Obesity and the Overactive Bladder
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- Fry, C.H. Curr Bladder Dysfunct Rep (2013) 8: 62. doi:10.1007/s11884-012-0172-5
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Obesity (BMI greater than 30 kg.m-2) and overweight (BMI greater 25-30 kg.m-2) are associated with an increased prevalence of pelvic floor disorders, including urinary incontinence and overactive bladder (OAB) syndrome. A positive association between obesity and OAB is present in women, although it is more difficult to demonstrate in men. OAB may result from several obesity-related conditions including the mechanical effect of increased body mass on the bladder, a result of type-II diabetes or the presence of metabolic syndrome. The underlying metabolic defects of the latter two conditions in generating OAB are discussed. Finally the involvement of endothelial dysfunction as a cause of OAB is considered, as this pathology is a result of several obesity-related conditions.
KeywordsOveractive bladderObesityOverweightBMIStress urinary incontinenceLUTSType-II diabetesMetabolic syndromeHypoxiaReactive oxygen species
An increase of basal metabolic index (BMI) in the population continues each year [1, 2] and poses increasing burdens on the individuals themselves, through the development of a number of morbid conditions, and on the healthcare budget. An overweight condition is regarded as a BMI between 25-30 kg.m-2, whilst obesity is defined as a BMI >30 kg.m-2. Of the many conditions associated with a raised BMI are included pelvic floor disorders (PFS) that include a range of conditions from overactive bladder, stress urinary incontinence, pelvic floor prolapse and anal incontinence. This article will be limited to the association between obesity or overweight and urinary tract conditions and propose potential causal links. Although most studies have concentrated on the association between obesity and lower urinary tract conditions, some have also included an overweight cohort to identify any continuous relationship between BMI and the prevalence of a particular condition. The term obesity in subheadings will include data from both cohorts.
Obesity and Pelvic Floor Disorders
If urinary incontinence (UI) is used as a PFS its prevalence is greater in women than in men . Several studies have identified obesity as an independent risk factor for UI in women [2–5] and moreover after surgical or non-surgical weight loss UI prevalence is reduced [6, 7]. In men the association is evident in some studies but absent in others [8, 9].
Urinary incontinence, in turn, is associated with a number of causative factors; significant among these is stress urinary incontinence (SUI) in women, and overactive bladder (OAB) syndrome in both men and women. There is a positive association between raised BMI and prevalence of SUI [10–12]. In accordance with this, SUI is also associated with an increased waist-hip ratio; this measure of obesity has been proposed to be superior to BMI as it reflects better ‘central obesity’ . Several mechanisms have been proposed including: a mechanical process whereby increased body weight raises abdominal pressure that transmits to the bladder lumen to overcome outflow resistance ; loss of pelvic floor support associated with obesity .
Overactive Bladder Syndrome
Lower urinary tract dysfunction is represented by a triad of symptoms; nocturia, frequency and urgency . These symptoms may or may not be associated with urinary incontinence, the latter occurring more often in women than men , presumably due to anatomical differences of the outflow tract. Urgency is a sudden compelling desire to void urine that is difficult to defer. Overactive bladder syndrome (OAB) is equated with this symptom complex in the absence of infection or other proven aetiology. When combined with urodynamic demonstration of uncontrollable rises of detrusor pressure during filling the complex suggests detrusor overactivity. Detrusor overactivity may be associated with neurological conditions (NDO), but in the majority of cases is idiopathic (IDO). However, OAB is also associated with outflow tract obstruction as with benign prostatic hypertrophy in men as the increase of outflow resistance generates bladder hypertrophy that results in altered detrusor muscle function, including an increase of spontaneous activity. The causes of OAB are unknown but are likely to be several-fold and related to: dysfunction of afferent mechanisms associated with bladder filling; damage to spinal and brain pathways involved in co-ordination of the micturition reflex; or alteration to the efferent neural and muscle pathways . The inter-relationship between obesity and particular pathologies that might lead to OAB are considered in more detail below.
Obesity and Overactive Bladder
Overactive bladder is significantly associated with obesity in women [10, 19–22]. The same observation is less easy to make in the male population with some finding no association [21, 23, 24] and others finding a weaker link between the two variables . However, for a group of women, participation in a structured behavioural weight loss programme which generated a relatively modest (8%) loss of weight, there was a significant improvement of urge incontinence episodes .
Different analyses have attempted to ascertain if different indices of obesity and OAB yield similar conclusions, and if a link between obesity and OAB is present in subsets of the target populations. A Finnish study used nocturia (≥2 voids per night) as an index of OAB and reached similar conclusions, namely that in women there was a positive association with being overweight or obese, such that 71% of women with nocturia in the study group were either overweight or obese, the association was weaker in men .
The association between BMI>30 kg.m-2 and OAB in the female population is stronger in women of pre-menopausal status compared to the general population, and if only the post-menopausal group is considered the association is lost . Whether this is a true effect of altered hormonal status or if other age-related co-morbidities also associated with OAB hide any relationship between OAB and obesity has not been evaluated.
Other studies have reported that reduced physical activity is associated with development of OAB. Whether this is an independent risk factor, or associated with obesity also requires clarification as obesity itself is generally associated with reduced physical activity. Certainly, lack of physical activity is associated with stress incontinence in women compared to more active counterparts of the same age . OAB in middle-aged or older women is strongly associated with poor health, as defined from questionnaires of general health, and physical impairment . This study claimed that these general health conditions were not causative, i.e. did not precede, of OAB, but rather developed in parallel.
Different measures of obesity have also been systematically analysed and compared: BMI; waist circumference; hip circumference; and waist-to-hip ratio . The latter are used to reflect better central obesity that is assumed to impact more on development of lower urinary tract symptoms. Some refer to these measures as a measure of adiposity, i.e. it is assumed that most of the weight gain is due to deposition of adipose tissue. In women, the increase of adiposity by whatever measure was positively associated with the probability of the subject experiencing OAB, with the waist-to-hip ratio being the least effective correlate. For men the relationship between an adiposity index and probability of OAB was more complex showing an actual negative trend for OAB with any adiposity ratio except waist-to-hip ratio, with a positive association with OAB only at higher values of BMI. These gender-dependent differences were independent of age between 30 and 70 years of age.
In summary, a positive association between OAB prevalence and increased adiposity may demonstrated in women, although this is more difficult to show in men. BMI and different measures of ‘central adiposity’ have been used. This relationship is especially evident in obese individuals and in some studies the trend has even been detected in the overweight, suggesting that this is a continuous relationship. Whilst most studies analyse data from either men or women, some do not and this may account for conflicting conclusions regarding the relationship between OAB and obesity in the general population. It is recommended that future studies should only use separate men and women cohorts.
Causes of OAB in Overweight and Obese Individuals
Because OAB has many potential underlying pathologies a number of factors associated with obesity may have a primary or secondary influence on its development. These include physical factors associated with raised body mass, factors produced by the increased mass of adipose tissue or co-morbidities such as vascular disease, diabetes or metabolic syndrome.
As described above in the context of stress urinary incontinence, an increase of body mass and BMI increases intra-abdominal pressure . A study of obese women with urinary incontinence showed that raised BMI values were associated with a corresponding increase of abdominal pressure, and less strongly but still significantly with a rise of intravesical bladder pressure . The implications are two-fold: firstly an increase of BMI and intravesical pressure are positively associated; secondly because the rise of abdominal and intravesical pressure were not better correlated the bladder wall acts as a physical damper implying that an increase of intra-abdominal pressure is also associated with a rise of transmural pressure.
Furthermore, the mean value of compliance reported in this group (42 ml.cmH2O-1) was lower than a reported value for healthy women , but the variability of values in both this study group and among control studies makes a statistical comparison difficult. However, if compliance were lower in obese patients then the threshold intravesical pressure to activate the micturition reflex would occur at smaller filling volumes, especially if starting from an already raised intravesical pressure and manifest as an OAB-like activity.
In the context of OAB a chronic rise of intravesical or transmural pressure could impact on bladder function in several ways, e. g: alter blood flow to the bladder wall; increase stretch of the bladder wall and influence afferent firing.
Bladder blood flow has a complex association with filling. In the human bladder, blood flow actually increases during filling until capacity is approached and intravesical pressure is above 20 cm H2O when flow starts to decline . This study further showed that in patients with low compliance bladders there were smaller increases of flow with filling and decreased perfusion at maximum cystometric capacity. This study was carried out on men with LUT symptoms, haematuria or follow-up for bladder cancer and their metabolic demographics were not reported. The conclusions to this study were similar to those in a conscious pig model in which compliant bladders showed no change to blood flow during filling whereas in low-compliance bladders filling was associated with progressive reduction of blood flow . A decrease of bladder blood flow would be expected to reduce PO2 in the bladder wall and generate acidosis . Hypoxia associated with bladder filling, especially with bladder outflow obstruction, has been measured in a canine model. Acidosis has complex effects on detrusor contractility, with an intracellular acidosis increasing contraction strength ; thus a component of overactive bladder activity might be associated with reduced blood flow in filling especially if compliance is reduced.
An increase of transmural pressure across the bladder wall, as may occur when abdominal pressure is raised in obesity, can also release neurotransmitters from the urothelium. Stretch or an increase of the pressure gradient across the bladder mucosa release a number of agents that can act as neurotransmitters, such as ATP . The ATP is proposed to activate afferents in the suburothelium of the mucosa and thus relay a sensation of filling , as well as induce spontaneous activity in the underlying mucosa via ATP itself or its breakdown products . An increase of stretch-induced ATP release is associated with a number of pathologies associated with increased urgency and this therefore represents an additional mechanism to generate increased urgency during filling . The increased ATP release and augmented spontaneous contractile activity under pathological conditions may be related to an increased suburothelial cell number . It would be of interest to characterise the histological structure of the bladder wall of patients with increased BMI.
Diabetes, Obesity and the Overactive Bladder
A link between being overweight or obese and diabetes, generally type-II, or insulin resistance is well-established [39, 40]. Moreover the odds ratio for diabetes increases significantly as BMI increases about five-fold from overweight to obese (30 > BMI > 39.9 kg.m-2) and grossly obese (BMI > 40 kg.m-2) . The question arises if diabetes is an independent risk factor for OAB or is linked to obesity. Because type-II diabetes has a higher prevalence in the ageing population conflicting conclusions describe it as an independent factor or not [12, 23]. A study of women with or without diabetes found that the odds of having OAB were the same for obese diabetic and non-diabetic women; non-obese diabetic women did not have raised odds for OAB . However, longevity of diabetes may be associated with OAB as its prevalence is 2.4-fold in patients with diabetes for more then ten years compared to those with the condition for a shorter duration .
However, bladder dysfunction is associated with diabetes that ranges from OAB to bladder underactivity and when there is a concomitant neuropathy the term diabetic cystopathy is used. This is characterised by reduced urge, increased bladder capacity and increased post-void residual volumes. Alternatively OAB may also be associated with diabetes, which in turn may result initially from polyuria and consequent bladder hypertrophy . Bladder hypertrophy is itself associated with increased bladder activity before it passes to a decompensated state characteristic of diabetic cystopathy. The pathogenesis of changes to bladder function associated with diabetes can range from alterations to detrusor smooth muscle or urothelial function and direct neuronal damage .
For diabetic patients with OAB, lifestyle modification through weight reduction is an effective initial strategy to reduce diabetes , that will in turn reduce the symptoms of OAB . Pharmacological therapy for the management of OAB may be useful for patients who find lifestyle modification is ineffective and OAB symptoms may be managed as for any population group. The use of botulinum toxin to reduce overactive bladder symptoms is now regarded as a successful alternative to conventional treatment but there have been no reported trials examining its action on the obese population. However, botulinum toxin treatment has been shown to cause a significant reduction of weight in an obese cohort by prolonging gastric emptying and reducing maximal gastric capacity . It may therefore offer an alternative therapeutic management of obese patients with OAB, with or without associated diabetes. Sacral neuromodulation has also been carried out for diabetic patients with overactive bladder syndromes. A study of such patients showed significant improvement of symptoms on a majority of patients, and a similar success rate to the general population. It was noted however that there was a higher rate of device failure as a result of infections .
Metabolic Syndrome and the Overactive Bladder
blood pressure: ≥130/85 mmHg or treatment of previously diagnosed hypertension
fasting glucose: ≥100 mg.dl-1 (5.6 mmol.l-1) or previously diagnosed type-II diabetes.
triglycerides: ≥150 mg.dl-1 (1.7 mmol.l-1) or treatment for this abnormality
HDL cholesterol: <40 mg.dl-1 (1.03 mmol.l-1) men, or <50 mg.dl-1 (1.29 mmol.l-1) women.
Several studies have shown associations between metabolic syndrome and genitourinary tract conditions including LUTS [50, 51], benign prostatic hyperplasia (BPH)  and erectile dysfunction . Because the definition of metabolic syndrome includes central obesity an increase of OAB prevalence may be expected in these patients compared to the normal population. However, the other conditions and co-morbidities associated with metabolic syndrome may exacerbate the prevalence.
A positive association between the prevalence of metabolic syndrome and LUTS was shown in a US male population, using an AUA-SI scoring questionnaire for LUTS . The American Urological Association Symptom Index (AUA-SI) is a questionnaire based on demonstrating LUTS as a result of BPH and contains four questions on storage and three on voiding. Metabolic syndrome prevalence was least with low AUA-SI scores and increased with moderate or severe scores; however prevalence was not increased as AUA-SI scores moved from moderate to severe. This association between the two conditions was maintained if only the voiding components of the AUA-SI score were evaluated, but not if the storage questions alone were used. Of interest also was that the association between AUA-SI score and metabolic syndrome prevalence was significant in men aged less than 60 years, but not in the older group, although this is contrary to other studies . Overall the data were consistent with a link between metabolic syndrome and prostate enlargement and voiding dysfunction but not directly with overactive bladder. The difficulty in showing an association between metabolic syndrome and OAB in men was also demonstrated in a Japanese study that showed a positive association between age and OAB prevalence independent of the presence of metabolic syndrome .
However, it has to be recognised that BPH, by causing bladder outflow obstruction and detrusor hypertrophy, will generate an overactive bladder phenotype, the basis of the so-called myogenic theory . This may be less significant in generating LUTS, as assessed by AUA-SI scores, than the decrease of voiding efficiency but nevertheless can contribute to total LUTS burden and offers additional avenues to generate therapeutic drug targets .
A corresponding study in women found a significant association between overactive bladder and metabolic syndrome. In this case subjects with diabetes, urinary tract obstruction and other co-morbidities were excluded . Metabolic syndrome was significantly more prevalent in patients with OAB than those without (about 65 vs 35%). In contrast to the above study in men, such an association was significant only in those aged more than 50 years and furthermore increased in the 60-70 decade compared to the 50-60 decade. Another study showed that in diabetic women additional metabolic syndrome increases the prevalence of OAB and it was hypothesised that this may be due to an exacerbation of the peripheral neuropathy associated with diabetes .
A variability in the association between metabolic syndrome and OAB is implied with the above studies. A small-scale study in the Korean population affirmed that in men there was no difference in the prevalence of LUTS between those who did or did not have concomitant metabolic syndrome. Whereas in women those with metabolic syndrome showed an increased prevalence of LUTS .
Animal studies can contribute to characterising the pathology of overactive bladder with metabolic syndrome. The fructose-fed rat develops an insulin resistance with characteristics similar to human metabolic syndrome . In such animals there is altered cystometry reminiscent of bladder overactivity, reduced contractility to muscarinic agonists an altered expression of muscarinic and purinergic receptors in detrusor tissue as well as alteration to cell proliferation and it remains to be determined if these correspond to similar changes in human tissue [61–63].
Obesity, Endothelial Dysfunction and Lower Urinary Tract Disorders
Proper vascular function crucially depends on the endothelium through its production of agents that regulate vascular tone, growth and proliferation of blood vessels, and inflammatory activity that influence development of conditions such as atherosclerosis. Endothelial dysfunction is an alteration of these properties that results in damage to the end organ and is associated with obesity-related diabetes, among other conditions . Endothelial dysfunction associated with hyperglycaemia is associated with a number of consequences, including the generation of reactive oxygen species (ROS) and a decrease of nitric oxide (NO) synthesis. There are several consequences to bladder function from an increased generation of reactive oxygen species or reduction of NO production. The loss of vasodilator tone would be expected to reduce blood flow to the detrusor, and has been considered above. However, a number of other pathways may be affected that may interfere directly with the properties of bladder wall tissue.
Installation of hydrogen peroxide (H2O2), as a source of ROS, into the bladders of rats activated afferent nerve fibres, specifically C-fibres, partly through a cyclo-oxygenase pathway. Installation of H2O2 was also associated with an induction of detrusor overactivity . H2O2 instillation also increased ATP and acetylcholine release into the bladder lumen that may reflect an overall increase of these compounds to activate afferent activity or smooth muscle contractility , these effects were reduced by installation of hyaluronic acid. ROS themselves depress detrusor contractility evoked by excitatory neurotransmitters through pathways that require proper characterisation . However, this paradoxically may increase spontaneous contractile function of the bladder as this enhances when nerve-evoked responses are suppressed. The importance of the urothelium and suburothelium in protecting against damage from ROS is evidenced by the high levels of antioxidants such as superoxide dismutase and glutathione in this layer .
The hypoxia associated with endothelial dysfunction may also impact on the development of bladder overactivity. Apart from the effects of low tissue PO2 on muscle function itself, as considered above, it may also affect urothelial function, as the mucosa (urothelium and suburothelium) is more vascularised than the smooth layer itself. Hypoxia induces the release of several angiogenic factors from the urothelium such as hypoxia-inducible factors and vascular endothelial growth factor (VEGF) . VEGF, in particular, also induces muscle and urothelial hypertrophy and so indirectly may contribute to overactive bladder function .
Overactive bladder (OAB) syndrome is an increasingly prevalent condition that greatly reduces the quality of life of individuals and represents an increasing healthcare burden. The incidence of OAB is increasing as the population ages and independently as obesity continues to increase. The positive association between OAB and obesity is especially evident in women, but more difficult to demonstrate in men for reasons that remain unclear. Several factors or co-morbidities associated with an obese state may contribute to the development of OAB. An increase of body mass itself by impacting on the bladder may induce OAB-like activity by raising pressure in the bladder or altering blood flow. Alternatively OAB prevalence is greatly increased in subjects with type-II diabetes and metabolic syndrome, themselves strongly associated with obesity. Again these associations are more easy demonstrated in women than men. Whether there is a causal link remains to be shown, a demonstration largely impeded by the fact that the pathology of OAB itself is unclear. Finally, obesity may induce endothelial dysfunction, either with or without diabetes and metabolic syndrome, that in turn can result in the appearance of an overactive bladder syndrome. Lifestyle changes to reduce the incidence of metabolic conditions such as diabetes and metabolic syndrome can lessen the impact of OAB, but more research is required into the pathological causes of this debilitating condition.
This article was written while the author was a member of an EU FP7 consortium, INComb.
No potential conflicts of interest relevant to this article were reported.