Overactive bladder in men as a marker of cardiometabolic risk

The lower urinary tract symptoms (LUTS) nocturia, urgency and frequency are grouped as “storage symptoms”. When troublesome, the presence of urgency plus one other symptom constitute overactive bladder (OAB).1 Dysfunction or irritability of the detrusor muscle of the urinary bladder is a primary cause of these symptoms, although coexistent prostatic disorders may be contributory. Based on American Urological Association symptom index scores, OAB affects about 25% of Australian men over the age of 40 years, and almost 50% of Australian men over the age of 70.2 It is associated with significant distress and very high direct and indirect costs.3

It is becoming increasingly evident that OAB may be associated with underlying systemic disease or disease risk factors, and with medication use. Strikingly, the risk factors for OAB are similar to those for cardiovascular disease and for diabetes mellitus. OAB and erectile dysfunction share similar risk factors, and so it is not surprising that erectile dysfunction and OAB are themselves closely linked.2

Data from recent epidemiological studies have shown an association between storage symptoms and factors related to obesity, in particular increased abdominal fat mass, elevated levels of fasting blood glucose, low levels of high-density lipoprotein cholesterol, hypertension, depression and lack of physical activity.2,4 All of these factors are also associated with metabolic syndrome. Other studies have shown an association between the presence5 and number of components6 of metabolic syndrome and storage symptoms. A recent review provides an in-depth analysis of the relationship between OAB and metabolic syndrome in men.7 In male rats, inducing the features of metabolic syndrome through long-term fructose feeding results in the development of an overactive bladder.8

Inflammation, as reflected by elevated plasma C-reactive protein, has been shown to be associated with nocturia9 and OAB.10,11 The association of OAB with both inflammation and depression is of interest given the increasing evidence of inflammation being important in the genesis of depressive disorders.12

Statins, which lower cholesterol levels, are associated with a lower prevalence of storage symptoms in men.13 This observation is of interest because myocardial infarction-prone Watanabe heritable hyperlipidaemic (WHHLMI) rabbits show detrusor instability,14 suggesting that hyperlipidaemia, or its associated vascular consequences, may play a role in the aetiology of OAB.

Obstructive sleep apnoea, a major determinant of cardiometabolic disease, has also been shown to be associated with storage symptoms.2 An increasing severity of obstructive sleep apnoea, as reflected by the apnoea–hypopnoea index, substantially increases the likelihood of the presence of OAB.15 Moreover, urgency and nocturia both affect, and are affected by, sleep quality.16

A relationship between nutritional factors and storage symptoms has also been shown. A greater intake of energy and sodium17 and lower levels of dietary lycopene, beta-carotene and total carotenoids18 are associated with an increased likelihood of significant storage symptoms.

The use of diuretics, in particular loop diuretics, has been associated with storage symptoms in older men.19

Detrusor muscle tone and contraction are regulated by a system analogous to that regulating vascular smooth muscle, involving L-type calcium channel receptors, nitric oxide (generated by nitric oxide synthase) and oestrogen receptors, in addition to M3-muscarinic receptors. Testosterone is converted to oestrogen by the action of aromatase, which is abundant in the urinary bladder; thus, the effects of testosterone are most likely mediated by oestrogen receptors promoting bladder relaxation. Just as occurs in vascular smooth muscle, we speculate that when insulin resistance, hyperglycaemia or inflammation are present, there will be instability in the detrusor muscle. Metabolic syndrome has also been shown to be associated with increased expression of M2,3-muscarinic receptor mRNA and protein in rats.8 Autonomic system overactivity or imbalance, which may be present in many of the aforementioned diseases, has been shown to be associated with OAB in a rodent model,20 and also in women.21 However as far as we can determine, such studies have not been performed in men with OAB.

OAB is associated with systemic disorders and, in particular, with reversible risk factors for cardiometabolic disease, including sleep disorders and depression. It is prudent therefore, in addition to excluding prostate and bladder disease, to specifically consider the presence of obstructive sleep apnoea, depression, the components of metabolic syndrome, lifestyle factors and the use of medication in all men presenting with OAB.

Specific risk factors such as hypertension, dyslipidaemia and disturbance of glucose metabolism must be managed appropriately. However, attention to diet and exercise, weight loss and reversal of sleep disturbances may reduce cardiometabolic risk and may improve erectile function and mood, as well as OAB, without the need for additional medication with its attendant risk of adverse effects. We have recently shown that diet-induced weight loss significantly improves LUTS and erectile, endothelial and left ventricular function22 in obese men with23 or without24 type 2 diabetes. Given the relationship between OAB and visceral obesity, inflammation, elevated blood glucose, hypertension, autonomic nerve dysfunction, depression and lack of physical activity, the focus on weight and associated cardiometabolic risk factors must be paramount.6 While intervention studies are highly suggestive of the benefits of weight loss, they are small, and further studies are needed that assess the prevalence and effect of weight loss on OAB symptoms in obese patients, particularly men.

In the presence of obstructive sleep apnoea, continuous positive airway pressure (CPAP) ameliorates nocturia,25 although CPAP may no longer necessary in many men if sufficient weight loss can be achieved and maintained.26

Consistent with the aforementioned mechanisms, it is perhaps no surprise that phosphodiesterase-5 (PDE-5) inhibitors have been shown to improve both LUTS and erectile function. On the other hand, in the presence of significant obstructive sleep apnoea, the use of sildenafil, a PDE-5 inhibitor, has been associated with worse overnight oxygen saturation in two small studies.27,28 This highlights the importance of performing a comprehensive assessment and identifying underlying disorders, so that the most appropriate treatment of a holistic and cost-effective nature, can be instituted.

Troublesome LUTS such as those that constitute OAB are common, severely compromise quality of life, and should be considered markers of underlying cardiometabolic disease or disease risk factors, irrespective of whether there are specific abnormalities of the prostate or other structures in the lower urinary tract. It is therefore essential to take the patient’s medical history, perform a physical examination and investigations, and to institute and evaluate a holistic management plan before considering specific medications that target muscarinic receptors, nitric oxide synthase, smooth muscle function or water balance.