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.

Is immune function in CPPS abnormal?

In CPPS “the baseline epinephrine output (but not cortisol and sex steroid hormones) correlated inversely with proinflammatory and positively with anti-inflammatory cytokine production. Thus, low vs high epinephrine excretors had a 2- to 5-fold higher TNF-alpha and IL-12 production but 2-fold lower IL-10 production induced by LPS. ...This indicates that baseline epinephrine conditions cytokine responsiveness and through this mechanism intrinsic hypo- or hyperactive adrenal medullas in some individuals may shape opposite cytokine profiles.”(1)

Interestingly CPPS improves during summer. Is it because of vitamin D regulation of immune function? Vitamin D is a potent immune regulator. It does e.g. downregulate excessive cellular response by inhibiting IL-12 and upregulating IL-10.

This may indicate CPPS sufferers are low epinephrine excretors (and thus have low IL-10) and have a hypoactive adrenal medulla. Which in turn may sustain a hypoactive SNS and cellular (Th1/Th17 biased) immune response (and thus autoimmunity).

Do CPPS sufferers have a low IL-10 phenotype? Actually it may be so. Shoskes et al and small Chinese study indicates a higher prevalence of low-IL-10 polymorphisms.(2,3) These are also more common in IBS(4), Crohn’s and other diseases. Another small Chinese study indicates the possibility of immune hypoactivity. They found that TGF-beta1 levels are lower and Foxp3 gene expression is defective.(5) IL-8, measured in seminal plasma, has also been found to be higher in CPPS, especially in NIH-IIIa and -IV.(6) NIH-IIIb has slightly elevated inflammatory markers, while –IIIa and IV have distinctly higher levels than IIIb. (The information about inflammatory immune response in CPPS is somewhat confusing, which is probably due to the fact that seasonal variation in disease activity is not accounted for -- in almost all the papers I have read. Vitamin D levels, for one, would have been interesting to know due to its effect on immune activity.)

IL-10 does also regulate IDO(7) expression, which has been proposed to mediate sickness behaviour, in cells derived from the HPA axis, leading to increased tryptophan availability for serotonin and melatonin pathways, which also may explain why CPPS sufferers feel better during summer.(8,9)

Estrogens (specifically E2, 17B-estradiol) has been shown (at female pregnancy levesl) in murine models to cause inflammation of the prostate histologically similar to those found in CP/CPPS (“chronic abacterial prostatitis”). Unfortunately estrogen levels have not been well studied in CPPS patients, but increased conversion to E2 has been found in SLE and RA. E2 has also been found to cause liver inflammation(10), which leads to increased SHBG levels and decreased free testosterone levels. Decreased testosterone should thus lead to amelioration, but other weak androgens may be converted to estrogens and thus sustain an inflammatory process. Unfortunately SHBG levels are also not studied in CPPS.

Andra bloggar om immunity, adrenal, cytokines, Th1/Th2, estrogens, SHBG, IL-6, HPA axis, IDO, IL-10, IL-12, hypoactive adrenal medulla, low epinephrine excretors.
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(1) Elenkov IJ, Kvetnansky R, Hashiramoto A, Bakalov VK, Link AA, Zachman K, Crane M, Jezova D, Rovensky J, Dimitrov MA, Gold PW, Bonini S, Fleisher T, Chrousos GP, Wilder RL. Low- versus high-baseline epinephrine output shapes opposite innate cytokine profiles: presence of Lewis- and Fischer-like neurohormonal immune phenotypes in humans? J Immunol 181(3):1737-1745, 2008.
(2) Peng FH, Yang JR, Peng LK, Xie XB. [Association of gene polymorphisms of cytokine and cytokine receptor with type III prostatitis] Zhonghua Nan Ke Xue 14(12):1069-1071, 2008. English abstract.
(3) Shoskes DA, Albakri Q, Thomas K, Cook D. Cytokine polymorphisms in men with chronic prostatitis/chronic pelvic pain syndrome: association with diagnosis and treatment response. J Urol. 168(1):331-335, 2002.
(4) Collins SM. Dysregulation of Peripheral Cytokine Production in Irritable Bowel Syndrome. Am J Gastroenterol 100:2517-2518, 2005.
(5) Wang SG, Bai J, Xi QL, Hu DL, Liu JH, Ye ZQ. [The role of CD4+CD25+ regulatory T cells in the pathogenesis of chronic abacterial prostatitis/chronic pelvic pain syndrome] Zhonghua Yi Xue Za Zhi. 88(40):2838-2841, 2008. English abstract.
(6) Penna G, Mondaini N, Amuchastegui S, Degli Innocenti S, Carini M, Giubilei G, Fibbi B, Colli E, Maggi M, Adorini L. Seminal plasma cytokines and chemokines in prostate inflammation: interleukin 8 as a predictive biomarker in CP/CPPS and BPH. J Eur Uro 51:524-533, 2007.
(7) Indoleamine 2,3-dioxygenase "is an that initiates the oxidative degradation of ... l-tryptophan, along the kynurenine pathway. The local cellular depletion ... may enable the host to inhibit the growth of various infectious pathogens ... IDO also represents an important immune control enzyme ... capable of suppressing local T cell responses to promote immune tolerance under [during] infectious diseases, foetal rejection, organ transplantation, neuropathology, inflammatory and auto-immune disorders and cancer". King NJ, Thomas SR. Molecules in focus: indoleamine 2,3-dioxygenase. Int J Biochem Cell Biol. 39(12):2167-72 2007.
(8) Tu, H, Rady P, Juelich T, Smith E, Tyring S, Hughes T. Cytokine Regulation of Tryptophan Metabolism in the Hypothalamic-Pituitary-Adrenal (HPA) Axis: Implications for Protective and Toxic Consequences in Neuroendocrine Regulation. Cell Mol Neurobiol 25(3-4):673-680, 2005.
(9) McNally L, Bhagwagar Z, Hannestad J. Inflammation, glutamate and glia in depression: a literature review. CNS Spectr 13(6):501-510, 2008.
(10) Straub RH. The complex role of estrogens in inflammation. Endocrine reviews 28(5):521-574.

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.

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

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

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, urinblåsa

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

Leukocytes, urates and citrates

Leukocyte (white blood cells) counts and common inflammatory markers have little or no correlation with CP/CPPS. Whether this be in urine (VB3), semen and or prostatic secretions. Cytokines show better correlation. See further discussion below in the sections on micro-organisms and inflammation.

Urates and other compounds typical for urine have been found in the prostate and prostatic calculi indicating reflux.

Added 2009-04-26
Various small studies have found a correlation between expressed prostatic secretion and semen contents of uric acid (urates) and CPPS symptoms. The assumption is that uric acid (urates) cause an inflammatory reaction and that the presence of uric acid is caused by reflux. (1-3)

Reflux, or retrograde flow, is the "backflow" of urine towards the prostate or kidney instead of out of the body. Causes of reflux are either "uncoordinated muscules" (dyssynergia) or physical abnormalities or urinary tract infections.

Citrate levels may be decreased in CPPS sufferers. (4)

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, urater, urinreflux
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(1) Persson BE, Ronquist G. Evidence for a mechanistic association between nonbacterial prostatitis and levels of urate and creatinine in expressed prostatic secretion. J Urol. 155(3):958-60, 1996.
(2) Hou BS, Xia XY, Pan LJ, Yang B, Shao Y, Shang XJ, Yao B, Cui YX, Huang YF. [Determination of uric acid in the expressed prostatic secretion of chronic prostatitis patients and its clinical significance]. Zhonghua Nan Ke Xue 14(3):245-7, 2008. Summary only, article in Chinese.
(3) Motrich RD, Olmedo JJ, Molina R, Tissera A, Minuzzi G, Rivero VE. Uric acid crystals in the semen of a patient with symptoms of chronic prostatitis. Fertil Steril. 85(3):751.e1-751.e4. 2006.
(4) Chen J, Xu Z, Zhao H, Jiang X. Citrate in expressed prostatic secretions has the feasibility to be used as a useful indicator for the diagnosis of category IIIB prostatitis. Urol Int. 78(3):230-4, 2007.
and
Chen J, Zhao HF, Xu ZS. The prostate has secretory dysfunction for category IIIA and IIIB prostatitis. J Urol. 177(6):2166-9, 2007.

General findings

In addition to patient self-reported symptoms various standard tests are performed to check for patient health (e.g. PSA test), bacteria and hyperplasia. All these are usually negative or within the normal range. The CPPS patient is 'healthy and well' despite pain, tiredness, frequency etc. And that quality of life is affected by conditions affecting micturition has been concluded repeatedly(1). It may be noted that older men with LUTS (lower urinary tract symptoms)(2) seem more prone to injuries from falls.(3)
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(1) E.g. Coyne KS, Sexton CC, Irwin DE, Kopp ZS, Kelleher CJ, Milsom I. The impact of overactive bladder, incontinence and other lower urinary tract symptoms on quality of life, work productivity, sexuality and emotional well-being in men and women: results from the EPIC study. BJU Int. 2008 Jun;101(11):1388-95. And Bernardes J, Cameron E, Dunn P."A summary report on the impact of Prostatitis and Benign Prostatic Hyperplasia on men's lives and those of their families", discussions on self-help group message boards etc.
(2) This is a borderline wastebasket term. For a fuller discussion see:
Chapple CR, Wein AJ, Abrams P, Dmochowski RR, Giuliano F, Kaplan SA, McVary KT, Roehrborn CG. Lower urinary tract symptoms revisited: a broader clinical perspective. Eur Urol 54(3):563-569, 2008.
(3) Kellogg Parsons J, Mougey J, Lambert L, Wilt TJ, Fink HA, Garzotto M, Barrett-Connor E, Marshall LM. Lower urinary tract symptoms increase the risk of falls in older men. BJU Int. 2009 Jan 9. [Epub ahead of print]

Seasonality etc part 2

Why these cycles? It is not uncommon in disease.

Many disorders show seasonality, but it is seldom explained. In an article in Medical hypotheses the authors (1) suggest that “temporal variations of autonomic balance” affect disease. What they essentially suggest is an expansion of the Th1/Th2 balance hypothesis of disease (which is a convenient simplification). If the immune system is over-balanced towards Th1 response (aka parasympathetic activity, Th1 bias, innate or [intra-]cellular immunity) it supposedly responds well to cancer cells, viruses, yeasts and intracellular pathogens but less well to extracellular pathogens. On the other hand auto-immune disease is more common.

If on the other hand immune response is prevalently Th2 (aka sympathetic activity, Th2 bias, adaptive or humoral immunity) it combats bacteria and extracellular organisms. But allergy and asthma is more common.

Th1/Th2 response shows a circadian rhythm with Th1 prevalence during sleep and Th2 prevalence during daytime. Diseases more common / worse during daytime (thus worsening because of increased Th2 and decreased Th1 response) are e.g. stroke, arrhythmias, seizures, sepsis and asthma. A seasonal pattern of increased Th2 bias during winter and Th1 bias during summer is also postulated.

Disease disrupting sleep will dampen Th1 response and thus worsen disorders affected by this.

They also suggest that Th1 bias is stronger in childhood and senescence (old age).

Their ideas are interesting as CPPS causes sleep disruption, remits during summer and is more common in mid-life. All of which suggest that Th2 bias worsens CPPS.

I’ll get back to this topic when discussing vitamin D, sleep and the HPA axis.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, biologiska rytmer, Th1/Th2-balans
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(1) Medical Hypotheses 63(1):155-177, 2004. Articles by AJ Yun, PY Lee and KA Bazar.

Counter indications part 2 -- why alcohol, caffeine and citrus?

I cannot but speculate, but all of these have in common that they affect vasopressin levels and the CNS.

Alcohol (ethanol)
“Humans have practiced the art of fermentation for millennia, observing the many actions of ethanol on physiology and behavior in the process. Despite our familiarity with ethanol, we have remarkably little insight into the mechanisms by which it reduces inhibitions and anxiety, nor do we know much about how it produces signs of more severe intoxication.” (1)

What is known is that ethanol affects plasma AVP concentrations thus affecting water balance. Ethanol does also affect the HPA axis in other ways modulating the release of e.g. adrenocorticotropic hormone (ACTH) and corticosterone (CORT)(2) and human growth hormone (hGH). The latter is interesting as acute application of GH results in a reduced urinary electrolyte and water excretion(3), while alcohol suppresses hGH secretion and LH, FSH, testosterone, estradiol etc.

Coffee, tea and chocolate (caffeine)
Caffeine has been shown to induce relaxation and increased alertness and cognition in lower doses, as well as anxiety and nervousness as dosage increases. Even panic attacks in individuals with high anxiety (Bourin et al. 1998). Caffeine also increases corticosterone, cortisol and ACTH levels.

Citrus fruits
It is intriguing that citrus fruit would affect CPPS. Current hypothesis suggest that citrus fruit act as irritants in the bladder. New research suggest that apigenin (a bioflavonoid found in citrus fruits, but also e.g. celery and parsley) may affect the CNS (HPA-axis). Murine tests has e.g. shown it to affect dopamine and serotonin, and to decrease serum corticosterone levels.(4) Other research indicate that it "inhibits the proliferation of prostatic stromal cells"(5), i.e. may inhibit the development of benign prostatic hyperplasia. Is there enough apigenin in eaten citrus etc to have any effects? Further research is needed.

Added nov 18 2009:
As vitamin C deficiency causes diminished thrombosis and fibrinolysis (blood clotting) a speculative cause for citrus exacerbations may be improved blood clotting ability. Especially as most successful CPPS treatments seem to decrease the propensity for blood clotting.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb
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(1) Harris RA, Trudell JR, Mihic SJ. Ethanol's molecular targets. Sci Signal. 1(28):re7, 2008. (I liked the introduction to their report.)
(2) Haddad JJ. Alcoholism and neuro-immune-endocrine interactions: physiochemical aspects. Biochem Biophys Res Commun. 323(2):361-71, 2004.
(3) Dimke H, Flyvbjerg A, Frische S. Acute and chronic effects of growth hormone on renal regulation of electrolyte and water homeostasis. Growth Horm IGF Res. 17(5):353-68, 2007
(4) Yi LT, Li JM, Li YC, Pan Y, Xu Q, Kong LD. Antidepressant-like behavioral and neurochemical effects of the citrus-associated chemical apigenin. Life Sci 82(13-14):741-751, 2008.
(5) Bektic J, Guggenberger R, Spengler B, Christoffel V, Pelzer A, berger AP, Ramoner R, Bartsch G, Klocker H. The flavonoid apigenin inhibits the proliferation of stromal cells via the MAPK pathway and cell-cycle arrest in G1/S. Maturitas 55(S1):S37-46, 2006.

Managment, evaluation and differential diagnosis

Below follows an overview of the current management recomendations (1-3) [and personal experience]. The obvious goal of the procedure is to exclude other possible conditions with similar presentation to CPPS.

The standard procedure is to:

• take an anamnesis (ambition varies, but used medications, previous surgery and treatment directed at the lower abdomen and pelvis should be checked for),
• do some tests (PSA, standard blood, urinalysis and presence of STD),
• palpate the prostate and testicles and
• give anti-biotics (e.g. ciprofloxacin), anti-inflammatories and alpha-blockers.

An ambitious urologist may also perform a urography, suprapubic and transrectal ultrasound scans, especially on NIH-I suspicion, and do the NIH-CPSI, IPSS or similar. A Meares-Stamey test is not likely to be performed. If further evaluation is warranted urine cytology and urography / flow rate is recommended.

Some optional procedures are also recommended. These are semen analysis (especially if the patient is young and can be expected to want children), urethral swab (to search for micro-organisms), flow-EMG, cystoscopy (e.g. if IC is suspected) and MRI / CAT-scan / X-rays (especially on suspiscion of cancer). If CPPS is assumed an in-depth evaluation of pain, sexual discomfort, dysuric discomfort, abdominal-pelvic status and muscular tone (“pelvic floor assessment”) should also be made (by palpation).

Conditions to differentiate from (the list is not to be regarded as a complete listing):

• Abdominal wall defects: inguinal or ventral wall hernias, myofascial trigger points.
• Gastrointestinal causes: appendicitis, diverticulitis, constipation, anal fissures, hemorrhoids. [Do notice that constipation may occur in CPPS!]
• Infection: sexually transmitted diseases, chronic bacterial prostatitis, fungal infection.
• Musculoskeletal causes: neoplasm (primary or metastatic), degenerative joint disease of the hips, sacroileitis.
• Neurologic causes: low thoracic or lumbar herniated nucleus pulposis, lumbar stenosis, Parkinson disease, diabetic cystopathy, demyelinating disease.
• Urologic causes: urinary retention, prostatic abcess, renal calculi, varicocele, epididymitis, testicular neoplasm, interstitial cystitis, bladder outlet obstruction, bladder neck hypertrophy, vesical sphincter dyssynergia, prostatic cysts, kidney disease.
• And of course prostate cancer and BPH.

Pituitary disorders were not mentioned in the references.

Do also see discussion on co-morbidities that will follow later.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb
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(1) Potts J, Payne RE. Prostatitis: Infection, neuromuscular disorder, or pain syndrome? Proper patient classification is key. Cleveland Clinic Journal of Medicine, vol. 74, suppl 3, May 2007.
(2) Nickel JC. Recommendations for the evaluation of patients with prostatitis. World J Urol 21:75-81, 2003.
(3) Nickel JC, Baranowski AP, Pontari M, Berger RE, Tripp DA. Managment of men diagnosed with CP/CPPS who have failed traditional management. Reviews in Urology 9(2):63-72, 2007.

Counter indications

Anecdotal information indicates that coffee, citrus fruit, tomatoes, vinegar, alcohol and spicy foods may worsen symptoms, but a study of 1759 participants shows no correlation with these (1). (It may be interesting to note that porphyria, AIP, may be triggered by some of these irritants.) The same irritants are also mentioned by IC patients(2). But it may be so that foods increasing uric acid (protein rich foods) or potassium levels (like apple and orange juice) are causing exacerbations, if the patients problems are caused by uric acid or potassium irritation from reflux of urine or bladder epithelium abnormalities.

Alcohol and caffeine (in coffee, tea and chocolate) and nicotine cause increased urgency and frequency because both inhibit vasopressin (AVP) production. AVP may also affect mood – anger, anxiety, depression etc (3).

Finally substances causing muscle relaxation may cause disruption.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, vasopressin
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(1) Hochreiter WW, Madersbacher S, Temml C, Zbrun S, Wolfensberger P, Studer UE Prevalence of prostatitis symptoms and LUTS in 1759 men using validated questionnaires. 2005 EAU meeting, Istanbul.
(2) Shorter B, Lesser M, Moldwin RM, Kushner L. Effect of comestibles on symptoms of interstitial cystitis. J Urol. 178(1):145-152, 2007.
(3) Caldwell HK, Lee HJ, Macbeth AH, Young WS 3rd. Vasopressin: behavioral roles of an "original" neuropeptide. Prog Neurobiol. 84(1):1-24, 2008.

Seasonality, cyclicity and circadian rhythm

There seems to be a distinct seasonality in CP/CPPS. Overall symptoms worsen the more northerly you live. Over the year symptoms improve from about may to august and worsen from october to april. Overlying this longer cycle there is anecdotal evidence of a shorter cycle of about 3-6 weeks for dysuria and of a diurnal cycle were symptoms, especially dysuria and muscle pain, are worse in the morning and improve during the day.

I'll revisit this topic later.

Disease progression

N.B. there is very little scientific data and tons of anecdotal. The following is mainly based on personal recollection and anecdotal data from websites. It is very sketchy. There is notable personal variation in pain experience and symptom intensity.

The disease/condition develops over many years. Initial symptoms are diffuse and mainly concern dripping progressing to obviously split stream (but most likely muscular pain has preceded that). At some point back pain and occasional perineal spasms start occurring. Unclear if the back pain and spasms precede dripping or developes during or even after.

In addition to the above vague problems with “penile sensitivity” start occurring and slowly semen/ejaculate start changing appearance. Parallel to this bouts of fatigue and malaise occur with increasing frequency and usually during winter with possibly a late winter early spring peak. Spring does also see an increase in depression-like symptoms. Palpitations do also occur but have no obvious pattern. Painful and/or uncoordinated (early and/or unexpected) ejaculation and “discoloring” of glans seems to be some sort of “end stage” problem.

Cold and freezing seems to precipitate spells of dysuria, but initiation of really bothersome dysuria and frequency seem to need a precipitating event. It seems that many sufferers seek medical attention at this point. Thus explaining the focus on urological causes.

Full blown CPPS tends to persist “unabated” for years, while milder forms tend to resolve with a few years. (In small study by Nickel symptoms resolved within a year in 38% of the subjects.) Or at least get manageable.

There may be a hereditary component!

A flare may look like this: dripping and nocturia begins, then back pain and some events of short inexplicable bursts of irritation and anger occur (hours), after these longer periods (days) of listlessness follow and finally palpitations occasionally occur. During the flare intestinal motility and libido diminishes and a progressive feeling of tiredness and fatigue develops. Micturition intervals decrease. Pain may occur during micturition and intercourse. Back pain is relieved by micturition. Flare ends pretty abruptly. Duration may be 3-4 weeks.

There is a collection of patient stories on this page: http://home.swipnet.se/isop/fallbeskrivningar.htm. The numbered links lead to english text.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, ISOP

Do all these symptom clusters mean anything

What conclusions or inferences can be drawn from the symptom clusters?

If only there were the Sickness behaviour, Ejaculatory-genital and Micturition problems symptom clusters it would reasonable to assume some urinary or kidney infection, but some signs, like e.g. fever and hematouria are missing.

What may the Seasonal cluster indicate? Seasonality and a cyclical pattern of excacerbations and remissions is a common finding in auto-immune disease. Could there be an auto-immune component to CPPS? Research is unfortunately not too helpful here. Most studies are small and preliminary.

What can the Pituitary cluster indicate? Yes the name of the cluster is very leading. I choose it to point out that the pituitary may be implicated in many odd symptoms reported by CPPS sufferers. What is interesting is that the Micturition, Cardio-vascular and, maybe, the Seasonal clusters also fit in. Sickness behaviour may fit in as indicative of a condition that cause the release of pro-inflammatory cytokines that activates the HPA axis. Could that cause be infectious, auto-immune, dietary or environmental?

What about the remaining clusters? These are more difficult to fit in. Some, like mouth dryness, may be related to the pituitary (diabetes insipidus), abdominal pains may be caused by referred pain from the scrotum. Abdominal distension may be caused by pituitary dysfunction.

You may wonder if there are there any studies on the HPA axis and CPPS, or if these are only my personal musings? Yes, the pituitary angle is my personal idea, but when I perused PubMed to see if there were any studies made I did actually find a couple (see below for references).

A distinctive problem with the pituitary/HPA axis idea is that it may be related with dental amalgam fillings and mercury accumulation in the pituitary and not adrenal dysfunction as suggested by some. The association of amalgam and CPPS seems to never have been researched and the pretty infected debate re. mercury toxicity makes it doubtful if any researcher would be eager to endure the, possibly, years of controversy such a study would cause.

In the following I will review general information about CP/CPPS, current treatment and research into various etiologies, before returning to the symptom subject.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, symptomkluster
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Anderson RU, Orenberg EK, Chan CA, Morey A, Flores V. Psychometric Profiles and Hypothalamic-Pituitary-Adrenal Axis Function in Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome. J Urol. 179(3):956-960, 2008.
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):261-6, 2008.
Dimitrakov J, Guthrie D. Genetics and Phenotyping of Urological Chronic Pelvic Pain Syndrome. J Urol. 2009 Feb 19.
Björkman L, Lundekvam BF, Laegreid T, Bertelsen BI, Morild I, Lilleng P, Lind B, Palm B, Vahter M. Mercury in human brain, blood, muscle and toenails in relation to exposure: an autopsy study. Environ Health. 6:30, 2007.

Remaining symptoms and signs

Below follow some anecdotal symptoms and signs that do not fit any cluster and that may or may not be related to CPPS.

• Improvement of symptoms during other infection: e.g. influenza and cold.

• Decrease lung capacity (by decreased bronchodilation)?

• Sudden feeling of mouth dryness (no noticeable concomitant thirst -- disruption of water balance?)

• Lower back pain / burning sensation.

• Inter-scapular (thoracic) back pain / burning sensation.

• Axel pain and weakness and arm paresthesias especially with carrying and physical exercise.

• Sinusitis.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, symptomkluster