Genetic findings

Not much research has been done. There is a study showing an association between a "highly polymorphic short tandem repeat (STR) locus near the phosphoglycerate kinase gene within Xq11-13" (1) and another indicating low TNF-alpha (NIH-IIIa) or low IL-10 expression (NIH-III).(2) A newer study showed differences in manganese superoxide dismutase and gluthathione polymorphisms versus controls.(3)

A general discussion on genetic research in CPPS and IC is given by Dimitrakov and Guthrie.(4)
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(1) Riley DE, Krieger JN. X Chromosomal short tandem repeat polymorphisms near the phosphoglycerate kinase gene in men with chronic prostatitis. Biochim Biophys Acta 1586(1):99-107, 2002.
(2) 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.
(3) Arisan ED, Arisan S, Kiremit MC, Tiğli H, Caşkurlu T, Palavan-Unsal N, Ergenekon E. Manganese superoxide dismutase polymorphism in chronic pelvic pain syndrome patients. Prostate Cancer Prostatic Dis. 9(4):426-431, 2006.
(4) Dimitrakov J, Guthrie D. Genetics and phenotyping of urological chronic pelvic pain syndrome. J Urol 181(4):1550-1557, 2009.

The female prostate

As mentioned in passing in an earlier post some women have a vestigial prostate (and some men a vestigial uterus: the utriculum). The organ is more known as Skene's or the paraurethral gland. Oddly enough it is semifunctional in some cases and may eject a fluid and be stimulated. A popular overview was recently published in the may 30 issue of New Scientist.

Andra bloggar om prostata

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.

Clinical phenotyping

While symptoms clusters are practical groupings helpful to elucidate disease causes and suggesting treatment options, clinical phenotyping is supposed to be a more precise indication of underlying genetical differences. An attempt to phenotype CPPS sufferers have been made by Shoskes et al (2009) (1-2). In my opinion their approach is more like a mix of symptom clusters, select clinical findings and co-morbidities. They suggest six groups: urologic (essentialy the micturition & genito-urinary symptom clusters), psychosocial (more or less sickness behavior), organ specific (clinical findings about the prostate and ejaculate), infection (clinical findings about bacteria), neurological/systemic (essentially the remaining symptom clusters in my previous posts) and muscle tenderness. Although useful I am of the opinion that their categories are a bit too rough and disparate to be useful for research, but they may be helpful in improving the treatment of patients.

And an evaluation just agreed with me. The author concluded that "a weak or lacking correlation with the studied clinical parameters suggest that further development is required".(3)

Other researchers (Anderson et al, and Dimitrakov et al) have focused on profiling of HPA function and hormonal testing, both of which will be discussed under the findings chapters.

Updated 2009-09-04
Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb, klinisk fenotypning
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(1) Shoskes DA, Nickel JC, Rackley RR, Pontari MA. Clinical phenotyping in CP/CPPS and IC: a management strategy for urologic chronic pelvic pain syndromes. Prostate Cancer Prostatic Dis 2008, 7pp.
(2) Shoskes DA, Nickel JC, Dolinga R, Prots D. Clinical phenotyping in CP/CPPS and correlation with symptom severity. Urology 73(3):538-542, 2009.
(3) Hedelin HH. Evaluation of a modification of the UPOINT clinical phenotype system for the CPPS. Scand J Urol Nephrol 9:1-4, aug 2009 (epub ahead of print).

Socio-economic differences and education

No or small differences in incidence due to economic or education level differences have been found, although lower socio-economic status (SES) predict that symptoms will be experienced as worse / more painful (1). Why this difference in experience? Two causes are probable: a) worse nutrition and more stress caused by the lower SES causing an objectively more severe disease, or b) subjectively experiencing being more ill.

Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, kronisk abakteriell prostatit, NIHIIIb
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(1) McNaughton Collins M, Pontari MA, O'Leary MP, Calhoun EA, Santanna J, Landis JR, Kusek JW, Litwin MS,.Quality of life is impaired in men with chronic prostatitis: the Chronic Prostatitis Collaborative Research Network.J Gen Intern Med 16(10):656-662, 2001.

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.

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.