulin (p = 0.001) and age (p < 0.001) became statistically significant. Similarly, Nandeeshaet al12   also reported hyperinsulinemia associated with insulin resistance as an independent risk factor in the development of BPH, and found that levels of fasting serum insulin were significantly higher in men with BPH than in controls (p<0.001). These evidences clearly support the hypothesis that hyperinsulinemia is causally related to the development of BPH.

Metabolic syndrome

While each component of the metabolic syndrome (obesity, dyslipidemia, hypertension, and insulin resistance) has individually been linked to an increased odd of BPH/LUTS prevalence or progression; the syndromeperse may predispose patients to a higher risk of BPH and LUTS. Hammarsten Jet al16   elaborated this concept in a clinical study. The authors investigated relationship between prostate volume and individual components of metabolic syndrome in 158 men with BPH. The study demonstrated that type 2 diabetes mellitus, hypertension, obesity, high insulin, and low HDL-cholesterol levels were all risk factors for the development of BPH. Men with diabetes, hypertension, obesity, low HDL-cholesterol levels and high insulin levels had a larger prostate gland than those without these conditions. Thus, prostate gland volume correlated positively with the systolic blood pressure, obesity and fasting insulin level, and negatively with HDL-cholesterol (Table 2). These findings generated the hypothesis of a potential causal relationship between high insulin levels and the development of BPH, which in clinical setting could suggest a bi-directional relationship between metabolic syndrome and BPH; i.e., in a patient presenting with BPH, the possible presence of type 2 diabetes, hypertension, obesity, high insulin and low HDL-cholesterol levels should be considered; and conversely, the possibility of a clinically important BPH should be kept in mind in patients suffering from these metabolic conditions.

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Thus, numerous studies (Table 3)12,15,23        based on the concept of metabolic construct, validate this association between the presence of metabolic syndrome components and further increase in prostate volume, even if the relationship between metabolic syndrome and LUTS is more subtle. A negative impact perhaps becomes particularly pronounced with increasing number of metabolic syndrome factors (Figure 2).24  

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Early pharmacotherapy for enlarged prostate in patients with comorbidities

As a westernized lifestyle is generally thought accountable for most components of the metabolic syndrome affecting BPH; lifestyle modifications through increased physical activity and dietary strategies may benefit these individuals to improve their LUTS in early course of disease onset. Medical or surgical approaches can be used for definite control of BPH symptoms, but must consider patients' comorbid disease states in favor of reduced morbidity and complications. This might possibly justify the fact why drug treatment is the usual first choice in most cases and remains the mainstay of treatment for patients with symptomatic BPH.

Pharmacotherapy approach for LUTS and BPH is generally directed at relaxing prostatic smooth muscle, reducing prostate volume, or a combination of these effects. This therapeutic need frequently employs use of two classes of drugs, i.e., the α1-adrenergic receptor antagonists and 5-α-reductase inhibitors (5-ARIs); which are also the most commonly used drugs for this indication to relieve LUTS, and are frequently used in combination. While α1-adrenergic receptor antagonists play an important role in the sympathetic control of prostatic muscle contraction, relaxing prostatic smooth muscle; 5-ARIs reduce prostatic androgen levels, and consequently prostate size, providing long-term benefit.25

Role of α1-selective adrenergic receptor antagonists

There exist three known subtypes of α1-selective adrenergic receptors (α1A, α1B, α1D); amongst which the expression of α1A receptor predominates in the prostate (~70%) and mediates its contractile response. In effect, this forms an important drug target to provide quick symptomatic relief in patients with BPH. All α1-selective adrenergic receptor antagonists bind to the α1A subtype, effectively reducing the tone of prostatic smooth muscle, and thereby relieving bladder outlet tension and increasing the urinary flow. However, it is seen that the relative selectivity of individual members of this drug class is not the same, which may even limit clinical usefulness of some of the agents. While terazosin, doxazosin and alfuzosin show equal affinity for all α1-adrenergic receptor subtypes (thus categorized as non-subtype selective); tamsulosin is identified as a super-selective α1-adrenergic receptor antagonist. Like this, tamsulosin appears to have an advantage over other α1- adrenergic receptor antagonists. The drug was designed to have a higher affinity for the α1A- and α1D-adrenergic receptors, while showing less affinity for the α1B subtype found in vascular tissue (tamsulosin is about 10 times more selective for the α1A subtype than for the α1B subtype) 26  ; the α1D subtype is thought to be associated with bladder muscle contraction.

Tamsulosin - a safer alternative in BPH

Tamsulosin can be beneficial in real life clinical practice where BPH exists in the elderly and those with cardiovascular co-morbidity and/or co-medication, who are more vulnerable for blood pressure variations. The subtype-selective nature of tamsulosin has obvious benefits, including a rapid onset of therapeutic effect and symptomatic relief without dose titration and with minimal effects on blood pressure. This is in contrast to the older α-adrenoceptor antagonists, terazosin and doxazosin, that are associated with higher rates of dizziness, syncope and hypotension. Per se, such was the impact of high risk of major cardiovascular events with doxazosin that doxazosin arm of The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was needed to be discontinued.27   In contrast, tamsulosin demonstrates a placebo-like cardiac safety profile, with comparable incidence of cardiovascular adverse events and a low potential for interference with concomitant antihypertensive therapy. Accordingly, its use has in fact resulted in a lower incidence of clinically relevant effects on blood pressure or heart rate, and minimal cardiovascular adverse effects.28   Therefore, tamsulosin may be used safely in elderly men requiring BPH therapy and receiving parallel antihypertensive medications (for cardiovascular disease).25,29

5- α-reductase inhibitors (5-ARIs)

As prostatic growth is influenced by androgens, modulation of androgenic activity may effectively reduce prostate volume in men with BPH. This forms the basis for introduction of 5-ARIs for men with enlarged prostates (with no evidence of prostate cancer) in addition to BPH symptoms. The rationale is founded on the fact that inhibition of prostate 5-α-reductase with the 5-ARIs blocks conversion of testosterone by the enzyme 5- α-reductase to its metabolite, 5-α-dihydrotestosterone (DHT), thereby affecting prostate growth. Prostate size at baseline appears to be an important determinant of therapeutic response to these drugs, and larger prostates are expected to experience greater improvement in symptom score and flow rate.

Finasteride and dutasteride are the two drugs in this class; both of them act to reduce androgen-dependent increases in prostatic volume, but may require several months of therapy for adequate symptomatic relief.25   Amongst the two, finasteride is a competitive inhibitor of the type 2 isoform of 5-α-reductase, while dutasteride possesses a dual-enzyme inhibition mechanism and blocks both type 1 and type 2 isoforms (Figure 3).30   This blockade of both subtypes by dutasteride results in added suppression of DHT synthesis (> 90% of DHT production is suppressed); accounting for its relative advantage as evident by significant reductions in prostate volume size. Additionally, dutasteride has a much longer half-life when compared with finasteride (5 weeks vs. 5-6 hours).31

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Combination therapy with tamsulosin and dutasteride

Combination therapy with an alpha1-selective adrenergic receptor antagonist and a 5-ARI is an enticing option for rapid symptomatic relief in patients with BPH and LUTS; accompanied by gradual, concomitant reduction in prostate size.25   While alpha-blockers will provide rapid symptomatic relief by relieving the dynamic component of obstruction, the 5-ARIs target the underlying disease process and will provide mid- and long-term symptom relief by relieving mechanical component of the obstruction.32

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Incidentally, the combination of tamsulosin with dutasteride is available in a unique single tablet containing tamsulosin with ADS (Advanced Delivery System) advantage (Box 1). Tamsulosin with ADS technology is a new improved formulation that has been developed to ensure continuous and consistent drug release, resulting in a more constant exposure to tamsulosin over 24 hours. Such a Controlled Absorption System can be particularly beneficial in real life practice where also the very elderly and patients with cardiovascular co-morbidity and/or co-medication, who are more vulnerable for orthostatic hypotension, are treated. In such settings, tamsulosin ADS may provide safe treatment of LUTS/BPH, enabling a constant release of tamsulosin over a 24-hour period, without an effect on blood pressure and without the risk for orthostatic hypotension (Figure 4).33-35     The improved pharmacokinetics of this formulation, compared with the standard modified release (MR) capsules, thus may translate into an improvement of the efficacy/safety ratio during the treatment of LUTS/BPH. Of note, combination therapy with tamsulosin and dutasteride has been found to significantly reduce the risk of BPH clinical progression, supporting the long-term use of tamsulosin plus dutasteride in men with moderate-to-severe BPH symptoms because of prostatic enlargement.36-38

Adding flavoxate to the therapeutic regimen

Supplemental administration of flavoxate hydrochloride, a flavone derivative with smooth muscle relaxing activity, in combination with an alpha-1 adrenoreceptor blocker may also be considered to more effectively alleviate the symptoms of LUTS.39   This is because up to 50% of men with bladder outlet obstruction have detrusor overactivity and symptoms of overactive bladder as well.40   The presence of phosphodiesterase enzymes in the prostate and detrusor muscle of bladder implies that this phosphodiesterase inhibitor (flavoxate) shall be appropriate therapy for those with BPH related LUTS and detrusor instability. The clinical study by Katoet al41   appears supporting this outlook. The authors in this study examined effectiveness of supplemental administration of flavoxate with an alpha1-adrenoceptor blocker in BPH patients with uncontrolled nocturia, and observed significant improvement in the number of nocturnal micturition, total International Prostate Symptom Score (IPSS), quality of life (QOL) score and BPH impact index. Besides, tamsulosin may possibly address the irritative symptoms to some extent.

Conclusion

With increased life-expectancy across the world, the population is aging and the medical world faces increased challenges due to concomitant increases in disease burden. These elderly patients may present with various combinations of disease states, which may correlate negatively to impact their overall prognosis. Both metabolic syndrome and prostatic diseases are common in aging men and express rising association with one another; such that prostatic enlargement has recently been distinguished as a urologic construct of the former. An etiological relationship is hence established, influenced by multiple pathologic commons. This could account for increased emphasis on lifestyle modifications, such as increased physical activity and dietary strategies, in elderly patients, not only to check the metabolic aberrations but also their effect on the prostate health. Pharmacotherapy for BPH/LUTS is another enticing option in early course of the disease for effective control of symptoms, for which combination of tamsulosin and dutasteride can be used.

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Prof. Dr. Sudhir Khanna

M.S., DNB (Surgery), MCh, DNB (Urology) MNAMS
Chairman Department of Urology
Senior Consultant Urologist
Sir Ganga Ram Hospital, New Delhi

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