LUTS and sexual dysfunction are highly prevalent in ageing men; the relationship between LUTS and sexual dysfunction has received increased attention recently because both diseases are highly prevalent, frequently associated in the same ageing men, and contribute significantly to the overall quality of life. For instance, in the Massachusetts Male Aging Study, 52% of men aged 40–70 years had some degree of erectile dysfunction (ED), ranging from 39% in men aged 40 years to 67% in those aged 70 years . Besides age, ED was also strongly related to comorbidities such as diabetes, hypertension and heart disease. Similar to ED, Berry et al. showed that the prevalence of histological BPH increased progressively with age, from 8% in the fourth decade to 82% in the eighth decade. The prevalence of gross, potentially clinically significant BPH lesions also shared this association with increasing age. In the Baltimore Longitudinal study, which followed prospectively 1057 healthy men for up to 30 years, the cumulative prevalence of a history/physical examination-based diagnosis of LUTS or BPH voiding dysfunction matched with the autopsy prevalence of BPH, ranging from 26% in the fifth decade to 79% in the eight decade of life . Similarly, in the Olmsted County Study , which followed a randomly selected cohort of men aged 40–79 years for 12 years, 26% of men aged 40–49 years had moderate to severe LUTS, and this increased to 46% in men aged 70–79 years. LUTS and sexual dysfunction also strongly affect men's quality of life [5,6].
The conventional opinion among urologists has long been that there was no relationship between LUTS and sexual dysfunction, except their greater occurrence with ageing. Little evidence supporting the connection was available until the mid-1990s, when several epidemiological studies assessing the prevalence of BPH and associated quality-of-life issues suggested that LUTS by themselves could affect sexual function. In a large cohort of nearly 6000 French men with LUTS, Lukacs et al. first reported in 1996 that impairment of patients’ perceived sexuality was related to both age and severity of LUTS. Later, many authors reported an association between LUTS and various aspects of sexual dysfunction [8–12].
Hence, in a cross-sectional study of 2476 Spanish men aged 25–70 years (the EDEM study ), the overall prevalence of ED assessed by the erectile function domain of the International Index of Erectile Function (IIEF) was 18.9%, ranging from 8.5% in men aged 25–39 years to 48% in men aged 60–70 years. Interestingly, the presence of LUTS was the strongest risk factor of ED, with an age-adjusted odds ratio (OR, 95% CI) of 2.67 (1.48–4.80), followed by rheumatic problems, 2.46 (1.64–3.71); circulatory problems, 2.39 (1.48–3.85); lung problems, 2.31 (1.12–4.74); diabetes, 1.98 (1.09–3.60); hypertension 1.72 (1.16–2.55) and hypercholesterolaemia, 1.62 (1.04–2.52). In a representative population sample of ≈ 5000 German men aged 30–80 years (the Cologne Male Survey ), the overall prevalence of ED was 19.2%, ranging from 2% in men in their forties to 53% in men in their eighties. The prevalence of LUTS was 72.2% in men with ED, compared with 37.7% in those without ED. Multiple logistic regression showed that, in addition to age, diabetes, hypertension and pelvic surgery, LUTS was an independent risk factor for ED. Similarly, in the UrEpik study , which included 4800 men aged 40–79 years from four different countries, the overall prevalence of ED was 21.1% with a linear increase with age (P < 0.001). After adjusting for age and country, men with diabetes were more likely to have ED (OR 1.57, 95% CI 1.09–2.25) followed by those with liver problems, 1.55 (1.03–2.33); LUTS, 1.39 (1.10–1.74); and hypertension, 1.38 (1.09–1.75).
The link between LUTS and sexual dysfunction was unambiguously confirmed by the Multi-National Survey of the Ageing Male-7 which included ≈ 14 000 men aged 50–80 years representative of the population of six European countries and the USA . This landmark study showed that most men aged >50 years were sexually active despite a strong decrease in mean sexual intercourse/sexual activity with LUTS severity (ranging from with 7.5 per month in men in their sixties to 3.2 per month in men in their eighties). ED assessed by the IIEF score was strongly related to LUTS severity (Fig. 1). When controlling for age, LUTS severity was by far the strongest predictor of ED, with an OR for severe vs mild LUTS of 8.90 (6.85–11.55) followed by diabetes, 3.01 (2.60–3.49); cardiac disease, 2.17 (1.92–2.46); hypertension, 1.83 (1.66–2.01) and hyperlipidaemia, 1.57 (1.41–1.73). Ejaculatory dysfunction (reduced amount of ejaculate and pain/discomfort on ejaculation) assessed by the sexual section of the Danish Prostate Symptom Score was also strongly related to LUTS severity. Similar findings were reported in Europe by Vallancien et al. in 1274 men with LUTS suggestive of BPH, and in Asia, in a large survey which included 1155 men aged 50–80 years . In these two studies, multiple regression analyses clearly showed that the severity of LUTS was the second most important risk factor for sexual dysfunction after age. Even a prospective analysis of the Medical Therapy of Prostatic Symptoms (MTOPS) study detected a strong association between various domains of sexual function (libido, erectile function, ejaculation, bother due to sexual problems and overall satisfaction with sex life) and LUTS severity . Interestingly, sexual function domains in MTOPS were also significantly related to two objective variables of BPH progression, peak flow rate and prostate size.
Hence, epidemiological studies provide clear evidence that LUTS and sexual dysfunction, including ED and abnormal ejaculation, are strongly linked [13–15]. However, a causal relationship between LUTS and sexual dysfunction cannot be established based on these data alone, as the underlying pathophysiological mechanisms need to be determined. Is sexual dysfunction the consequence of BOO, as suggested by Elliott et al., who found that obstructive LUTS were better predictors of ED than irritative LUTS, or does it reflect the psychological impact of LUTS on patient self-image?
The causal relationship between ED and LUTS can be explored using Hill's causality method, which separates causal from non-causal explanations. This establishes a link using general epidemiological data, case-control reports, and cohort studies grounded by a supportive plausible mechanism of action. The epidemiological data are examined for the strength of association (relative risk), between study consistency (replication of findings), dose–response effect and temporal relationship (effect of onset or cessation of LUTS on ED and vice versa). Moreover, even if there is a link between ED and LUTS from an epidemiological perspective, then the causal relationship must be shown to have biological plausibility before any widespread acceptance is possible. Four theories supporting biological plausibility currently exist: (i) the nitric oxide synthase (NOS)/NO theory; (ii) the autonomic hyperactivity and metabolic syndrome hypothesis; (iii) the Rho-kinase activation/endothelin pathway; and (iv) pelvic atherosclerosis.
The NOS/NO theory
This hypothesis attempts to explain the link between ED and LUTS by the reduced production of NOS/NO in the pelvis, which includes the penis, bladder and prostate (Fig. 2) . NO is a multifunctional molecule originally described as a vasodilator . It is synthesized from its precursor l-arginine via NOS, which exists in three isoforms; two are constitutively expressed in endothelial (eNOS) and neuronal (nNOS) structures, and produce small amounts of NO, whereas inducible NOS (iNOS) is induced by cytokines, infection or other stimuli, and produces large amounts of NO .
It is widely accepted that NO is important in the relaxation of corpus cavernosum smooth muscle and vasculature. Neurogenic NO is considered the main factor responsible for the immediate relaxation of corpus cavernosum, while endothelial NO is essential for maintaining relaxation . Conditions associated with reduced function of nerves and endothelium, e.g. ageing, hypertension, smoking, hypercholesterolaemia and diabetes, can cause circulatory and structural changes in penile tissues, resulting in ED.
NO is also present in the human prostate and bladder and putatively modulates smooth muscle tone. Histochemical staining and immunohistochemistry confirmed dense nitrinergic innervation of glandular epithelium, fibromuscular stroma and blood vessels in the normal human prostate . Interestingly, NOS/NO levels are decreased in the transition zone of human hyperplastic prostate and this may alter the relaxation of prostatic tone. The nitrinergic innervation is also less in hyperplastic human prostate than in normal prostate, and this may also contribute to affect voiding function . These findings are supported by the reduction in NOS gene expression with increased age in adult rat prostates, the reduced intensity of NOS immunohistochemical staining in the transition zone of human hyperplastic prostates , and relaxation of human prostatic smooth muscle exposed to NO in vitro.
The theory is further supported by characterization and functional relevance of cyclic nucleotide phosphodiesterase (PDE) isoenzymes of the human prostate . The isoenzymes, PDE-4 and PDE-5, are most abundant in the ageing prostate, although the functional relevance in relaxing smooth muscle is a matter of debate . Characterization of the human PDE-11A gene has also shown that this particular isoenzyme is more abundant in prostate than in other organs , although its relatively low abundance makes a pivotal role in the ED/LUTS relationship less plausible. The specific distribution of PDEs and use of PDE inhibitors present an opportunity for PDE isoenzyme manipulation to improve LUTS and ED simultaneously.
The NOS/NO theory therefore suggests that reduced NOS/NO results in smooth muscle cell proliferation, which may result in structural changes in the prostate and simultaneous increased contraction which affects outlet resistance and bladder compliance, leading to LUTS. Nevertheless, the recent finding that pharmacological or genetic decreases in iNOS in mice resulted in amelioration of functional and fibrotic changes in the bladder after partial BOO suggest that NO released in such conditions is detrimental for the bladder, and underlines the complexity of the NO system .
Autonomic hyperactivity and metabolic syndrome
It was also proposed that LUTS secondary to BPH is a part of the metabolic syndrome, which includes glucose intolerance, insulin resistance, obesity, dyslipidaemia and hypertension, all known risk factors for ED [28,29]. Manipulation of the autonomic innervation of the pelvis has a profound effect on prostate growth and differentiation . Increased autonomic nervous system activity has been shown to induce BPH in ageing rats, and ED . Concordant evidence also comes from observations in spontaneously hypertensive rats that develop autonomic hyperactivity, prostate hyperplasia and ED, and have increased voiding frequency and detrusor overactivity . Altered responses to corpus cavernosum nerve stimulation and smooth muscle contraction in these rats correlate with ED .
In humans, autonomic nervous system hyperactivity is also associated with signs and symptoms of LUTS secondary to BPH. McVary et al. as part of the MTOPS study, evaluated the autonomic nervous system activity in 38 men before enrolment. Tilt-table testing (a measure of autonomic tone and reactivity) revealed that increased sympathetic tone (as measured by changes in blood pressure, heart rate, urinary and serum catecholamine levels) was significantly associated with the level of LUTS even when controlled for cofactors known to influence the sympathetic tone (age, body mass index, abdominal obesity, C-peptide and insulin levels, physical inactivity). Further analyses showed that autonomic hyperactivity was strongly related to the total IPSS, the BPH Impact Index and the bother score (IPSS question 8) and to a lesser extent to the prostate total volume and transitional zone volume.
Given that increased sympathetic activity is strongly associated with LUTS, it is highly likely that a relationship between this increased tone and ED also exists. It was hypothesized that noradrenaline and α1-adrenoceptors, that mediate adrenergic contraction of smooth muscles in the prostate, bladder neck, urethra and the corpus cavernosum, constitute the common link (Fig. 3).
Increased Rho-kinase activation/endothelin activity
Smooth muscle contraction has been attributed to an increase in the intracellular calcium concentration. However, some regulatory mechanisms can modify the sensitivity of contractile and regulatory proteins to calcium, leading to a smooth muscle contraction without changing intracellular calcium concentration . One of these mechanisms is the Rho-kinase pathway, which is thought to be a major calcium-sensitising mechanism in smooth muscle.
Rho-kinase is activated by a G-protein, RhoA, thought to be coupled to excitatory α1-adrenoceptors, resulting in the inhibition of smooth muscle myosin regulatory light chain (MLC) phosphatase (Fig. 4). This leads to an increase in MLC phosphorylation by basal level activity of MLC kinase, and subsequent smooth muscle contraction with no changes in sarcoplasmic calcium concentration. Rho-kinase can be regulated by levels of NO, with increases in NO altering calcium concentrations.
The Rho-kinase pathway is likely to regulate smooth muscle tone in conditions in which tonic contraction or high basal tone is involved . The specific inhibitor of Rho-kinase, Y-27632, has been shown to decrease human and rat prostatic smooth muscle cell proliferation, and to decrease adrenergic contractions in rat prostatic tissue . Increased Rho-kinase activity, and consequently increased calcium sensitivity of the contractile machinery, can be found in the smooth muscle of unstimulated prostates from spontaneously hypertensive rats , in the detrusor of rabbits with partial BOO , in the corpus cavernosum smooth muscle of rabbits with partial BOO  or diabetes , and in vascular smooth muscle in hypertension . The actions of several factors beside noradrenaline (e.g. endothelin-1, angiotensin II), possibly involved in the increased smooth muscle activity found in both LUTS/BPH and sexual dysfunction, are dependent on Rho-kinase activity that acts downstream from these receptors . It is therefore tempting to speculate that the common link between LUTS and sexual dysfunction is increased Rho-kinase activity.
There is a high prevalence of vascular risk factors (hypertension, diabetes, hypercholesterolaemia, smoking) in elderly men, suggesting the possible involvement of atherosclerosis in the aetiology of BPH. Animal models mimicking pelvic ischaemia and hypercholesterolaemia show a striking similarity in the smooth muscle alterations of the detrusor and corpora. In the rabbit, chronic ischaemia results in fibrosis, smooth muscle atrophy and non-compliance of the bladder . Hypercholesterolaemia also interferes with bladder structure and compliance but to a significantly lesser extent. Similarly, chronic ischaemia results in stromal fibrosis, glandular cystic atrophy and increases in smooth muscle contractility of the prostate [44,45] and penile fibrosis in the corpus cavernosum tissue.
There are several potential mechanisms to explain these findings. Chronic ischaemia is associated with an increased production of TGF-β1 that correlates with the severity of fibrosis . It also impairs neurogenic relaxation in the prostate, which appears to involve the NO pathway, and may result in a loss of elasticity and increase in smooth muscle tone of the prostate . In fact, atherosclerosis-induced pelvic ischaemia is likely to be compatible with all theories mentioned above, as it may induce autonomic nervous system hyperactivity, reduce NOS expression, and up-regulate Rho-kinase .