Micturition and the soul II -- antidepressants against CPPS ?

Mood disorders and pelvic disorders are commonly comorbid and antidepressants are effective treatments of nocturia and bowel disorders. Thus suggesting “a common, or at least overlapping, pathophysiology at a level where the functions of the different pelvic viscera are integrated” e.g.viscerosensory nerves, vagus nerve, the lumbosacral spinal cord and the pons (more specifically the locus coeruleus, Barrington’s nucleus, vagus nerve termini). (1,2) (Regarding the use of anti-depressants and cytokine-suppressants, e.g. etanercept, a TNF-alpha inhibitor, for CPPS, some studies have been done, but I have not found any information about what the results where. May I assume no success or too much side effects?)

Murine studies show “diffuse overlap within the brain stem and spinal cord of autonomic innervation to peripheral tissues” indicating a possible cause of referred pain from the bladder/pelvis and that “ongoing pathology” from a “dysfunctional lower urinary tract may cause symptoms and functional changes in distinct peripheral regions of the body” and that “flooding of these neuronal circuitries with noxious information from one peripheral organ may also cause changes within the system and other organs”.(3)

Experiments also indicate that even short time bladder obstruction / dysfunction may lead to neurobehavioural effects like hyper-arousal, sleep changes, anxiety, attention disorders and “disruption of sensorimotor integration”. (4) Question is if these disturbances are directly caused by the underlying cause of the bladder dysfunction, or as a consequence of the sleep disruption or some other factor. (Also see Micturition and the soul part I.)

Interestingly enough the same pathways are sensitized by chronic cold exposure, which may explain why cold worsens CPPS symptoms.(5) About which I'll talk inte next installment.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, nokturi, överaktiv blåsa, anti-depressiva medel, köld, etanercept, neurologiska besvär.
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(1) Valentino RJ, Miselis RR, Pavcovich LA. Pontine regulation of pelvic viscera: pharmacological target for pelvic visceral dysfunctions. Trends Pharmacol Sci 20:253-260, 1999.
(2) Goehler LE, Lyte M, Gaykema RPA. Infection-induced viscerosensory signals from the gut enhance anxiety: implications for psychoneurimmunology. Brain Behav Immun 21:721-726, 2007.
(3) Zermann DH, Ishigooka M, Schubert J, Schmidt RA. Is there a relationship between chronic bladder dysfunction and somatic symptoms in other body regions? 2. An experimental neuroanatomical approach. Int Urol Nephrol 37:263-273, 2005.
(4) Rickenbacher E, Baez MA, Hale L, Leiser SC, Zderic SA, Valentino RJ. Impact of overactive bladder on the brain: central sequelae of a visceral pathology. PNAS 105(30):10589-10594, 2008.
(5) Jedema H, Finlay JM, Sved AF, Grace AA. Chronic cold exposure potentiates CRH-evoked increases in electrophysiologic activity of locu coeruleus neurons.

Concluding remark about the urodynmic findings

Urodynamic and ecographic studies have shown a high prevalence of urodynamic abnormalities. Are these under-diagnosed in male urologic patients? The problem with any of the above conditions is: what came first? In some cases physiological changes may be the obvious precursor, in other case they may be caused by the subsequent chronic inflammation. Urography and trans-rectal ultrasound should be performed to rule out these problems.

CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, miktionsfysiologi, miktion, urodynamic findings, ultrasonography.

Varicocele and hemorrhoids

A higher prevalence of varicocele (=varicose veins in the scrotum) has been found in “chronic prostatitis syndrome” (sorry the category is from the study, but I guess NIH-III can be assumed) patients. About 15% were affected compared to 5% of the asymptomatic controls.(1-2)

CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, miktionsfysiologi, miktion, urodynamic findings, varicocele, hemorrhoids.
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(1) Pavone C, Caldarera E, Liberti P et al. Correlation between chronic prostatitis syndrome and pelvic venous disease: a survey of 2554 urologic outpatients. Eur Urol 37(4):400-403 2000
(2) Lotti F, Corona G, Mancini M, Biagini C, Colpi GM, Innocenti SD, Filimberti E, Gacci M, Krausz C, Sforza A, Forti G, Mannucci E, Maggi M. The Association between Varicocele, Premature Ejaculation and Prostatitis Symptoms: Possible Mechanisms. J Sex Med. 2009 Aug 11. [Epub ahead of print]

Concretions / calculi / calcifications

These are hardened grains that can form in the bladder, prostate or ductus deferens and ejaculatorius. The composition of prostatic calculi indicates that they too are caused by reflux.(1) Small concretions occur in healthy men, but men with many or larger ones have shown improvement upon elimination of those.(2-3)

CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, miktionsfysiologi, miktion, urodynamic findings,calculi, prostate, ductus deferens.
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(1) http://www.prostatitis.org/stones.html
(2) Geramoutsos I, Gyftopoulos K, Perimenis P, Thanou V, Liagka D, Siamblis D et al. Clinical correlation of prostatic lithiasis with Chronic Pelvic Pain Syndromes in Young Adults. Eur Urol 45(3):333-338, 2004.
(3) Shoskes DA, Lee CT, Murphy D, Kefer J, Wood HM. Incidence and significance of prostatic stones in men with chronic prostatitis/chronic pelvic pain syndrome. Urology 70(2):235-238, 2007.

Urodynamic problems and intraprostatic pressure

An often overlooked factor seems to be screening for physiological and mechanical and fluid dynamical causes related to bladder, prostate and seminal vesicles. Studies have found physical abnormalities, and a transrectal ultrasonography study found physical (urological) abnormalities or other conditions in as many as 70% of the patients ! (1)

The most common cause of pathology is reflux(2), or urine flow up into the canalicoli (i.e. prostate) is caused by urethral strictures (due to trigonitis or urethral stenosis, both uncommon in men, or muscular hypertonus or physical abnormalities(3)) or sclerosis/dysectasia of the bladder neck (cervicis vesicae) affecting normal defluition (“deflux”) of urine (micturition). Non-infectious epidydimitis may also occur for the same reasons. Reflux is thought to cause inflammation by the presence of purine and pyrimidine (uric acid) in the urine. (Aside: high values of uric acid in blood causes gout.) Another possible cause of inflammation could be turbulent flow of the urine damaging urethral tissues.(4)

A recent ultrasound study of the bladder neck area found differences of: prostate volume, hypoechoic periurethral zone volume, posterior prostate lip thickness, bladder neck thickness and bladder muscle (detrusor) thickness between CPPS patients and controls. No differences in calcifications were found.(5)

A study indicated that NIH-IIIa patients have significantly higher intraprostatic pressure than IIIb or BPH patients(6), This may be caused by strictures, as mentioned above, muscular tension or concretions, or by tissue damage caused by blood pressure and other problems affecting interstitial tissue pressure.(7) This latter would also be consistent with the presence of inflammation markers.

Fall et al. concluded that: “Urodynamic studies [of prostatitis patients] demonstrate decreased urinary flow rates, incomplete relaxation of the bladder neck and prostatic urethra, as well as abnormally high urethral closure pressure at rest. The relaxation of the external urethral sphincter during urination is normal”.

CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, miktionsfysiologi, miktion, urodynamic findings, intraprostatic pressure, ultrasonography, reflux. stenosis, trigonitis, varicocele, detrusor, urethral sphincter.
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(1) Nicolai M, De Thomasis R, Di Federico G, Palmerio A, Iantorno R, Tenaglia R. [Role of transrectal echography in the evaluation of obstructive seminal vesicle pathology in prostatitis syndrome] Arch Ital Urol Androl. 68 (5 Suppl):101-4, 1996.
(2) Mehik A, Leskinen MJ, Hellström P Mechanisms of pain in CPPS: influence of prostatic inflammation. World J urol 21:90-94, 2003
(3) Hochreiter WW Zbrun S CPPS and voiding dysfunction. Curr Urol Rep 5(4):300-304, 2004
(4) Martinez-Borges AR Turbulent urinary flow in the urethra could be a causal factor for benign prostatic hyperplasia. Medical hypothesis 67(4):871-875 2006
(5) Dellabella M, Milanese G, Muzzonigro G. Ultrasound evaluation of bladder neck complex alterations in CP/CPPS. 2005 EAU meeting, Istanbul. (Also published in J Urol 176:112-118, 2006. Correlation between…)
(6) Mehik A, Hellstrom P, Nickel JC et al The CP/CPPS can be characterized by prostatic tissue pressure measurements. J Urol 167(1):137-140, 2002
(7) Mehik A, Leskinen MJ, Hellström P Mechanisms of pain in CPPS: influence of prostatic inflammation. World J urol 21:90-94, 2003

Nocturia and quality of life

A couple of months ago I discussed how nocturia affects neurological health. Below follows a diagram presented at the EAU 2009 in Stockholm (based on Tikkinen et al poster presented at ICS 2008, abstract 434). It illustrates well how even one nocturnal void affects quality of life (QoL).



CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, miktionsfysiologi, miktion.

Micturition-concluding thought

Micturition troubles are a strong cause of worsened quality of life (QoL). There is no good explanation for those in CPPS, but the fact that many of the "irritants" affect vasopressin regulation and the pituitary is an indication of cause. Especially nocturia is very troublesome as it deeply affects daily life for persons with family and work. Improving nocturia by dietary changes and maybe additional small doses of vasopressin analogues would probably lead to much improved QoL for the average CPPS sufferer.

Pelvic tenderness

A study has shown that men with CPPS have more tenderness in the pelvic-pubic area. Internal and external "tender points" were examined.(1) How the tender points were selected and/or identified was not clear. The tender points bore no correlation to the fibromyalgia tender points.

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(1) Berger RE, Ciol MA, Rothman I, Turner JA. Pelvic tenderness is not limited to the prostate in CPPS… comparison of men with and without CPPS. BMC Urol 7:17-24, 2007.

Urinary nitrites

Urinary nitrites are higher in patients with enuresis (1) indicating a connection between nitric oxide (NO) regulation and enuresis ("over-active bladder"). "NO plays an important role in the micturition process and disorders [IC, cystitits, enuresis] of the lower urinary tract."(2) Some IC patients show significant improvement with decreasing bladder NO.(3)
Nitric oxide (NO) has been shown to be significantly higher in the prostatic urethra of NIH-IIIa patients, but not in NIH-IIIb patients.(4)

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(1) Al-Waili NS Increased urinary nitrite excretion in primary enuresis: effects of indomethacin treatment on urinary and serum osmolality and electrolytes, urinary volumes and nitrite excretion. BJU Int 90:294-301, 2002.
(2) Ho MH, Bhatia NN, Khorram O. Physiologic role of nitric oxide and nitric oxide synthase in female lower urinary tract. Curr Opin Obstet Gynecol 16(5):423-429, 2004.
(3) Hosseini A, Ehren I, Wiklund NP. Nitric oxide as an objective marker for evaluation of treatment response in patients with classic interstitial cystitis. J Urol 172(6 Pt 1):2261-2265, 2004.
(4) Hosseini A, Herulf M, Ehren I. Measurement of nitric oxide may differentiate between inflammatory and non-inflammatory prostatitis. Scand J Urol Nephrol 40(2):125-130, 2006.

Bladder lining findings

Many CPPS sufferers react with pain/discomfort on potassium instillations (a potassium ion containing fluid is injected into the bladder) in a manner similar to IC patients, but the so called potassium sensitivity test is not wholly reliable as both false negatives and positives are common. It is believed that the potassium sensitivity is caused by impaired “barrier function” of the bladder urothelium to irritants or cytotoxic substances in the urinary fluid. It is assumed that potassium influx into nerve and muscular cells causes abnormal nerve firing and muscular relaxation.

Sulfated polysaccharides, like heparin, are thought to lower adherence to the bladder and urethral etc mucosal wall, which would also improve urine flow dynamics. If adherence increases bacteria, molecules etc can attach to the surface, as well as flow become more turbulent.

Other research has shown that instillation with resinifera-toxin modulates nerve firing in such a way as to (permanently?) alleviate bladder related symptoms. See additional discussion under treatment.

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Prostate findings

Bacterial prostatitis
Inflammation in bacterial prostatitis is characterized by the "presence of polymorphonuclear leukocytes and macrophages in the glandular ducts, epithelium and/or adjacent stroma" around the acini or ducts. Stromal involvement depends on intraluminal inflammation(1). Other findings are: abnormal glandular ducts, epithelial atrophy, metaplasia and dysplasia, and hyperchromasia ("with polymorphism of the epithelial cell nuclei and cytoplasmic basophilia"). Changes that may be misinterpreted as cancerous. If palpated the prostate is often enlarged and "soft" in bacterial prostatitis.

CP/CPPS
In CP/CPPS "glandular atrophy with stromal fibrosis, accompanied by a mild residual inflammatory reaction" is commonly observed(2). But only 5% of biopsies show significant inflammation(3). Although variation between studies is high up to 100% (4) prevalence has been found. The variation is obviously due to the varying (read: poor!) selection criteria of the studies. There is minimal correlation between histopathology and visible/clinical symptoms, but histological findings increase with age and are more common in infertile men. If palpated the prostate is never abnormal in CPPS.

It is unclear whether some minimal inflammation of the prostate is normal or not, so if this is of any clinical use remains to be seen. The recent REDUCE trial involving 5597 subjects has shown that no "clinically meaningful" difference is present between healthy subjects and CP/CPPS sufferers.(5)

PSA levels are insignificantly elevated in CPPS (NIH III) and slightly to highly elevated in NIH IV. CPPS sufferers with elevated levels should be screened for cancer and BPH.(6)

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, prostata
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(1) Mehik A, Leskinen MJ, Hellström P Mechanisms of pain in CPPS: influence of prostatic inflammation. World J urol 21:90-94, 2003
(2) Mehik A, Leskinen MJ, Hellström P Mechanisms of pain in CPPS: influence of prostatic inflammation. World J urol 21:90-94, 2003
(3) True LD, Berger RE, Rothman I, Ross SO, Krieger JN. Prostate histopathology and CP/CPPS: a prospective biopsy study. J Urol 162:2014-2018, 1999.
(4) PHF Schatteman, L Hoekx, J J Wyndaele, W Jeuris, E van Marck. Inflammation in prostate biopsies of men without prostatic malignancy or clinical prostatitis. Eur Urol 37:404-412, 2000
(5) Nickel JC, Roehrborn CG , O'Leary MP, Bostwick DG, Somerville MC, Rittmaster RS. Examination of the Relationship Between Symptoms of Prostatitis and Histological Inflammation: Baseline Data From the REDUCE Chemoprevention Trial. J Urol. Jul 13 2007.
(6) Nadler RB, McNaughton Collins M, Propert KJ, Mikolajczyk SD, Knauss JS, Landis JR, Fowler JE jr, Schaeffer AJ, Alexander RB. PSA test in diagnostic evaluation of CP/CPPS. Urology 67:337-342, 2006.

Urodynamic findings

Coordination of voiding, sphincter and pelvic floor activity differs from controls. Average sphincter pressure is increased, while urine flow is decreased. Bladder neck and prostatic urethra may not be completely relaxed. Functional urethral length is increased and resting closure pressure may be higher than normal. Urethral sensitivity was increased, while the profile pattern is dysfunctional and/or obstructed. Cystometry is normal.(1)

It is unclear whether the muscular findings are causing the symptoms or an effect of an underlying pathology.

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(1) Zermann DH, Ishigooka M, Doggweiler R, Schmidt RA. Neurological insights into the etiology of genitourinary pain in men. J Urol 161(3):903-908.

Micturition and the soul

This great heading introduces an article by Gert Holstege (1) in which he describes the "close connection between micturition and emotion". He points out that "several species use micturition to signal important messages as territorial demarcation and sexual attraction". And goes on to point out that it is for this reason that "micturition is coordinated ... in the brainstem, where it is closely connected to the limbic system". Brain lesions on the mictirition control center of the pons cause Overactive Bladder (OAB) and urge-incontinence. What is interesting is that nucleus of Onuf (ON) controls both the somatic motoneurons controlling the urethral and anal external sphincter and some other muscles, which together form the pelvic floor. The ON is also involved in e.g. abdominal muscle regulation, breathing etc. The author suggests that micturition problems may be related to disrupted communication between the brainstem (where micturition is controlled) and the forebrain. The orbitofrontal cortex, that should be strongly activated is only weakly activated.

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(1) Holstege G. Micturition and the soul. J Comp Neurol 493:15-20, 2005

Nocturia and neurological health

Two interesting studies by Asplund and Asplund et al. showed that self-reported poor somatic and mental health, pain, sick leave and visual impairement all increased with increasing nocturnal voids, while quality of life decreased.(1,2) This is very interesting in view of the importance of sleep for immune function (see below) and the possibility of neurological causes. Hypercalciuria has been implicated with nocturia in children and with concomitant hypokalemia also with diabetes insipidus, while in adults hypertension has been associated with nocturia. Sugaya et al. (7) have also shown that patients with nocturia have higher levels of serum catecholamines (adrenaline, noradrenaline and dopamine) which indicates that nocturia is stressful per se, or caused by a disorder of or affecting the adrenal gland. Other causes are: heart disease, sleep apnea, bladder and prostate problems, diabetes mellitus, HPA dysfunction (nocturnal polyuria and diabetes insipidus).

Nocturia is the leading cause of sleep disruption in adults. It is not a sickness of old age but afflicts young adults, 35+, too. "Nocturia patients are sleeping on average only 2-3 hours before waking for the first void." Traditionally nocturia has been indicated if two or more voids per night, but nocturia once a night is almost as disruptive as twice a night. Especially if the void occurs during slow wave sleep (during the first 4 hours of sleep).(3) "This results in disruption of the restorative sleep period with physiological consequences such as mood disturbance, cognitive and memory impairment and reduced performance at work. In addition, it is accountable for increased morbidity and mortality, increased risk of falling, cardiovascular disease, depression and lowered immune response." Sleep disruption also causes lowered testosterone and LH levels. Especially if disruption occurs during REM sleep.(8) It is more bothersome for younger people especially as they have work and families to care for and cannot take a nap or two during the day.(4) (Notice that lack of sleep causes daytime tiredness, mood disturbances, memory impairment, increased falling, accidents, more often sick, decreased life expectancy, depression, diabetes, obesity etc.) Nocturia affects QoL as much or even more as prostate cancer (except terminal cancer) and cardio-vascular disease regardless whether it is one or more nightly voiding.(5)

The preferred treatment for nocturia is desmopressin as it ensure the longest uninterrupted sleep period. Time to first void is on average 4-5 hours. Desmopressin increaes mean initial sleep period with about 100 minutes while indiplon and temazepam only with about 45-50 and 65-70 minutes.(6)

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(1) Asplund R, Marnetoft S-U, Selander J, Åkerström B. Nocturia in relation to somatic health, mental health and pain in adult men and women. BJU Int 95:816-819, 2005.
(2) Asplund R. Visual impairment, sleep and nocturia in the elderly. Arch Gerontol Geriatr. 41(1):61-67, 2005.
(3) N Stanley, Sleep, is it a waste of time and is nocturia causing relevant problems?, EUA 2009 Congress
(4) JP Norgaard, Nocturia: a disease or a natural consequence of ageing, EUA 2009 Congress
(5) T Holm-Larsen Why treat nocturia... EUA 2009 Congress
(6) van Kerrebroeck et al Eur Urol 52:221-229, 2007
(7) Sugaya K, Nishijima S, Miyazato M, Ogawa Y. Central nervous control of micturition and urine storage. J Smooth Muscle Res 41(3):117-132, 2005.
(8) In papers by Luboshitzky and Axelsson. Additional detail in post about testosterone.

Micturition frequency in CPPS

Disrupted urinary frequency is an important problem in CPPS. Causes are unknown, but vasopressin dysregulation or desensitization of the kidney vasopressin receptors is likely, as may also be detrusor dyssynergia (meaning the muscles controlling the bladder do not function as they should either due to neurological causes or localized muscular dysfunction). In addition to this muscles in the pelvis floor and urethra may be dysfunctional ("uncoordinated").
See posts on the physiology of micturition and on nocturia for additional detail.

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Physiology of micturition

In very young children micturition has no circadian rhythm. A circadian rhythm with daily micturition and absence of nocturia (nightly vasopressin peak) will slowly assert itself during childhood and usually be mostly set by three years of age. Sporadical nocturia may though continue to occur for a few years. This situation is the essentially stable until old age. So it may safely be assumed that you should be able to undisturbed sleep for 6-8 hours and not need to immediately rush to micturate as soon as you wake up. (And certainly not to suddenly feel an overwhelming and even painful need to immediately micturate.) Normal average 24 hour diuresis is 1600 +/- 350 ml. Daytime average diuresis is about 1100 +/- 250 ml at age 30 and slightly lower in older people, about 800 +/- 150 ml.(1) (These figures vary somewhat and e.g. Raman et al. calculated 2200 ml as average normal diuresis.(2))

A healthy subject needs about 50 ml of liquid in the bladder, after a complete voiding, for some feeling of fullness. At about approximately 200 ml desire of voiding should start to occur, after which sensations of discomfort increase. At about 400 ml a strong urge to urinate is normally forcing an individual to void. (Stretch receptors in the detrusor signal the CNS, which leads to relaxation of the bladder neck, trigone, and urethra muscles.) During the day you should thus not need to micturate more than 3-5 times. Intervals between voidings should be longer than 2
hours with no feelings of urgency. (It should be noted that the Incontinence Society regards more than 8 voidings per 24 hours as an abnormal frequency a.k.a. an "overactive bladder".(3))

Regulation of micturition is very complex. It is an interplay between the HPA axis, the Pontine micturition center and neurological feedback from the bladder and pelvic floor. The bladder (detrusor muscle) is innervated by hypogastric (sympathetic nervous system) nerve fibres from the lumbar spinal region (control of storage) and pelvic (parasympathetic) nerve fibres from the sacral spinal region (to the ‘detrusor pelvic plexus’; control of voiding). Urethral smooth longitudinal and circular muscle are also innervated by hypogastric nerve fibres. The striated muscle of the urethral sphincter by pudendal nerve (somatic motor) fibres from the sacral spinal region. And the striated muscle of the pelvic floor by sacral nerve (somatic motor) fibres. The somatic fibres are involved in volitional micturition control (i.e. is under your "voluntary" control). Additional detail can be found in references 4-7.

Bladder filling is regulated by water homeostasis, especially the regulation of electrolyte levels (and then especially sodium) and blood volume (to avoid hypovolemia). This is in turn regulated by the release of vasopressin (AVP) and it’s binding to the type-2 receptor in renal principal cells. AVP production is regulated by specific regions of the hypothalamus and release by the pituitary. Regulation of AVP levels is also dependant on various hormones (PGE-2, bradykinin, dopamine, EGF etc). Vasopressin maximum occurs normally between approximately 1900 and 0700 hours. Nocturia may occure due to a shift of this interval.

Do notice that prostaglandin E2 levels are affected by many of the CPPS treatments, which may explaine their beneficial effect on diuresis/water balance (stimulates diuresis in the absence of AVP, otherwise it counteracts it). A full review of the current understanding can be found in Boone and Deen.(8)

A recent murine study (9) showed that partial bladder obstruction induced neurological sequelae (through locus coeruleus hyperactivity). It would have been interesting if the authors also had reported sleep patterns and changes in behaviour, to clarify if the causality was due to bladder distension or sleep disruption. Animal studies have shown that reduced serotonin levels trigger increased urinary frequency and detrusor overactivity. And in Europe duloxetine, a serotonin
norepinephrine reuptake inhibitor (anti-depressant) is approved for treatment of incontinence. A controversial treatment due to its adverse effects.

The "Musculo-Elastic Theory of anorectal function and dysfunction in the female" regarding "suspensory ligaments inactivating anorectal muscle forces" is also interesting as stress incontinence has been cured by surgical reinforcement of damaged ligaments correcting muscular dysfunction. An interesting overview is found in the journal of Pelviperineology.(10)

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(1) Asplund R. Nokturi och nattlig polyuri bland äldre [Nocturia and nocturnal polyuria in the elderly]. Läkartidningen 99(44):4370-4373, 2002. (In swedish).
(2) Raman A et al. Water turnover in 458 American adults 40-79 yr of age. Am J Physiol Renal Physiol 286: F394-F401, 2004
(3) Overactive bladder. ICS factsheet 2, july 2005.
(4) Andersson K-E, Hedlund P. Pharmacologic perspective on the physiology of the lower urinary tract. Urology 60(suppl 5A):13-21, 2002.
(5) Sugaya K, Nishijima S, Miyazato M, Ogawa Y. Central nervous control of micturition and urine storage. J Smooth Muscle Res 41(3):117-132, 2005.
(6) Birder LA, de Groat WC. Mechanisms of Disease: involvement of the urothelium in bladder dysfunction. Nature Clinical Practice Urology 4:46-54, 2007.
(7) Drake MJ. The Integrative Physiology of the Bladder. Ann R Coll Surg Engl. 89(6):580-585, 2007.
(8) Boone M, Deen PMT. Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption. Eur J Physiol 456:1005-1024, 2008.
(9) Rickenbacher E, Baez MA, Hale L, Leiser SC, Zderic SA, Valentino RJ. Impact of overactive bladder on the brain: central sequelae of a visceral pathology. Proc Natl Acad Sci USA. 105(30):10589-94, 2008.
(10) Pelviperineology Vol 27 N.3 September 2008.