**2. Etiology**

#### **2.1 Normal micturition**

The normal micturition cycle includes inhibition and contraction of detrusor smooth muscle, afferent signaling from the urothelium, contraction and relaxation of the smooth and striated sphincter muscles, and the central, peripheral, and autonomic nervous systems.

Urine storage occurs secondary to afferent signals stimulated by bladder filling. These afferent signals activate sympathetic pathways in the hypogastric and pudendal nerves, which lead to contraction of the smooth and striated sphincters, and at the same time inhibit detrusor contraction. In addition, high cortical centers are activated, (Griffiths et al, 2007), and stimulate the storage center in the pons. (Fowler et al, 2008) When further bladder filling leads to increased afferent signaling from the bladder, spinobulbospinal reflex pathways are carried via the pelvic nerve and spinal cord to the pontine micturition center, which activates parasympathetic pathways that cause bladder contraction and inhibit sympathetic and pudendal contraction of the sphincter (Fowler et al, 2008)

Diagnosis and Treatment of Overactive Bladder 165

is a reduction of blood flow due to increased intravesical pressure during voiding or the increased tissue pressure of hypertrophied bladder wall during filling. (Azadzoi et al, 1996)

The prevalence of OAB in both men and women increases with age. In addition, storage symptom scores increase with age while bladder compliance decreases. (Koelbl et al, 2009) This implies that bladder function in both sexes has age related alterations. (Araki et al, 2003) There can be difficulty however, in determining in the elderly, the difference between

Menopause and estrogen deficiency have been implicated in the etiology of OAB symptoms. (Koelbl et al, 2009) Estrogen receptors (ERs) have been identified in the bladder and urethra. (Blakeman et al, 2000) The effect estrogen has on bladder contractility has yet to be elucidated. However, it has been shown that estrogen replacement therapy can significantly improve the symptoms of frequency, urgency and urge incontinence. (Eriksen & Rasmussen,1992) In addition, a metaanalysis of the effects of estrogen therapy on symptoms of OAB in postmenopausal women showed that estrogen therapy was associated with significant improvements in all symptoms of OAB. (Cardoza et al, 2004b) Thus it appears that menopause plays role in the development of bladder overactivity and OAB symptoms in

Idiopathic detrusor overactivity is a diagnosis of exclusion of all other known causes. Mechanisms that have been proposed for idiopathic detrusor overactivity include myogenic,

Mills et al, noted that denervation is consistently found in detrusor biopsies from patients with non-neurogenic detrusor overactivity. (Mills et al, 2000) They hypothesize that partial denervation of the detrusor alters the properties of smooth muscle, which leads to increased excitability and increased coupling between cells. Thus, myogenic changes in the bladder

Another mechanism that has garnered interest in idiopathic detrusor overactivity is the roles of the urothelium and suburothelial myofibroblasts in afferent activation. The C-fiber afferents have endings in the suburothelial layer of the bladder wall, and may reach the urothelium. (Koelbl et al, 2009) Upon bladder distention ATP has been shown to be released from the urothelium. (Ferguson et al, 1997) ATP receptors on afferent nerve terminals are stimulated by ATP release to evoke a neural discharge. It has been proposed that there is up-regulation of the afferent activation mechanisms(eg. an increased generation/release of ATP increased sensitivity of afferent nerves to mediators, increased number of afferent

nerves) can cause the symptoms of OAB. (Koelbl et al, 2009)

(Greenland & Brading, 2001)

**2.2.2.3 Estrogen deficiency** 

**2.2.3 Idiopathic etiologies** 

urothelial and muscarinic.

increase contractility locally.

**2.2.3.1 Myogenic** 

**2.2.3.2 Urothelial** 

neurogenic and non-neurogenic causes.

**2.2.2.2 Aging** 

women.

For coordinated micturition to occur, parasympathetic stimulation of the detrusor occurs via cholinergic muscarinic receptors. Urethral smooth muscle contraction occurs chiefly by stimulation of alpha-adrenerigic receptors. (Fowler et al, 2008) In addition, a variety of neurotransmitter systems in the urothelial lining of the bladder and in bladder interstitial cells likely play a role in mediating bladder contraction and relaxation via afferent signaling. (Andersson, 2002) This complex interplay results in socially appropriate and effective voiding. Any disruption in this pathway can lead to storage and/or emptying disorders. Bladder overactivity may be related to neurogenic, myogenic, or idiopathic origins.

### **2.2 OAB etiology**

The presumed etiology of OAB is uninhibited bladder contractions, but overactivity is not sufficient to cause incontinence (e.g. OABdry). In addition, leakage symptoms may be due to factors outside of the lower urinary tract such as failure of compensatory mechanisms in the lower urinary tract (e.g. fascial and muscular urethral support "hammock" that compresses the urethra when there is increased abdominal pressure or when the pelvic muscles are contracted) , and functional impairments in some patients.
