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.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, urodynamik
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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.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, nokturi, överaktiv blåsa
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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)

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, nokturi, överaktiv blåsa
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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.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, miktionsfrekvens, miktion

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)

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, miktionsfysiologi, miktion
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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.

Women

It may be of interest that women are affected by similar disorders (interstitial cystitis, vulvodynia and vulvo-vestibulitis(1)) that may co-involve Skene’s glands (also known as the lesser vestibular or paraurethral glands), which are the vestigial female homologue of the prostate. Not all women have these as I said above they are vestigial. Causes are unclear, but vestibulitis mat be related to contraceptives.
Curio: many men have a vestigial uterus the utriculum.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, interstitiell cystit, vulvodyni
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(1) Vulvodynia: Toward Understanding a Pain Syndrome Workshop, April 14-15, 2003, Bethesda, USA

HPA axis and sympathetic nervous system

At the 2006 and 2007 AUA meetings a couple of interesting presentations were held. "Heart rate variability and sympathetic skin response in men with CPPS" by U Yilmaz et al., looked at the heart rate (ECG) and hand and foot sympathetic response (by electrical nerve stimulation). CPPS patients differed from controls indicating a possible altered autonomic response.
"CPPS patients show evidence of allostatic overload" by Lee Jaeseop et al. was a small study of CRH (corticotropin releasing hormone), DHEA, EGF (epidermal growth factor), galanin and neuropeptide Y levels in urine. The assumption is that abnormal values indicate HPA axis dysregulation. The researchers found that CRH and DHEA was higher, and NPY and galanin lower, in CPPS patients compared to controls.

Anderson et al. reported that circadian cortisol levels differed in sufferers.
Another group, Dimitrakov et al., did a similar study to "identify adrenocortical hormone abnormalities as indicators of endocrine dysfunction". Their results did also indicate a possible HPA axis dysregulation too. More specifically they found higher progesterone, androstenedione and testosterone; and lower corticosterone and aldosterone than in controls. DHEA and estradiol did not differ in this study. The group suggests additional studies searching for signs of late-onset non-classical (congenital) adrenal hyperplasia. (Addenda: it would have been very interesting if they would also had measured prolaction, LH and FSH levels. Dr D Shoskes has purportedly measured prolactin in CPPS patienst and found no abnormalities.)

This is interesting as the micturition irregularities and pain in CPPS patients also are indicative of a possible HPA axis dyregulation. But the question to be asked is of course: are these changes part of the underlying cause of CPPS or an effect e.g. sleep disturbances caused by e.g. the micturition problems.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, hypofysen, HPA-axeln
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(1) Dimitrakov J, Joffe HV, Soldin SJ, Bolus R, Buffington CA, Nickel JC. Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome. Urology 71(2):261-266, 2008.