Lower urinary tract symptoms and its potential relation with late-onset hypogonadism

Abstract

The study of the health status of the aging male takes presently a more integrative approach and it appears that ailments typical of male aging, such as lower urinary tract symptoms (LUTS), (visceral) obesity, metabolic syndrome and erectile failure are significantly interrelated. A common denominator of the above ailments is lower-than-normal testosterone levels occurring in a significant proportion of elderly men. This review addresses the potential connections between LUTS and late-onset hypogonadism. In animal studies there appear to be androgen and estrogen receptors in the urothelium and smooth muscle cells of the urethra and bladder of the rat and rabbit, as well as in the neurons in the autonomic ganglia of the prostatic plexus of the male rat. Upon castration electrically evoked relaxations of the smooth muscle of the prostatic urethra were decreased. There is a Rho-kinase activation/endothelin pathway; possibly involved in the increased smooth muscle activity found in both LUTS/benign prostate hyperplasia. Nitric oxide (NO) appears to have a smooth muscle relaxing effect in the urogenital organs. Studies in humans have convincingly shown that phosphodiestererase inhibitors have a beneficial effect on LUTS. More intervention studies should be undertaken to test the clinical validity of the theoretically plausible interrelationship between LUTS and late-onset hypogonadism.

Keywords:

• Androgen receptor
• aging
• nitric oxide
• penis
• testosterone

Introduction

It is common for aging men to experience urinary problems ranging from nocturia, increased frequency of micturition, urgency, hesitancy, poor stream, post-micturition dribbling, loss of bladder control resulting in incontinence, and retention. Many of these complaints were previously referred to as ‘prostatism’. However, these complaints need not be caused by disease of the prostate itself and, therefore, now the term ‘lower tract urinary symptoms’ (LUTS) is preferred to describe these problems. LUTS may be subdivided into voiding and storage problems. Voiding problems are usually due to bladder outlet obstruction or detrusor dysfunction. The storage capacity of the bladder and the detrusor contractility decreases with age. Population studies show a frequency of moderate-to-severe LUTS from 8–31% in men in their fifties, increasing to 27–44% of men in their seventies. But many men experience symptoms of LUTS much earlier in life.

Over the last two decades there has been a more integrative approach to the health situation of the aging male and it is becoming clear that many age-related health problems of men are interrelated. At the epidemiological level an association between central obesity in adulthood and LUTS could be established [1]. A recent study trying to explain the epidemiological relationship hypothesized that metabolic syndrome is associated with an overactivity of autonomic nervous system. This overactivity of the autonomic nervous system is supposedly not responsible for the development of LUTS but plays a key role in increasing the severity of LUTS above an intrinsic basal intensity that is determined by the genitourinary anatomical/pathophysiological characteristics of other ailments leading to LUTS [2]. (Central) obesity is a hallmark of metabolic syndrome of which the other components are: dyslipidemia, hypertension, impaired glucose metabolism with insulin resistance and diabetes type 2, all conducive to the development of erectile dysfunction. It is therefore not surprising that a large number of studies have established a relationship between LUTS and erectile dysfunction [3-5].

As indicated above, with a more integrative approach to the ailments of the aging male, the age-related decline of plasma testosterone levels has been found to be a feature of erectile failure and central obesity in elderly men, with proven successes of administration of testosterone to correct lower-than-normal levels [6-9].

Many studies have tried to establish a relationship between sex steroids and benign prostate hyperplasia, and a few studies have analysed the relationship between circulating testosterone and LUTS symptoms. One study found that hypogonadism was seen in approximately one fifth of elderly men with LUTS, but it had no impact on symptom status [10]. Another study found a relation between symptoms of LUTS and plasma total and bioavailable testosterone but this relationship disappeared after statistical adjustment for age [11]. No consistent correlations were found between total and calculated free testosterone and symptoms of LUTS in another study [12]. But it is of note that, within certain limits, the signs and symptoms of testosterone deficiency in men do not relate in a uniform pattern to testosterone concentrations [13] which may be (in part) explained by properties of the androgen receptor (the CAG repeat polymorphism in exon 1 of the androgen receptor gene) [14].

The male urogenital tract is exquisitely sensitive to the action of androgens, in prenatal life for its primary development and during puberty for its secondary development. Traditionally, the focus has been on genital development and on the prostate and their abnormalities in cases of androgen deficiency or impaired action as in androgen-insensitivity syndromes. The urinary tract has been less well studied. But there are some intriguing studies highlighting the role of sex steroids in structure and function of the urinary tract, be it that the information has been mainly collected in animal studies.

Prenatally, the sex-neutral external genitalia start to masculinize in the presence of the potent androgen dihydrotestosterone (DHT) toward the end of the first trimester of development. DHT is required for fusion of the urethral and labioscrotal folds, lengthening of the genital tubercle, and regression of the urogenital sinus. With the pubertal testosterone surge the penis and penile urethra reach their adult size. The question arises whether in adulthood and in old age testosterone has still a role to play on the urinary tract. There is, indeed, a growing body of evidence that this is the case, though, as indicated above, the data have largely been collected in animal models.

Sex steroids and their receptors in urinary tract organs and pelvic ganglia

There are androgen and estrogen receptors in the urothelium of the bladder and the urethra of the rabbit [15]. Androgen and estrogen receptors were also found in the urothelium, bladder smooth muscle, striated muscle cells of the proximal urethra and in the neurons in the autonomic ganglia of the prostatic plexus of the male rat suggesting that androgens and estrogens have a role to play in the lower urinary tract [16].

Most of the motor innervation of the urogenital organs originates from autonomic (sympathetic and parasympathetic) neurons of the pelvic ganglia. These neurons show a remarkable sensitivity to androgens and estrogens [17]. Testosterone appears to be an important ‘maintenance factor’ for the morphology of pelvic autonomic neurons which control the bladder, lower bowel and internal reproductive organs of the male rat. In addition, the steroid has potent, selective effects on transmitter synthesis and receptor expression of the autonomic neurons throughout adulthood [18].

Several studies have investigated the effects of castration and sometimes of androgen replacement on characteristics of the morphology of the autonomic neurons supplying the urinary tract organs. Upon orchiectomy noradrenergic pelvic neurons that supply the vas deferens, prostate gland, urinary bladder or colon achieved only approximately 60% of the size of those in controls. In contrast, cholinergic pelvic neurons were unaffected by castration unless they supplied reproductive targets [17-20]. Somewhat surprisingly, part of the effects of testosterone on pelvic autonomic ganglia may be mediated by estrogens derived from aromatization from testosterone. In vitro studies of cultured pelvic ganglion neurons revealed that testosterone, dihydrotestosterone and estradiol each stimulated the growth of longer and more complex neurites in both noradrenergic and cholinergic NOS-expressing neurons [21].

Another study found that castration down-regulates the alpha-adrenergic receptors of the bladder base while testosterone administration increases the density of muscarinic cholinergic receptors, and increases the ratio of the bladder to the total body. Although no contractile changes were observed in the bladder base tissue, it is conceivable that prolonged testosterone deficiency might ultimately affect the bladder outlet resistance because of the reduced alpha-adrenergic receptor activity [22]. Castration decreased the alpha-1 adrenergic and the muscarinic cholinergic receptors function, and testosterone replacement restored those functions again indicating that testosterone affects the autonomic receptor-mediated function in the smooth muscle of lower urinary tract [23].

Effects of castration on function of the lower urinary tract

Upon castration, electrically evoked relaxations of the smooth muscle of the prostatic urethra were decreased, possibly as a result of an impaired ability of the smooth muscle itself to respond to relaxant agents. This could not be demonstrated in the pre-prostatic urethra [24].

A more recent study demonstrated that castration had an impact on tissue enzymes of the lower urinary tract in the rabbit. Castration resulted in decreased activity in the mitochondria-specific enzyme, citrate synthase, the activity of which was greatest in the urethra and lowest in the corpora. Cholinergic nerve density indicator, choline acetyltransferase activity, was greatest in the bladder body and lowest in the urethra. Ca⁽²⁺⁾ATPase, a marker for sarcoplasmic reticular calcium storage and release, was significantly higher in the control corpora than in the control bladder or urethra. It was concluded that significant differences exist in the activities of all three enzymes in the various organs associated with the lower urinary tract, and that castration results in significant alterations in the activities of all three enzymes in the bladder body, base, urethra, and corpora [25].

Angiotensin II and rho/rho-kinase activity in urinary tract organs is perhaps testosterone dependent

Angiotensin II may have an important role in the cellular regulation of smooth muscle growth and collagen production in the bladder. The exact mechanisms by which angiotensin II elicits its cellular effects are, however, not known [26].

A recent study found that castration induced an increase of angiotensin II receptor mRNA and caspase-3 protein (an apoptosis-related protein) in the rat bladder, and these increases were again reduced to control levels upon testosterone administration [26].

Mechanism of action of angiotensin II in the cells is related to the Rho/Rho-kinase pathway. The Rho/Rho-kinase pathway plays an important role in various cellular functions, not only in vascular smooth muscle cell contraction but also in proliferation, cell migration, and gene expression of the vascular smooth muscle cells. Rho-kinase has a central role in the regulation of smooth muscle contraction of the urinary bladder. There can be increased Rho-kinase activity, and consequently increased calcium sensitivity of the contractile machinery in prostate smooth muscle in benign prostate hyperplasia, in the detrusor in bladder outlet obstruction, in the corpora cavernosa in erectile dysfunction and in the blood vessels leading to higher flow resistance in hypertension. There is a Rho-kinase activation/endothelin pathway; and the actions of several factors besides noradrenaline (e.g. endothelin-1, angiotensin II), possibly involved in the increased smooth muscle activity found in both LUTS/benign prostate hyperplasia and sexual dysfunction, are dependent on Rho-kinase activity [27]. The above interaction was recently reviewed by McVary [4].

Nitric oxide production is androgen dependent in urinary tract

Nitric oxide (NO) acts as a non-adrenergic non-cholinergic neurotransmitter in the urogenital tract and appears to have a smooth muscle relaxing effect in the urogenital organs both in various animals and in humans. NO is a mediator of erection and dilatation of the bladder neck and urethra. The potential clinical relevance of NO was demonstrated in a study in mice. Testosterone administration decreased frequency of urination in nNOS-deficient mice [28]. A study in the human indicated that NO is an important nerve-induced mediator of erection and in the micturition reflex, but NO may also be involved in several other functions in the human urogenital tract [29]. In humans 72–96% of neurons in the wall of the bladder appear to contain nitric oxide synthase. Nitric oxide synthase-immunoreactive nerve terminals provide a moderate innervation to the detrusor muscle of the bladder body, and a denser innervation to the urethral muscle. Nitric oxide may be an inhibitory transmitter involved in the relaxation of the bladder neck [30]. Cyclic nucleotides are important secondary messengers of nitric oxide involved in modulating the contractility of various smooth muscles.

Phosphodiesterases (PDE) play important roles in this process by modulating the levels of cyclic nucleotides and their duration of action. Their presence in the urinary bladder could be identified in a study of the rat [31] and the human [32].

Phosphodiesterase 5 (PDE-5) is an inhibitor of nitric oxide/cGMP signalling. A recent study, investigating PDE-5 expression and activity in the human bladder, elegantly demonstrated that PDE-5 regulates smooth muscle tone of the bladder. Vardenafil appeared to block PDE-5 activity, and therefore, may be a possible therapeutic option for bladder dysfunction by ameliorating irritative lower urinary tract symptoms. The study also found that castration decreased, and testosterone supplementation restored, PDE-5 gene expression in rat bladder [33].

As a further substantiation of the role of androgens in the urogenital tract, NO-synthase in an earlier study had appeared to be androgen dependent in the urogenital tract of the rat [34]. Meanwhile a large number of clinical studies have convincingly shown that phosphodiestererase inhibitors have a beneficial effect on LUTS [35-41].

From the above it would appear that androgens are not only essential for the formation of a male urogenital tract prenatally and its adult development during puberty but that maintenance of its functionality in adult life is subserved by androgens. It could be that declining testosterone production with aging contributes to the discomfort elderly men experience with micturition.

Testosterone and the penis

A parallel may be drawn with another target organ of androgens prenatally and pubertally: the penis. Until recently it was believed that androgens had no further effects on the penis once pubertal penile growth was completed. But animal experiments and, to a more limited degree, human observations now suggest that androgens are necessary to maintain the integrity of the anatomical structures of the penile erectile tissue and, further, that androgens are significant in the biochemical mechanisms subserving penile erection. In a rat model Shen et al. [42] demonstrated that androgen deprivation leads to loss of elastic fibres in the tunica albuginea and of smooth muscle fibrse in the corpus cavernosum which were replaced by collagenous fibres in both structures. Similar findings were reported in the rabbit by Traish et al. [43] noting a reduced trabecular smooth muscle content, reversible upon androgen replacement. Singh et al. [44] analysing the increase of muscle mass and decrease of fat mass upon replacement of testosterone in hypogonadal subjects, found as an explanation that the mesenchymal pluripotent cells follow a myogenic lineage or adipogenic lineage depending on circulating levels of testosterone. Traish et al. [45] could demonstrate a similar mechanism in the rabbit with an accumulation of fat containing cells in the subtunical region of the corpus cavernosum thus reducing the elasticity of the tunica albuginea if testosterone levels are low. This study confirmed also that androgen deprivation leads to loss of trabecular smooth muscle and increase of connective tissue fibres. In the study of Traish et al. [43] it was also found that intracavernosal pressure, expression of alpha-1-adrenergic receptor and PDE-5 activity were clearly dependent on the presence of androgens. In a follow up on this study Traish and coworkers [46] demonstrated that a 50% reduction in circulating testosterone reduced intracavernosal blood pressure which could not be enhanced by administration of the PDE-5-inhibitor vardenafil. Nitric oxide synthase and arginase activities in the corpus cavernosum were not significantly affected by the reduction in circulating testosterone. What is known about the human? There are androgen receptors in the human corpus cavernosum [47]. The dependence of PDE-5 on androgens in the muscular and endothelial compartment of the corpus cavernosum was confirmed in the rat but also in human tissue by Morelli et al. [48]. Numerous clinical observations confirm the beneficial effects of combining PDE-5 inhibitors with testosterone [49-51]. Testosterone administration can also restore venous leaks from the penis attesting to its role on penile anatomy [52].

Summary

The increased interest in the health status of the aging male takes presently a more integrative approach and it appears that ailments typical of male aging such as LUTS, (visceral) obesity and metabolic syndrome, and erectile failure are significantly inter-related. A common denominator of the above ailments is lower-than-normal testosterone levels in a significant proportion of elderly men. This review addressed the potential connections between LUTS and late-onset hypogonadism. Intervention studies should be undertaken to test the clinical validity of the theoretically plausible interrelationship between LUTS and late-onset hypogonadism.