Saturday, March 28, 2009

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 , , , , ,
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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 , , ,
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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.

Tuesday, March 17, 2009

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 , , ,
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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 , , , ,
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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.

Wednesday, March 11, 2009

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 , , , ,

Sunday, March 8, 2009

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 , , , ,
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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 , , , ,

Tuesday, March 3, 2009

Cardio-vascular symptom cluster

The part about blood clotting is tentative and inferred from the fact that many of the of treatments (incl. phytotherapies) have an anti-thrombotic component.

• Increased propensity för blood-clotting due to cold. Increased fibrinogen production?

• Platelet disruption?

• Palpitations (i.e. different heart rhythm) occuring e.g. at bedtime or at wakening.

• Tachycardia, i.e. a faster than normal heart rhythm occuring despite an absence of physical effort.

(There are many causes of heart arrythmias. In our case it could e.g. be caused by disruptions of water and electrolyte balance or acid-base imbalance.)

Andra bloggar om , , , , ,

Sunday, March 1, 2009

Pituitary symptom cluster

This is a tentative cluster. It is based on anecdotal evidence, facets of urinary and sickness behaviour symptoms, and foods reported to exacerbate symptoms. (The pituitary is also called hypophysis.)

Possibly pituitary / HPA-axis related problems
• Problems with vasopressin regulation. This is indicated by increased susceptibility to vasopressin antagonists. E.g. worsening of nocturia, diuresis and urgency after alcohol and caffeine intake. (I.e. symptoms showing a similarity with diabetes insipidus.)

• Sleep disruption (nocturia-caused or not?)

• Abrupt mood fluctuations (irritability, aggression and anger).

• Sudden feelings axiety with no obvious cause.

• Cold sweats. Similar to night sweats. Body temperature regulation. Anecdotal.

• Depression.

• Fatigue.

• Leg weakness.

• Lower than average bone density.

• Decreased / low libido. (Added march 4th 2009)

Possibly thyroid related problems
These symptoms may be caused by hypothyroidism. And yes there is a point in mentioning those with pituitary/HPA problems as pituitary regulation problems may cause secondary hypothyroidism.

• “Uncontrollable” nightly sweating / hot flashes. Indicates problems with body temperature regulation. Anecdotal.

• Cold sweats. Similar to night sweats. Body temperature regulation. Anecdotal.

• Feeling unfocused / not alert.

• Fatigue.

• Constipation.

• Feeling cold.

Andra bloggar om , , , , , ,
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Further reading
Sievers C, Ising M, Pfister H, Dimopoulou C, Schneider H, Roemmler J, Schopohl J, Stalla G. Personality in patients with pituitary adenomas is characterized by increased anxiety related traits: comparison of 70 acromegalic patients to patients with non-functioning pituitary adenomas and age- and gender matched controls. Europ J Endocrin 160:367, 2009.