NEW TARGET FOR INTERVENTION: THE NEUROUROLOGY CONNECTION * Donald R. Ostergard, MD, FACOG ABSTRACT Urine storage and release are under the control of the parasympathetic, sympathetic, and somatic nervous systems. Coordinated interaction of multiple reflexes is required for normal bladder filling and voiding. Several neurotransmitters play a role in micturition. Urinary continence is preserved by maintaining lower pressure within the bladder and proximal urethra. During increases in intraabdominal pressure, this balance depends on equal pressure being exerted on the bladder and proximal urethra. Excessive movement of the urethra outside the abdominal cavity disturbs the balance and can result in urine leakage. Potential causes of urine loss can be evaluated effectively in the clinic, and basic urodynamic testing can confirm a clinical diagnosis of stress urinary incontinence. Clinicians might soon be able to treat stress incontinence with a drug therapy that augments urethral resistance by inhibiting the reuptake of neurotransmitters thought to make key contributions to micturition. (Adv Stud Med. 2004;4(3C):S220-S224) *Based on a presentation given by Dr Ostergard at a symposium held in conjunction with the American Urogynecologic Society 2003 Scientific Meeting. Professor of Obstetrics and Gynecology, University of California, Irvine; Director, Division of Urogynecology, Department of Obstetrics and Gynecology, and Associate Medical Director for Gynecology, Women s Hospital, Long Beach Memorial Medical Center, Long Beach, California. Address correspondence to: Donald R. Ostergard, MD, FACOG, Women s Hospital, Long Beach Memorial Medical Center, Female Uro-General Gyn, 701 East 28th St, Suite 212, Long Beach, CA 90806. E-mail: cmcgowan@memorialcare.org. Normal micturition involves complex interaction and coordination among a multitude of reflexes and neurotransmitters. Growing recognition of the many physiologic contributors to normal urine storage and voiding has given rise to new concepts about the management of bladder and urethral dysfunction. Stress urinary incontinence (SUI) is a common presenting clinical problem in urology, obstetrics and gynecology, and primary care practices. In most cases, the problem can be diagnosed by means of a careful and targeted office evaluation that includes basic urodynamic testing. A type of therapy based on recent advances in understanding the neurophysiology of micturition will soon be available, providing physicians with a new tool to help patients manage SUI without the need for surgical intervention. PHYSIOLOGY OF NORMAL MICTURITION The normal micturition cycle involves 2 distinct phases: storage and emptying (Figure). The process involves complex coordination and interaction among almost 3 dozen different reflexes. As urine accumulates and the bladder expands, action potentials generated by stretch receptors in the bladder wall are transmitted through the pelvic nerve. Reflex activation of the sympathetic nucleus causes release of norepinephrine via the hypogastric nerve and subsequent relaxation of the bladder via activation of beta-adrenergic receptors. At the same time, norepinephrine activation of alpha-1 adrenergic receptors causes urethral smooth muscle to contract. Sympathetic activation and concomitant suppression of parasympathetic activity allow the bladder to fill with little if any increase in pressure. 1 S220 Vol. 4 (3C) March 2004
With any sudden external pressure on the bladder, such as that caused by coughing or sneezing, a rapid somatic response (sometimes called the guarding reflex) occurs to prevent urine leakage. Action potentials are transmitted to pudendal motor neurons in Onuf s nucleus in the sacral spinal cord, and activation of these motor neurons causes the pudendal nerve to release acetylcholine. Rapid activation of nicotinic cholinergic receptors induces rhabdosphincter contraction to help avoid accidental leakage. As bladder storage approaches capacity, impulse transmission in the pelvic nerve increases substantially and activates the pontine micturition center. Descending impulses from the center stimulate the sacral parasympathetic nucleus to cause acetylcholine release. Muscarinic receptors in the bladder are activated, and bladder contraction ensues. In coordination with bladder contraction, the sympathetic and somatic reflexes associated with urine storage are inhibited to allow the urethra and rhabdosphincter to relax, resulting in efficient emptying of the bladder. In addition to the contributions of reflex pathways to normal micturition, conscious control over reflex activity can be exerted by cortical inhibition of bladder contraction and cortical stimulation of rhabdosphincter contraction. The cortical influence permits conscious postponement of micturition until voiding can occur at an appropriate time and place. 2 Several different neurotransmitters are involved in normal bladder function including acetylcholine, norepinephrine, serotonin, glutamate, gammaaminobutyric acid, and dopamine. 1 Norepinephrine is involved in several key functions in micturition, including control of urethral smooth muscle, central urine storage, and micturition centers in the brain and spinal cord, particularly in Onuf s nucleus. Serotonin exerts a controlling influence in the same centers. Glutamate plays a key role in bladder storage and is inhibited during the transition from storage to urge to voiding. A final requisite for micturition is normal urethral mobility, which typically is associated with good urethral tone and the ability to induce urethral contraction on command. Normal urethral mobility can be defined as a straining angle of less than 30 degrees from horizontal on a cotton-swab test. The proximal urethra remains in the abdominal cavity, and the proximal urethra and bladder are subject to the same pressure. Under those conditions, no urine leakage occurs. 3 PATHOPHYSIOLOGY OF SUI Urethral hypermobility is a key contributor to the pathophysiology of SUI. Hypermobility occurs when the proximal urethra moves outside the abdominal cavity and is no longer subject to the pressure forces that prevent urine leakage. As previously suggested, hypermobility can be defined by a cotton-swab test that reveals a straining angle of more than 30 degrees from horizontal. Because SUI is a multifactorial condition, hypermobility does not immediately cause SUI in every patient. The body has the ability to compensate to some extent for hypermobility to prevent urine loss. However, with repeated episodes of hypermobility over time, such as those caused by coughing or sneezing, patients lose the ability to compensate, and urethral hypermobility assumes a major role in the pathophysiology of SUI. 4 Figure. Normal Micturition Cycle Advanced Studies in Medicine S221
In some cases, urethral hypermobility coexists with intrinsic sphincter deficiency, which is defined by low urethral closure pressure or low leak-point pressure. Urine leakage from a relatively empty bladder in the supine position indicates a high probability of intrinsic sphincter deficiency. With the combination of urethral hypermobility and intrinsic sphincter deficiency, intra-abdominal pressure on the bladder easily overrides urethral resistance, causing urine loss. To put the pathophysiology into a practical perspective, consider that under normal circumstances the proximal urethra and bladder rest above the pelvic floor and share a common abdominal cavity. Water pressure of 100 cm impinging on the bladder creates an equal and opposite 100 cm of pressure on the proximal urethra. The equal and opposing pressures prevent urine loss. In response to a sudden increase in intra-abdominal pressure from a sneeze or cough, the striated urethral sphincter will contract as part of the guarding reflex to prevent urine leakage. In the SUI patient, the proximal urethra is outside the confines of the abdominal cavity, and the hypothetical 100 cm of water pressure on the bladder no longer transmits to the proximal urethra. Without the pressure transmission from the bladder, resisting forces in the urethra are easily overcome, and urine is lost. CLINICAL EVALUATION OF SUI Office evaluation of SUI should cover several key diagnostic possibilities, including urinary tract infection, overactive bladder, urinary retention, extraurethral causes of incontinence, and urethral diverticulum, as well as urethral hypermobility (see sidebar). The most common cause of urinary tract infection is Escherichia coli, which produces an endotoxin that can produce symptoms that mimic SUI or overactive bladder. A cystometrogram can accurately determine whether the patient has an unstable bladder. Urinary retention must be ruled out because of its potential to cause overflow incontinence. Postvoid of residual is the key measurement to diagnose or rule out urinary retention. Consideration of extraurethral causes of incontinence is of particular importance in patients who have had recent surgery involving the pelvic floor, such as a hysterectomy, which has a well documented incidence of fistulae. Ectopic ureter, though uncommon, also can cause symptoms similar to those observed in SUI and should be ruled out. Urethral diverticulum can be detected by palpation of the anterior vaginal wall. A diverticulum can fill with urine during voiding and then empty during subsequent exposure to stress to give the appearance of SUI. URODYNAMIC EVALUATION Accurate urodynamic assessment requires a combination of appropriate equipment and technique. 5 Multichannel urodynamic testing employs a microtransducer catheter that comprises a double catheter for the urethra and bladder and a single catheter for evaluation of intra-abdominal pressure in the vagina. Appropriate technique begins with patient positioning for the test. Urethral closure pressure differs substantially when a patient is in a supine position with an empty bladder versus upright with a full bladder. These differences should be taken into account during the evaluation. Accurate testing requires an upright patient who has a comfortably full bladder. Stress for the test can be created by continuous coughing or Valsalva maneuver. Regardless of how the stress is created, the technique should strive for equivalent intensity throughout the test. During the test, the microtransducer catheter should be withdrawn slowly through the urethra. Pressure profiles differ markedly between patients who have normal urethral function and those who have SUI. In a patient who has normal urethral clo- Office Evaluation for Stress Urinary Incontinence Evaluate for: Urinary tract infection Overactive bladder Retention Urethral hypermobility Extraurethral incontinence Vesicovaginal fistula Ureterovaginal fistula Ectopic ureter Urethral diverticulum S222 Vol. 4 (3C) March 2004
sure pressure, the supine position is associated with a pressure of about 80 cm H 2 0. Upon sitting upright, pressure increases to about 100 cm H 2 0. During a cough stress test, the pressure spikes and then falls back toward the point of normalization, perhaps resulting in a total difference of 75 cm in maximal water pressure; however, the pressure does not fall below the point of normalization, the point at which urine leakage could occur. In contrast, a patient with SUI and intrinsic sphincter deficiency might have a water pressure of 20 cm in the supine position, declining to 10 cm in the upright position. Looking across the functional length of the urethra, the difference might decrease from 24 cm in the supine position to 8 cm in the upright position. The differences emphasize the loss of continence defense mechanisms in the upright position. Similar changes occur with bladder filling. The cough profile demonstrates pressure equalization and urine loss. Continuous coughing results in continuous pressure equalization, and blips in the tracings associated with flow rate indicate urine loss, providing the basis for a definitive diagnosis of stress incontinence. Calculation of the pressure-transmission ratio (PTR) is not required to diagnosis SUI but is useful for anyone involved in SUI research. PTR represents urethral pressure with acutely increased abdominal pressure as a percentage of the simultaneously measured intravesical pressure. To calculate the PTR, divide the height of the pressure spike in the urethra by the height of the spike associated with the pressure transmitted to the bladder. In the normal setting, the PTR would be 100% in the proximal urethra, declining gradually across distal areas. In a patient with SUI, the PTR will be much lower in the proximal urethra and decline more rapidly along the length of the urethra. 6 NEUROLOGY OF MICTURITION Recent studies have suggested that the release and uptake of the neurotransmitters serotonin and norepinephrine play a key role in normal micturition. 7 Conceptually, norepinephrine and serotonin are thought to be released into the synaptic cleft in response to action potentials that reach the nerve terminal. The neurotransmitters continue from the synaptic cleft onto motor neurons in Onuf s nucleus, where serotonin and norepinephrine bind to postsynaptic receptor sites, increase motor neuron output, and induce contraction of the rhabdosphincter. Upon activation of the postsynaptic receptors, serotonin and norepinephrine are released and reabsorbed into the presynaptic nerve terminal by means of reuptake pumps. The end result is decreased output from the pudendal motor neuron. 8 Three primary mechanisms are involved in modulating the effects of norepinephrine and serotonin, as well as acetylcholine: Administration of a receptor agonist to mimic the effect of the neurotransmitter. When endogenous neurotransmitter is released from the nerve terminal, it binds to the muscle receptor, causing contraction. A circulating receptor agonist can induce the same effect, including muscle contraction, by binding to the muscle receptor. In contrast to the neurotransmitter, a circulating agonist is not reabsorbed into the nerve terminal by reuptake mechanisms, so that receptor stimulation continues until the agonist is metabolized or excreted. Use of a receptor antagonist to block the effect of the neurotransmitter. By blocking neurotransmitter binding to its receptor, the antagonist inhibits the neurotransmitter s effect on muscle. The inhibitory effect continues until the receptor antagonist is metabolized or excreted. Prolonging the effect of the neurotransmitter by inhibiting reuptake. Blocking reuptake causes the endogenous neurotransmitter to remain in the synaptic cleft longer and allows it to bind repeatedly to the post-synaptic receptor. Each of these strategies suggests possibilities for development of SUI therapies based on modulation of neurotransmitter activity. The first such therapy will likely become commercially available in the near future. The drug is duloxetine, which inhibits the reuptake of both serotonin and norepinephrine. SUMMARY Normal micturition is under the control of a number of reflexes that ensure normal urine storage Advanced Studies in Medicine S223
and release. Urethral hypermobility and intrinsic sphincter deficiency have key roles in the pathophysiology of SUI. An office evaluation, including basic urodynamic testing, can identify most patients with SUI. Recent advances in the understanding of the neurourologic components of micturition have raised the possibility that modulation of key neurotransmitters might have a role in the treatment of SUI. The first of these neuromodulatory agents should be available in the near future, giving physicians and patients the first approved pharmacologic therapy for SUI. REFERENCES 1. degroat WC. Basic neurophysiology and neuropharmacology. In: Abrams P, Khoury S, Wien A, eds. Incontinence. Plymouth, UK: Health Publications, Ltd; 1999. 2. Fraser MO, Chancellor MB. Neural control of the urethra and development of pharmacotherapy for stress urinary incontinence. BJU Int. 2003;91(8):743-748. 3. Walters MD, Shields LE. The diagnostic value of the history, physical examination, and the Q-tip cotton swab test in women with urinary incontinence. Am J Obstet Gynecol. 1988;159(1):145-149. 4. Bump RC, Norton PA. Epidemiology and natural history of pelvic floor dysfunction. Obstet Gynecol Clin North Am. 1998;25(4):723-746. 5. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn. 2002; 21(2):167-178. 6. Bump RC, Copeland WE Jr, Hurt WG, Fantl JA. Dynamic urethral pressure/profilometry pressure transmission ratio determinations in stress-incontinent and stress-continent subjects. Am J Obstet Gynecol. 1988;159(3):749-755. 7. Thor KB, Katofiasc MA. Effects of duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, on central neural control of lower urinary tract function in the chloralose-anesthetized female cat. J Pharmacol Exp Ther. 1995;274(2):1014-1024. 8. Thor KB. Serotonin and norepinephrine involvement in efferent pathways to the urethral rhabdosphincter: implications for treating stress urinary incontinence. Urology. 2003;62(4 suppl 1):3-9. S224 Vol. 4 (3C) March 2004