Factors Associated with Lower Urinary Tract Symptoms

When reviewing the literature examining risk factors for male LUTS, the evidence sources fall into three main categories: 1) longitudinal community-based studies, 2) cross-sectional epidemiological or clinical studies, and 3) case-control studies. The majority of the research has been cross-sectional, demonstrating associations, but not causal pathways, of risk factors and conditions.

1.4.1 Aging and lifestyle factors

Aging is a risk factor for LUTS prevalence and severity (58–71). While LUTS have long been consid-ered a normal part of the aging process, Parsons posits that there are modifiable risk factors during the aging process that can alter the onset of LUTS (72). The 5-year study of Parsons et al. of men aged 65 years and older found that increased physical activity had a protective effect against LUTS, whereas obesity (defined as body mass index [BMI] ≥30) was associated with a 41% increase in LUTS (73). Penson et al. found similar results in their 5-year Southern Community Cohort Study in a slightly younger, but more racially diverse, cohort of men (aged 40–79 years old) (73). Laven et al.

examined a cross-section of 27,858 men and found that abdominal obesity and low birth weight were associated with an increased risk of LUTS (74). The findings regarding physical activity were further supported by two case-control studies (70,75) and one meta-analysis (76).

Both metabolic syndrome (a complex of hypertension, obesity, hyperlipidemia, and insulin resis-tance) and vascular risk factors (hypertension, dyslipidemia, diabetes, and smoking) have also shown to be associated with LUTS, though results have been mixed.

One longitudinal study with a 4-year follow-up examined lifestyle risk factors and LUTS and found that a history of coronary heart disease, depression, and alcohol intake (7 drinks or more per week) were associated with moderate to severe LUTS. Body mass index, hypertension, dietary intake, and physical activity, however, were not associated with LUTS (71).

In cross-sectional population cohort studies, however, the results were mixed. Storage symptoms were associated with abdominal fat, plasma glucose, low high-density lipoprotein (HDL), and obstructive sleep apnea in a sample of men in Australia (62). In a community sample of men in China, Gao et al. did not find any relationship between metabolic syndrome and LUTS (60). However, Wong et al. found that history of heart disease was associated with an increased risk of moderate to severe LUTS in their cohort of men in China (70). Joseph et al. found that hypertension and diabetes were associated with an increase in LUTS among a population cohort of African American men in the US (77), while Kim et al. reported that a culmination of three or more vascular disease risk factors had a 3-fold greater risk of moderate to severe LUTS (61). Interestingly, in this last study, only increasing age was an independent factor associated with LUTS. Ponholzer et al. (78) also looked at the number of risk factors versus individual risk factors and their association with LUTS, and found that two or more vascular risk factors were associated with symptoms. Further longitudinal and cross-sectional population cohort studies need to be conducted in various community samples to gain a better understanding of the relationship between metabolic syndrome and vascular risk factors to LUTS.

Using cross-sectional clinical samples of patients, Demir et al. found that waist circumference (>102 cm), fasting blood glucose (>110 mg/dL), and hypertension were associated with LUTS (79).

Paick et al. reported that only elevated triglycerides were associated with moderate to severe LUTS, but not prostate-specific antigen (PSA), glucose, smoking, cardiovascular disease, BMI, hyperten-sion, or diabetes (80). Similarly, three other cross-sectional clinical studies did not find a relationship between metabolic syndrome and LUTS (64,81,82). Ng et al., however, found hyperuricaemia to be associated with LUTS (82).

The BACH investigators examined dietary intake and LUTS in a more detailed manner using a food frequency recall. In the baseline analysis of this study, dietary sodium and total energy intake (as well as waist circumference and diabetes) were significantly associated with LUTS, while carbohydrate and total fat intake were not (83). Additional analyses of the BACH data also found that dietary intake of carotenoids, lycopene, vitamin A, and vitamin C (with high-dose iron) was associated with decreased odds (40%–50%) of having LUTS; however, men taking high-dose supplemental vitamin C had increased odds (84).

The data regarding alcohol intake and smoking as risk factors for LUTS have been contradictory.

Moderate alcohol intake appears to have a protective effect against LUTS (75), whereas heavy alco-hol intake (defined as >72 g per day or >7 drinks per week) is associated with an increase in LUTS (71,77). However, several studies did not find any relationship between alcohol intake and LUTS

(70,80,85,86). Two studies reported that current and former smokers were at an increased risk for moderate to severe LUTS compared with non-smokers (77,82), while other researchers found no association between smoking status and LUTS (60,70).

While medications may cause LUTS (e. g. diuretics), there are a variety of medication classes that have not been evaluated. The association between psychoactive medications (atypical anti-psychotics [AAPs] and selective serotonin reuptake inhibitors [SSRIs]) and the prevalence of LUTS was exam-ined in the BACH study (87). No association was found with either AAP or SSRI use and LUTS in men (although an association with AAP use and LUTS was noted among women). However, the longitudinal study of Kok et al. identified antidepressants and calcium antagonist use as significant risk factors predicting moderate to severe LUTS (85).

Finally, neither horseback riding nor motorcycle riding lifestyles were associated with an increase in the prevalence of LUTS, although LUTS appeared to be associated with erectile dysfunction (ED) in motorcyclists (63,88).

1.4.2 Inflammation

As inflammation is thought to be involved in the pathogenesis of LUTS, the presence of inflam-matory markers may be used as objective risk factors for LUTS. This was demonstrated by Choi et al., who found significantly greater high-sensitivity C-reactive protein (hsCRP) levels in men with moderate to severe LUTS than in men with mild or no LUTS (89). However, in their study of men from a urology clinic, Chang et al. did not find a relationship between hsCRP and LUTS, leaving the usefulness of hsCRP open to debate (90).

In a cross-sectional web survey of men over 30 years old, Breyer et al. found that HIV-infected men reported greater LUTS than men without HIV. As well, HIV-infected men with AIDS reported more moderate and severe LUTS than HIV-infected men without AIDS (91). The authors posit that the increased risk for LUTS among HIV-positive men is related to chronic urinary tract inflammation, weakened immune system, toxicity of treatments, and/or the HIV virus itself.

1.4.3 Hormones

Very little has been done to evaluate the impact of testosterone on LUTS (92). Chang et al. examined the impact of total testosterone, calculated free testosterone, and bioavailable testosterone, and found that low levels of calculated free testosterone and bioavailable testosterone, but not total testosterone, were related to the presence of severe LUTS (90). In Demir et al.’s clinical sample of men with LUTS, only total testosterone levels were examined, and no relationship was found between total testoster-one and LUTS (79). The impact of testostertestoster-one on LUTS merits further investigation.

1.4.4 Erectile dysfunction

There is overwhelming evidence to support that ED and LUTS are related (8,59,62,63,65,66,70,79,85,93–

97). However, there is no evidence to support that ED is a risk factor for LUTS or that LUTS precede ED. Common underlying pathophysiology between these two conditions have been hypothesized (98), but given that the vast majority of research in this area is cross-sectional, there is no indication that one condition precedes the other. However, the 6.5-year follow-up longitudinal study by Kok et al. provides some data regarding a causal link between LUTS and ED, where ED is a significant determinant of LUTS (85).

1.4.5 Genetics

There is a lack of research examining genetic influences on the development of LUTS. In their longi-tudinal study, Kok et al. found that a family history of prostate cancer was a significant predictor of moderate to severe LUTS (85). While Wennberg’s longitudinal Swedish Twin cohort offers promise for the future, the most recent analysis of this study noted that there are too few men with LUTS in their cohort (age 20 to 46 years) to evaluate genetic influences (69).

In an analysis of over 184,000 men, racial/ethnic differences were reported in men with LUTS.

Hispanic and black men were at higher risk for moderate LUTS than white men, though only Hispanic men were at greater risk for severe LUTS (68). Asian men were at lower risk than white men for moderate or severe LUTS.