Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia and Erectile Dysfunction


Benign prostatic hyperplasia (BPH) is very common in aging men and causes lower urinary tract symptoms (LUTS), which decrease health-related quality of life. A number of evidence suggests that other than aging, modifiable factors, such as increasing prostate volume, obesity, diet, dyslipidemia, hormonal imbalance, hypertension, metabolic syndrome, alcohol, and smoking, also contribute to the development of BPH and/or LUTS. More recently erectile dysfunction (ED) has been linked to LUTS/BPH as a part of this syndrome, suggesting that patients with BPH or LUTS easily develop ED, and that LUTS/BPH symptoms often coexist with ED. This chapter focuses on the physiology of ED, epidemiology, physiopathology, clinical aspects, and treatment of the combined phenotype LUTS/BPH-ED.


Erectile dysfunction, Benign prostatic hyperplasia, Lower urinary tract symptoms, Phosphodiesterase 5 inhibitors, Alpha-blockers, Epidemiology, Pathophysiology, Penile Doppler


Anatomy and Physiology of Erectile Dysfunction

The central erectile structures are bilateral corpora cavernosa, seen as dorsolaterally placed low-reflectivity bodies on ultrasound, surrounded by the thick fibrous tunica albuginea. The corpora cavernosa are formed by multiple sinusoids composed of endothelium and smooth muscle. These sinusoids are capable of substantial volume expansion. The ventrally located corpus spongiosum is enclosed by a thinner layer of tunica albuginea and surrounds the penile urethra. The corpus spongiosum is anatomically independent of the cavernosa. The three corpora are enclosed by the more superficial Buck’s fascia.

The penile arterial supply displays slight variation in its anatomy. The penis is usually supplied by branches of the internal pudendal artery, which continue as the penile artery. The bulbar artery supplies the proximal shaft and is the first branch of the penile artery, which then divides into the dorsal and cavernosal arteries. The cavernosal artery enters and supplies the corpora cavernosal via several helicine arteries, which in turn flow into the sinusoids via multiple arterioles. The intercavernous septum is perforated, allowing for communication of blood (and injected pharmacological agents) across the midline. Emissary veins pierce the tunica albuginea to drain into the deep dorsal vein, via the spongiosal, circumflex, and cavernosal veins [ ] ( Fig. 4.1 ).

Fig. 4.1

Penile anatomy.

The penile erectile tissue, specifically the cavernous smooth musculature and the smooth muscles of the arteriolar and arterial walls, plays a key role in the sequence of events that brings to erection. In the flaccid state, smooth muscles are tonically contracted, letting a small amount of arterial flow for nutritional purposes. The blood partial pressure of oxygen (pO 2 ) is about 35 mmHg. The flaccid penis is in a mild state of contraction, as shown by a further shrinkage following exposure to cold temperatures or after phenylephrine intracavernous injection. Sexual stimulation triggers the release of neurotransmitters from the cavernous nerve terminals. This results in relaxation of these smooth muscles and the following chain of events:

  • 1.

    Dilatation of the arterioles and arteries resulting in an increased blood flow in both diastolic and systolic phases;

  • 2.

    Trapping of the incoming blood by the expanding sinusoids;

  • 3.

    Compression of the subtunical venular plexuses between the tunica albuginea and the peripheral sinusoids. This results in a decreasing venous outflow;

  • 4.

    Stretching of the tunica to its maximal capacity, which occludes the emissary veins between the inner circular and the outer longitudinal layers and further decrease of the venous outflow;

  • 5.

    A pO 2 of about 90 mmHg and an intracavernous pressure of about 100 mm/Hg raise the penis from the dependent position to the erect state (the full-erection phase);

  • 6.

    A further pressure increase (to several hundred mm/Hg) with contraction of the ischiocavernosus muscles (rigid-erection phase).

Three phases of detumescence have been distinguished in animal studies. The first entails a transient intracorporeal pressure increase, indicating the beginning of smooth muscle contraction against a closed venous system. The second phase shows a slow pressure decrease, suggesting a slow reopening of the venous channels with resumption of the basal level of arterial flow. The third phase shows a fast pressure decrease with fully restored venous outflow capacity. Erection thus involves sinusoidal relaxation, arterial dilatation, and venous compression.

This process is dependent upon the parasympathetic nervous system, which induces smooth muscle relaxation allowing arterial pressure blood into the corpus cavernosum by nitric oxide (NO) action [ ]. NO is generated by three nitric oxide synthase (NOS) enzyme isoforms: neuronal, endothelial, and inducible. The neuronal isoform appears to be the primary mediator of physiologic erection [ ]. Neuronal NO induces erections while shear stress also propagates the erectile response via endothelial NO. Regardless of the source, NO modulates smooth muscle cyclic GMP to induce relaxation in a paracrine fashion. Vascular relaxation in turn allows arterial blood to fill the corpora that, by distention, creates a venous seal to maintain erection.

Epidemiology and Risk Factors of Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia and Erectile Dysfunction

The term erectile dysfunction (ED) is widely mentioned nowadays within both the medical professional and lay public communities, and many understand its basic meaning and reference to sexual dysfunction. However, its clinical implications are far more extensive and very likely less well understood.

The clinical condition, commonly referred to as ED, is accurately defined as the inability to attain and maintain a satisfactory erection of the penis to permit sexual intercourse sufficiently [ ]. Therefore, this definition is effective to establish sexual dysfunction boundary among an array of sexual disorders. It is fair also to comprehend the term as a descriptive symptom, in acknowledgment that it portrays erection difficulty or inability without specific attribution to a medical disease. However, this sexual dysfunction is indisputably associated with underlying adverse health conditions and risk factors, and clinical evaluation is used to establish the apparent clinical association. Current biomedical advances in sexual medicine affirm its real pathophysiologic basis and support its strong links with clinical health and disease. Moreover, beyond its multiple associations with health comorbidities, ED appears also to carry long-term health risks and adversely influence survival.

Men who recognize a defect in their ability to achieve an erection might not immediately recognize that ED is the problem. The quality of man’s erections deteriorates gradually over time. Consequently, men may be uncertain whether their erectile difficulties are permanent or temporary [ ] and may wait to see if ED resolves on its own [ ]. The most frequent reasons for such passiveness are the belief that lack of complete erection was part of a normal aging, sexual inactivity caused by widowhood, lack of perception of ED as a medical disorder, ashamed to talk with a physician about sexuality. Moreover, the stigma or embarrassment of having ED may lead to denial of the problem. For these issues, the incidence of ED is often undervalued. This problem is further increased by a bad clinical practice, in which specialists or general practitioners do not investigate sexual habits while managing other conditions. Many men with risk factors associated with ED have ED, including those who had moderate or severe dysfunction; however, the awareness of these men of having ED is often low [ ]. Considering the impact that ED has on quality of life and that it may often respond to treatment, ED should be suspected and assessed in men with risk factors, such as cardiovascular disease or presence of cardiovascular risk factors, diabetes mellitus (DM), and lower urinary tract symptoms (LUTS), regardless of their apparent level of awareness of ED [ ].

BPH causes LUTS and approximately 70% of men with LUTS/BPH have coexisting ED [ ]. This prevalence ranges from about 35% to 95% and increases with LUTS severity [ ]. Often patients referring to clinician for LUTS/BPH are found to have ED and vice versa. The prevalence of coexisting LUTS and ED increases with age; the severity of one disease often correlates with the other, with most men who sought treatment for either LUTS or ED having both conditions [ ].

LUTS/BPH and ED share similar risk factors, suggesting that the pathophysiology of LUTS and its underlying mechanisms may be similar to those of ED. The main potential risk factors for LUTS/BPH and ED are discussed as follows.


Nowadays, sexual activity has been reconsidered for aging men and the concept of sex is different from the past. Sexual activity is more common among older men than before, being an important component of quality of life for aging men [ ]. The majority of men between the ages of 50 and 75 years report that they are sexually active, but many are bothered by sexual problems, including ED. Because of LUTS/BPH treatment-related sexual side effects and the known strong association between LUTS/BPH and ED, the effects of LUTS/BPH medical therapies on sexual function are an important consideration when selecting the most appropriate LUTS/BPH treatment and when monitoring men on LUTS/BPH treatment.

Sedentary Lifestyle and Lack of Exercise

Many evidence support the central role of exercise in ameliorating both LUTS/BPH and ED. No daily walking is associated with more progressive LUTS than to stable or remitting LUTS [ ], and physical exercise at a level that can decrease low-grade clinical inflammation has been recognized as central factors influencing both vascular NO production and erectile function. Moreover, this lifestyle habit may have a role in reducing the burden of sexual dysfunction [ ]. It can be stated that moderate physical activity can have significant effects in improving erectile function as well as on serum testosterone levels. Therefore as an independent risk factor, there may be a role for lifestyle measures to prevent progression or even enhance the regression of the earliest manifestations of ED, as well as to help stabilization or remission of LUTS/BPH.

Cigarette Smoking

The past three decades have led to a compendium of evidence being compiled into the development of a relationship between cigarette smoking and ED. A positive dose-response relationship suggests that increased quantity and duration of smoking correlate with a higher risk of ED (dose-dependent and cumulative effect). The risk of ED is higher for smokers and exsmokers than nonsmokers, but this risk is higher for smokers than exsmokers. It is possible that smoking cessation can lead to recovery of erectile function, but only if limited lifetime smoking exposure exists [ ].

Studies have shown that the increased risk of ED associated with smoking becomes statistically significant only after 20 pack-years or more (20 cigarettes/day for 1 year). The physiopathological mechanism that leads to ED involves decreased penile neuronal NOS expression, decreased endothelial integrity, and diminished smooth muscle content. Smoking has also been shown to impair endothelial NOS-mediated vascular dilation in young men.

In addition, to the vascular damage associated with tobacco smoking, some data suggests that it may lower testosterone levels [ ]. This effect may also explain the reported relationship between smoking and LUTS/BPH. Indeed, heavy smoking (defined as ≥ 50 pack-years) was found to increase the risk of LUTS exacerbation and can affect storage and voiding symptoms. Subjects who smoked ≥ 50 pack-years in a lifetime had greater probability of severe deterioration of storage symptoms. Nicotine may increase sympathetic nervous system activity and could contribute to storage symptoms by increasing the tone of the bladder smooth muscle [ , ]. Furthermore, smoking could cause hormonal and nutrient imbalances affecting the bladder as well as collagen synthesis [ ]. It also affects bladder wall strength and detrusor instability [ ]. Therefore it is mandatory to ask for smoking cessation in the combined phenotype LUTS/BPH-ED to increase chances of controlling both diseases.

Excessive Alcohol Intake

The role of alcohol in development of LUTS/BPH-ED is more difficult to establish, compared to other risk factors. The moderate consumption of alcohol may exert a protective effect on ED in the general population [ , ], but some studies have not confirmed this protective role. Population-based studies showed that low-alcohol consumption was predictor of ED [ ], and, among drinkers, the odds were lowest for consumption between 1 and 20 standard drinks per week [ ]. In general, the overall findings are suggestive of alcohol consumption of a moderate quantity conferring the highest protection [ ]. The beneficial effects of alcohol on erectile function may be due, in part, to long-term benefits of alcohol on high-density lipoprotein cholesterol and other variables that increase the bioavailability of NO.

Data on the association between LUTS/BPH and alcohol consumption is conflicting. While some studies have shown that alcohol consumption is associated with a decreased risk of BPH, others have not. Moreover, some studies have reported an association between alcohol and LUTS but not BPH. Light drinking (less than one per day) may increase the likelihood of LUTS, whereas moderate-to-heavy drinking has shown no associations with LUTS. Urgency symptoms may be the exception, as they more likely occur among all alcohol drinkers. A review of studies concluded that daily drinking might increase the likelihood of LUTS, while decrease the risk of BPH [ ]. Indeed, one out of the two prospective studies examining LUTS found that daily drinking increased the risk of moderate-to-severe LUTS over a 4-year follow-up [ ], whereas the other showed that heavier drinking decreased the risk of high-moderate-to-severe LUTS or medically treated BPH over 7 years [ ]. It is plausible that light alcohol intake increases LUTS by a diuretic effect or increasing sympathetic nervous system activity, while moderately high alcohol intake decreases the risk of BPH and concurrent higher-severity LUTS by altering androgen levels [ , ]. More data is needed to establish how to advice patients with LUTS/BPH-ED regarding alcohol intake, but light alcohol consumption has not strong evidence to be denied.


The Massachusetts Male Aging Study (MMAS) showed that ED was associated with depressive symptoms after controlling for potential aging and para-aging confounders [ ]. ED is also associated with untreated and treated depressive symptoms. The association between ED and depression may be disorienting in clinical practice. Indeed, depression can be the consequence of or trigger for ED, as moderate or severe depressive mood or antidepressant drug use may cause ED and ED independently may cause or exacerbate depressive mood [ , ].

This kind of bidirectional relationship has also been discovered for depression and LUTS/BPH: depression can be not only developing from the pathological condition of LUTS/BPH, but also be triggered or exacerbated by systemic inflammation, which is also associated with LUTS/BPH [ , ].

Hypertension and Cardiovascular Disease

Most men with hypothetic vasculogenic ED present at least one traditional cardiovascular risk factor [ ]. These evidences allowed the consideration of ED as a clinical manifestation of a functional (lack of vasodilation) or structural abnormality in penile circulation as component of a systemic vasculopathy. It is well known that ED may predict 5 years before the development of a major coronary event in 11% of ED cases; this, in terms of preventive medicine, means that ED could be considered equivalent to the coronary disease [ ].

The association between cardiovascular health and ED has not always been so clear in past years. One of the first studies to ask about sexual function among patients with hypertension was the classic TOMHS ( The Treatment of Mild Hypertension Study ) [ ] and its results contributed to the false belief that ED was rare in this population since they found only 12.2% of men referring any degree of sexual dysfunction at inclusion. TOMHS excluded subjects with comorbidities, such as DM or hyperlipidemia, older and moderate or severe hypertension. At the end of TOMHS, ED was more frequent among those patents using more antihypertensive drugs or with systolic blood pressure over 140 mmHg. Other trials also refuse the high prevalence of ED among patients with hypertension [ ] probably due to the characteristics of the sample and the method to diagnose ED.

Another issue relates to antihypertensive drugs and ED development, is an usual popular belief to blame medical therapy for hypertension as the main reason of ED, especially when there is a temporal coincidence between symptom initiation and the use of antihypertensive drugs, in particular when including the “old” diuretics and ß-blockers [ ]. In almost all trials where this topic was studied, ED was not the primary objective and was assessed by patient reports instead of questionnaire evaluation or measurement of penile rigidity. Therefore there is a lack of definitive evidence even with ß-blocker and diuretics. Recently, a systematic analysis of trials concluded that only thiazide diuretics and ß-blockers, not including nebivolol, might influence erectile function. ACE inhibitors, angiotensin receptor blockers, and calcium channel antagonists were reported to have no relevant or even a positive effect on erectile function [ ].

Hypertension worsens also LUTS/BPH and may decrease the efficacy of α1-blockers, especially for the increased frequency and severity of storage symptoms [ ]. Moreover, men with hypertension are more likely to have a higher IPSS and large prostate volume than men without hypertension. This finding implicates a pathophysiological association between hypertension and LUTS, and the need to manage comorbid symptoms simultaneously [ ]. It is likely that hypertension plays a role in physiopathological mechanisms common to ED and LUTS/BPH, and focus on this modifiable risk factor is mandatory in clinical approach.


Epidemiologic data has confirmed that hyperlipidemia is a strong independent risk factor for the development of ED via endothelial damage and inflammation. Statins are first-line medical therapy for hyperlipidemia and protect the vascular endothelium. In fact, statins have been shown to improve endothelial function prior to altering lipid levels. Various metaanalyses have supported the conclusion that statins improve erectile function [ ].

Prostate synthesizes cholesterol at a level similar to the liver and accumulates it in a deposit within the gland in an age-dependent manner. More than 70 years ago, Swyer analyzed the cholesterol content in the prostate of BPH subjects and reported that its concentration was twice that in a normal prostate [ ]. Studies on the effect of dyslipidemia on prostate are heterogeneous, showing positive and negative association for circulating total and HDL-cholesterol, respectively, with prostate enlargement [ ]. However, other studies did not confirm the association. Many observations suggest that dyslipidemia per se is not sufficient to determine a LUTS/BPH phenotype, but the presence of other metabolic derangements, such as type 2 DM, favors the process, because of an unfavorable total and LDL-cholesterol particle size and density [ ].

Type 2 Diabetes Mellitus

Diabetic patients have a well-known increased risk of developing ED, with prevalence ranging from 35% to 90%. In addition, patients with DM tend to develop ED 10–15 years earlier than the ED patients without DM. They appear to present with more severe ED and suffer a greater diminishment in health-related quality of life components than the general population. ED secondary to DM is more resistant to medical management with phosphodiesterase 5 inhibitors (PDE5i). Moreover, poor glycemic control in patients with type II DM contributes significantly to the development and severity of ED.

Reactive oxygen species generated because of hyperglycemia impacts erectile function in multiple pathways. The chronic complications of macrovascular changes, microvascular changes, neuropathy, and endothelial dysfunction increase the odds that a diabetic man will develop ED. Furthermore, many patients with type 2 DM ultimately experience the negative impact of metabolic syndrome (MetS) on erectile function [ ].

The links between LUTS/BPH and glucose metabolism diseases were known since 1966 [ ]. Hyperinsulinemia/glucose intolerance and type 2 DM have been considered as potential risk factors for BPH/LUTS based on several studies. Strong evidence correlates insulin levels and prostate volume, being the first an independent predictor of the second in symptomatic BPH patients aged over sixty [ ], and this association remains significant after adjusting for total testosterone, other metabolic factors, and blood pressure [ ]. These findings indicate that insulin is an independent risk factor for BPH, most probably stimulating prostate growth acting on IGF receptors. More studies are needed to establish a relation between glycemic controls and control/worsening of LUTS/BPH.

Obesity/Waist Circumference

It is not easy to identify the sole contribution of obesity to the development of ED, as it is often coexistent with DM and hypertension. Nevertheless, data do suggest that it has an independent contribution to ED, being an independent predictor of ED. Weight loss in obese men is also associated with a regain of normal erectile function [ ]. In worldwide conducted studies, obesity—and in particular visceral obesity—is often comorbid with BPH. A recent metaanalysis, including 19 studies, reported a positive association between BMI and LUTS associated with BPH. Obesity can have a role even in early adulthood in determining a LUTS/BPH phenotype, as shown by a sonographic study conducted in 222 young men seeking medical care for couple infertility [ , ].


Testosterone is essential for erectile function. Literature has proven the necessity of androgens to maintain sufficient intracavernosal pressures and smooth muscle function to obtain an erection. The literature showing the role of testosterone replacement therapy (TRT) on erectile function is heterogeneous, and sometimes conflicting, showing positive correlation with erectile function or no improvement. It may be that the improvement in erectile function after TRT is transient, or that poor control of other modifiable risk factors for ED may have played a role against TRT. The recently published multicenter randomized double-blind placebo-controlled Testosterone Trial study provides solid evidence that TRT has a positive impact on overall sexual function in men 65 years of age or older. This trial consisted of three separate studies: The Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The sexual function trial showed that sexual activity and sexual desire were increased. Men in the TRT group reported significantly increased international index of erectile function (IIEF) score with a mean improvement of 2.64 points. This provides sound evidence that treating hypogonadism can improve erectile function [ ].

The role of androgens in determining LUTS/BPH and the physiopathological ways that may lead to it are still a matter of debate. Although an increased androgen signaling is clearly implicated in the first two waves of prostate growth (the first one at birth, the second one at puberty—under the influence of increasing testosterone levels), its role in the third phase (starting at mid-late adulthood and involving selectively the periurethral zone) is not completely clear yet. In fact, a clear dose-response relationship between circulating androgen levels and BPH has never been demonstrated. In addition, during male senescence, androgens tend to decrease and not to increase. Several recent studies indicate that a low testosterone, more than a high one, might have a detrimental effect on prostate biology. In fact, LUTS can even be lessened by androgen supplementation in hypogonadal men [ ].

Recent data indicate that not only low testosterone but also high estradiol can favor BPH/LUTS progression. It is important to note that circulating testosterone is actively metabolized to estrogens and part of testosterone hormonal activity depends upon its binding to the estrogen receptors (ERs) that are present in both the prostate and bladder. In addition, the enzyme P450 aromatase that converts androgens to estrogens is highly expressed not only in fat tissue but also in the urogenital tract. Marmorston and colleagues showed an increased estrogen/androgen ratio almost half a century ago [ ] reporting that the estrogen/androgen ratio in 24-hour urinary collections was elevated in men with BPH, as compared to normal controls. Many studies have reported a correlation between plasma 17β-estradiol levels and prostate volume or other features of LUTS/BPH, while others have not. The fear of clinicians to start a TRT on hypogonadal men with LUTS/BPH must be redefined based on this upcoming evidence [ ]. It is necessary to establish ways to determine which patients with LUTS/BPH, and even combined phenotype LUTS/BPH-ED, may benefit from TRT and in which terms; for this purpose, more studies are needed [ ].

Genetic Predisposition

The underlying genetic mechanisms linked to LUTS/BPH are not fully known. Animal models have shown changes, often aging related, in genes related to nervous control, vascularization of lower urinary tract, and smooth muscles, but these models have shown discrepancies between in vitro and in vivo studies. More can be added if these two models could be studied in the same animal [ ]. In addition, a correlation has been shown between inflammatory genes and LUTS/BPH. Genes involved in physiology of erectile function, as well as development of ED, also involve control of NOS genes encoding various types of neurotrophic factors, and K + channel genes; these have been proposed as targets for gene-based therapy when other treatments fail [ ]. Full comprehension of aberrant signaling pathways common to LUTS/BPH and ED could lead to a form of personalized medicine based on gene therapy [ ].

Protective factors include increased physical activity, increased vegetable consumption, moderate alcohol intake [ ].

Pathophysiology of LUTS/BPH and ED

Two main pathways in LUTS lead to the development of symptoms in men: benign prostatic obstruction (BPO) and benign prostatic enlargement (BPE). In addition to this setting, detrusor overactivity/overactive bladder (OAB) can occur in both men and women. This dichotomy associates with voiding symptoms and/or storage symptoms.

Voiding symptoms are associated with BPO, which is linked to BPE because of BPH. Storage symptoms are more complex and do not appear to be BPH related or BPE related because they manifest in men and women; more likely, these symptoms are associated with involuntary detrusor contractions or detrusor overactivity (DO) [ , ]. Involuntary detrusor contraction during the storage phase of the voiding cycle [ ] seems to lead to OAB symptoms. Storage LUTS may be associated with bladder dysfunction due to changes or alterations in afferent nerves or in interstitial cells within the bladder rather than BPE [ , ].

Four pathophysiological pathways might lead to increased risk of LUTS development. These include reduced nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling, chronic inflammation/steroid hormone imbalance/increased RhoA-Rho-kinase activity, autonomic hyperactivity, and pelvic atherosclerosis [ , ]. These factors can lead to reduced function of nerves and endothelium, alterations in smooth muscle tone, arterial insufficiency, reduced blood flow and hypoxia-related tissue damage, increased smooth muscle cell proliferation in the prostate, and bladder hypertrophy/noncompliance [ ].

The vascular system of the low urinary tract is regulated by smooth muscle cell relaxation, which responds to PDE5 inhibition. LUTS/BPH may develop from decreased oxygenation of lower urinary tract tissue, which might ensue with the above-mentioned risk factors. Atherosclerosis contributes also with remodeling of smooth muscle structure and function in the pelvic vasculature to its development [ , ] in penis [ ], prostate [ ], and bladder [ ]. This results in chronic ischemia of the low urinary tract often associated with LUTS/BPH [ ].

Moreover, three nerve systems are involved in physiopathology of LUTS/BPH: the pudendal, pelvic, and hypogastric nerves. The voiding process involves stimulation of the detrusor and inhibition of the parasympathetic innervation of the urethra and bladder neck hypogastric nerves, plus recruitment of motor neurons to the urethral sphincter [ ]. The storage process involves inhibition of the parasympathetic innervation of the detrusor muscle with urethral sphincter contraction via sympathetic innervation of the hypogastric nerves and recruitment of the pudendal nerves. Storage symptoms may be the result of bladder dysfunction due to changes or alterations in afferent nerves or in interstitial cells [ ].

Similar mechanisms have been studied in pathophysiology of ED and are strongly linked to this condition. The NO-cGMP pathway is important in smooth muscle relaxation and erection of the penis. Activation of the RhoA/ROCK signaling pathway decreases smooth muscle relaxation tone in corpora cavernosa. Increased sympathetic nervous system activity might affect smooth muscle and vascular tone via α1-adrenergic receptors in the penis. Finally, atherosclerosis can result in decreased perfusion/ischemia of penile arteries [ , , ]. All of these pathophysiological mechanisms are thought to contribute to the development of either ED or LUTS/BPH [ ] and can explain a link between these conditions ( Fig. 4.2 ).

Fig. 4.2

Pathophysiologic pathways leading to LUTS/BPH-ED.

Etiology and Clinical Aspects of LUTS/BPH and ED

This chapter will not widely report the standard definition of LUTS/BPH (please consult other chapters of the book).

The European Association of Urology (EAU) and the American Urological Association (AUA) [ ] guidelines define LUTS as storage (irritative) symptoms (daytime urinary frequency, urgency, and nocturia), voiding (obstructive) symptoms (straining, weak stream, intermittent stream, and incomplete emptying), or postmicturition symptoms (postmicturition dribbling) that affect the lower urinary tract [ , ].

The clinical diagnosis of LUTS/BPH is a multistep process used to eliminate prostate cancer, identify risk factors, and obtain physiological measures. Symptoms of LUTS/BPH are generally assessed using the International Prostate Symptom Score (IPSS) or AUA Prostate Symptom Index (AUA-SI), serum prostate specific antigen (PSA) levels, urinalysis, a transrectal ultrasound of the prostate, the measurement of the maximal urinary flow rate ( Q max ) assessed by uroflowmetry, and the measurement of postvoid residual volume assessed by postvoid bladder ultrasound.

The definition of LUTS/BPH used in clinical studies and in the literature varies widely. Men with LUTS/BPH have generally been identified:

  • histologically by having BPH;

  • with symptom severity assessed by total IPSS as being either mild (0–7), moderate (8–19), or severe (20–35);

  • with increased prostate size (BPE—defined as prostate volume ≥ 20 mL [ ]. Since patients with prostate volume ≥ 30 mL have 3.5 times greater risk of having moderate-to-severe symptoms, 3 times greater risk of acute urinary retention, and a significantly greater risk of requiring BPH-related surgery [ , ], we suggest to start the treatment when prostate volume is found ≥ 25 mL);

  • and with a Q max of 4–15 mL/s, which is indicative of BPO.

The large overlap of men with both LUTS and ED has shown the strong link between the two conditions, being age a known predictor of the combined phenotype and LUTS/BPH severity an even better predictor, thus establishing an independent link between LUTS/BPH and ED [ ].

According to the underlying causes, ED can be classified as ( Table 4.1 ):

  • psychogenic

  • organic; this one further divided in nonendocrine and endocrine

Table 4.1

Etiology of Erectile Dysfunction

Etiology of Erectile Dysfunction
Psychogenic (stress, depression, anxiety)

  • Nonendocrine

    • Vasculogenic

      • Arterial inflow disorders (atherosclerosis, ischemic heart disease, peripheral vascular disease, cavernosal disorders)

      • Venous outflow disorders (venous incompetence, injuries of tunica albuginea, Peyronie’s disease, often associated with arterial, neurogenic, or psychogenic etiology)

    • Neurogenic

      • Upper motor neuron lesions (above spinal nerve T10)

      • Sacral lesions (S2–S4)

      • Lesions of pudendal nerves

    • Iatrogenic

      • Pelvic surgery (nonnerve sparing)

      • Medications (thiazide diuretics, β-blockers, spironolactone, digoxin, 5α-reductase inhibitors, antiandrogens, luteinizing hormone-releasing agonists and antagonists, tricyclic antidepressants, selective serotonin reuptake inhibitors, benzodiazepines, antipsychotics and phenytoin, H2 blockers, opiates)

    • Dysgenesis issues (i.e., phimosis, frenulum breve)

  • Endocrine

    • Hypogonadism

    • Hyperprolactinemia

    • Hyper- or hypothyroidism

    • Cushing’s syndrome

    • Addison’s disease

In the past, ED was considered, in most cases, to be a purely psychogenic, but current evidence shows that more than 80% of cases have an organic etiology. The two milestone epidemiological studies (MMAS and EMAS) have studied this condition in men aged 40–80 years. However, the prevalence of ED in younger men is increasing even due to social awareness and overcoming taboo issues. In this context, a recent naturalistic study has demonstrated that one out of four men seeking medical help for ED is < 40 years old [ ]. Currently, it is believed that most cases of ED in younger men have a psychological basis; this is often strengthened by sudden onset, good quality spontaneous or self-stimulated erections, major life events, or previous psychological problems. However, recent studies have been brought that consider ED in younger men a possible spy of subclinical or future organic problems, linked to endothelial dysfunction, insulin resistance Peyronie’s disease, neurogenic disorders, medication side effects, early onset hypogonadism, dysthyroidism [ ]. Often, even organic causes lead in the end to a psychological component, regardless of the trigger event, since ED imposes negative effects on interpersonal relationships, mood, and quality of life.

Psychogenic ED is also called adrenaline-mediated ED (noradrenaline-mediated or sympathetic-mediated ED). Stress, depression, and anxiety are generally defined as heightened anxiety related to the inability to achieve and maintain an erection before or during sexual relations and are commonly associated with psychogenic ED. This association is explained by the role of noradrenaline as the primary erectolytic (antierectile) neurotransmitter.

Among the nonendocrine causes, the vasculogenic mechanism is by far the most common one and can be divided into arterial inflow disorders and venous outflow disorders (defects in the veno-occlusive mechanism).The arterial changes related to atherosclerosis, diabetes, cigarette smoking, and other vascular risk conditions can lead to arterial stenosis and changes in arterial wall (decreased elasticity), thus decreasing corpora cavernosa oxygenation and paving road to collagen deposition and decrease of smooth muscle/collagen ratio. This may eventually lead to inability of the cavernosa to compress the subtunical veins, causing secondary veno-occlusive dysfunction.

Veno-occlusive defects are, by themselves, uncommon. The pathophysiology of structurally based corporeal veno-occlusive dysfunction is related to increase in corporeal connective tissue content. It may be present alone in injuries in penile tunica albuginea or Peyronie’s disease, but it is often associated to arterial inflow disorders, neurogenic disorders with reduction in NO load, or psychological etiologies that involve an increase in orthosympathic activation (i.e., stress, depression, anxiety) [ ].

Other organic etiologies include neurogenic factors (affecting innervation and nervous function), with deficit in nerve signaling to the corpora cavernosa; this may be due to various conditions, such as spinal cord injury, multiple sclerosis, Parkinson disease, lumbar disc disease, pelvic fractures, traumatic brain injury, radical pelvic surgery (radical prostatectomy, radical cystectomy, abdominoperineal resection), and diabetic neuropathy. Upper motor neuron lesions (above spinal nerve T10) do not create local changes in the penis but can inhibit the central nervous system (CNS)-mediated control of the erection. Instead, sacral lesions (S2–S4 typically responsible for reflexogenic erections) cause functional and structural alterations due to the decreased innervation. These changes in innervation of cavernosal tissue lead finally to the reduction in NO load that is available to the smooth muscle. From this condition, chronic ischemia can occur, leading to reduced arterial inflow, and changes in smooth muscle/collagen ratio, resulting in veno-occlusive dysfunction [ ].

Among iatrogenic factors (caused by medical or surgical treatment), the most common is radical pelvic surgery. The damaged structures are usually nerves (of periprostatic plexus or cavernous nerves); sometimes damage is done to accessory pudendal arteries. A variety of drugs and medications have been studied in association with ED. However, a clear role in determining ED for many medications has been recently debated and results difficult to define. TOMHS compared five antihypertensive drugs with a placebo for changes in quality of life (sexual function was assessed by physician interviews). Chlorthalidone (a diuretic drug used in hypertension) had the greatest effect on sexual function 2 years after treatment, but the placebo achieved almost the same level at 4 years. Accordingly, chlorthalidone may potentiate ED earlier in those who are likely to develop the condition later in life (see “Epidemiology and Risk Factors of Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia and Erectile Dysfunction” section of this chapter for more) [ ].

The endocrine factors leading to ED include low serum testosterone levels, since androgens are the major regulators of penile development and function. Few data have established a clear role of other hormones in ED. A role has been documented for thyroid hormones, prolactin, growth hormone, insulin-like growth factor 1, dehydroepiandrosterone, and oxytocin. Although these hormones play a part in the pathophysiology of erection, their epidemiological impact is likely to be small and must be confirmed through further studies. After testosterone, prolactin is the most commonly altered hormone in men with sexual dysfunction; its main effect is to inhibit gonadotropin secretion to induce hypogonadism. Thus prolactin should be considered for further screening in ED patients with low serum testosterone and LH levels [ ] ( Fig. 4.3 ).

Fig. 4.3

Normal and pathological hypothalamic-pituitary-testicular axis. (A) Normally functioning hypothalamic-pituitary-testicular axis. Gonadotropin-releasing hormone (GnRH) stimulates the release of luteinizing hormone (LH). This triggers the testes to respond by secreting testosterone, which, in turn, exerts a negative feedback on the hypothalamus and pituitary gland. Both circulating LH and testosterone are within the normal range. (B) Central hypogonadism. The pituitary release of LH is impaired, the testes are no longer stimulated and testosterone production drops; both circulating LH and testosterone are decreased. (C) Subclinical or compensated hypogonadism. The testicular responsiveness to LH is impaired, testosterone production is maintained owing to overstimulation by LH; circulating testosterone is normal or borderline, whereas LH is increased. In this case, the system is driven to its maximal capacity and no further adjustment can be achieved. (D) Primary hypogonadism. In testicular failure, increases in LH serum levels can no longer sustain testosterone release by Leydig cells; circulating testosterone is low and LH is high.

Patients with combined LUTS/BPH and ED are more complex and heterogeneous to examine. They will seek medical care for the impact of LUTS on quality of life and/or management of ED. Thus an integrated urological and andrological approach is essential to effectively treat the condition from all points of view. Typically, these patients are aged 50–80 years and often have both ED and LUTS/BPH. Thus establishing an accurate medical and sexual history is essential to ensure the correct treatment. We suggest avoiding empirical treatment before establishing a correct diagnosis, as failure in first-step therapy may eventually lead to dropout. This is particularly true for elderly patients who can easier renounce to medical help for ED after the first failure. A practical set of signs and symptoms to look for is summarized in Table 4.2 .

Table 4.2

Differences in Symptoms of Erectile Dysfunction by Etiology

Symptoms of Erectile Dysfunction
Psychogenic Organic
Rapid and sudden onset Gradual onset
Situational, variable Often constant response
Defect in maintaining erection Defect in achieving and/or maintaining erection
Good nocturnal erection Lack or absence of nocturnal erection
Excellent response to PDEI-5 Erection better in standing position than lying down (in the presence of venous leak)

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Aug 25, 2019 | Posted by in UROLOGY | Comments Off on Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia and Erectile Dysfunction

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