Sunday, May 23, 2010

Conclusions about vitamin D in CPPS

As vitamin D is a strong immuno-regulatory hormone(1) and has been proven effective for treating conditions, like musculoskeletal pain, there is reason to believe low D-levels, even if not causative, may exacerbate CP/CPPS. The findings above do also suggest why prostaglandin inhibitors are effective in treating CPPS, and why symptoms go in remission during summer.

This also lends support to the hypothesis that CP/CPPS has a neuromuscular/myofascial component. Cold and freezing may cause muscular tension. D-vitamin deficiency is implicated in myopathies, as are calcium and magnesium deficiencies, and depression (SAD).(2)

As Melatonin enhances cellular immunity and cold has an effect on at least some of the components involved in immunity this may also be a cause of winter-time flares, especially when bodily levels of D3 are low.

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(1) Hewison M. Vitamin D and the intracrinology of innate immunity. Mol Cell Endocrinol 321(2):103-11, 2010.
(2) Verstuyf A, Carmeliet G, Bouillon R, Mathieu C. Vitamin D: a pleiotropic hormone. Kidney Int. 2010 Feb 24. Epub ahead of print

Friday, May 14, 2010

Temporary pause due to RL

Sorry for posting nothing in the last month, but professional commitments in RL keeps me currently very busy.

Friday, April 9, 2010

Bladder overactivity and vitamin D

Few studies about vitamin D and its relation to bladder overactivity and incontinence have been done despite the association between vitamin D and muscle weakness and coordination. The only two I have found show a correlation with decreasing vitamin D levels and female pelvic floor disorders incl. urinary incontinence(1) and risk of onset of overactive bladder.(2) Especially with age. The studies have been made on women only, but there is no reason to believe men should differ in this respect.

Another study has also shown that bladder cells (“bladder epithelium and stromal cells along with vascular endothelial cells”) contain vitamin D receptoirs (as most of the other cells of the body also do) and that treatment with vitamin D analogues “inhibits basal and androgen-stimulated human bladder cell growth and enhances their apoptosis” and “prevent[s] starvation-induced cell phenotype modification”.(3) All factors thought to cause overactive bladder.

Thus different lines of evidence point at low vitamin D levels being a possible causative agent. As CPPS show distinct seasonality with summertime improvement, the studies are interesting and one can hope vitamin D levels will be studied in CPPS sufferers.

On a personal note I have been treating myself with vitamin D since 2008 (after noting the distinct seasonality of my symptoms) and have noted a distinct remission of all CPPS problems

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(1) Badalian SS, Rosenbaum PF. Vitamin D and pelvic floor disorders in women. Obstet gynecol 115(4):795-803, 2010.
(2) Dallosso HM, McGrother CW, Matthews RJ, Donaldson MM. Leicestershire MRC incontinence study group. Nutrient composition of the diet and the development of overactive bladder: a longitudinal study in women. Neururol urodyn 23:204-210, 2004.
(3) Crescioli C et al. Human Bladder as a Novel Target for Vitamin D Receptor Ligands. J Clin Endocrin Metabol 90(2):962-972, 2005.

Saturday, March 27, 2010

CPPS, darkness and melatonin

There is also the possibility that winter darkness worsens CPPS. Instead of absence of vitamin D. or possibly both. So how may winter darkness affect CPPS? Perhaps through melatonin level variation.

Melatonin is thought to affect the “inner clock” (synchronizing the photoperiod of an organism), reproduction, metabolism, thermoregulation and immune function. The effect on the “inner clock” is known since long, while the effects on the immune system are a pretty new area of research.

Recent research indicate that melatonin has an immuno-stimulating effect. It stimulates the production of e.g. IL-1, IL-2, IL-6, IL-12 and gamma-interferon, but not IL-4. Human studies “suggest that melatonin may favour a Th1 cell response”. Th1 regulation needs, as we just saw, vitamin D.

Excessive “melatonin production may be involved in glucocorticoid resistance”, which usually causes inflammation. Sufferers of rheumatoid arthritis (RA) have been found to have higher levels and longer night time peaks of melatonin and thus a more marked up-regulation of immune function than controls. RA sufferers do also normally have more pain and/or muscle/joint stiffness in the morning than in the evening.

What is interesting, is that levels of melatonin, some cytokines and interleukins was higher the more northerly RA-patients lived, thus explaining the higher prevalence of RA in Balto-Scandinavian countries compared to Mediterranean countries. The same study also measured cortisol levels and found no differences in those. “A diurnal rhythmicity in healthy humans between cellular (Th1 type) or humoral (Th2 type) immune responses has been found and related to immunomodulatory actions of cortisol and melatonin.” (1,2)

As CP/CPPS shows a similar south to north gradient it would be very interesting to study if CP/CPPS sufferers show a similar pattern of melatonin secretion. Decreased night-time melatonin secretion during the longer summer daylight above 50 degrees of latitude may explain summer (and early fall) remission in addition to vitamin D. RA has also been shown to improve with higher levels of vitamin D.(3) A bit odd though as a low night-time melatonin (and if the nighttime peak occurs too early or late) level is correlated with e.g. seasonal depression and prostate cancer growth, while CPPS is not correlated with prostate cancer but with winter time depression. On the other hand high night-time levels are correlated with higher anxiety, which seems more common during winter in CPPS.

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(1) Cutolo M, Maestroni GJM. The melatonin-cytokine connection in rheumatoid arthritis.Ann Rheum Dis 64:1109-1111, 2005.
(2) Cutolo M, Sulli A, Pizzorni C, Secchi ME, Soldano S, Seriolo B, Straub RH, Otsa K, Maestroni GJ. Circadian rhythms: glucocorticoids and arthritis. Ann N Y Acad Sci. 1069:289-299, 2006.
(3) Pelajo CF, Lopez-Benitez JM, Miller LC. Vitamin D and Autoimmune Rheumatologic Disorders. Autoimmun Rev. 2010 Feb 8. [Epub ahead of print]

CPPS, the sun and vitamin D part 2

Calcium, cancer and pituitary
Can rising parathyroid hormone concentrations or changed calcium metabolism / homeostasis with decreasing D-vitamin levels trigger CP/CPPS or some of its symptoms? Maybe, as vitamin D and “calcium malnutrition eventually causes a decrease in calcium concentration in extracellular fluid compartments, resulting in organ-specific… attenuation of signal transduction from the ligand-activated vitamin D receptor and calcium-sensing receptor” causing “perturbation of cellular functions in bone, kidney, intestine, mammary and prostate glands, endocrine pancreas, vascular endothelium, and, importantly, in the immune system.”(1) Calcium deficiency may also promote breast, prostate and colorectal cancer. Adequate calcium levels may also regulate Th1 (cellular) immune response.

It is interesting that the vitamin D receptor (VDR) is present in the pituitary, which is central in diuretic and prostaglandin regulation. Especially as there are many indications of pituitary dysfunction in CPPS sufferers.

Nutritional adequacy
More or less everyone living north of the 60th parallel will have insufficient levels of vitamin D or out-right deficiency by the end of winter. This is because there is not enough sunlight from November to March. This is also exacerbated by indoors living and clothing during the summer months.

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(1) Peterlik M, Cross HS. Vitamin D and calcium deficits predispose for multiple chronic diseases. Eur J Clin Invest 35(5):290-304, 2005.

Sunday, March 21, 2010

CPPS, the sun and vitamin D

Prostatitis is currently not one of the diseases thought to be related to low D levels, but many of the symptoms in CP/CPPS seem to be related to either immunological-inflammatory and/or neuromuscular problems. Anecdotal evidence and the studies mentioned earlier indicate that prostatitis symptoms worsen in winter and late spring when bodily D-vitamin stores are at their lowest. This raises the question if cold or D-vitamin insufficiency/deficiency is the cause, or maybe both? So why may vitamin D play a role?

Immuno-modulation and other properties
It was earlier believed that D3 (cholecalciferol) only use was to aid bone mineralization (calcium and phosphorus metabolism), but research has shown that it is a very “potent” and important substance for many bodily processes(1). D3 (or rather its metabolite calcitriol) is very important as mediator of gene transcription (e.g. the prostate specific antigen), immune response(2) (macrophage functions, T- and B-lymphocyte mediated response, NOS induction), blood pressure regulation, regulation of platelet aggregation, insulin production, cell cycle regulation (proliferation and differentiation) in epithelial tissues, synovial cells and many other cell types and tissues(3) (e.g. pituitary cells), and also of neuromuscular function. This is due to the almost ubiquitous vitamin D receptors (VDR).

Decreasing D-vitamin levels are associated with an increase in vulnerability to infection. Vitamin D (or rather its metabolite calcitriol) is a strong immuno-regulatory hormone (e.g inhibition of IL-1, IL-2, IL-6, IL-12, TNF-alpha, INF-gamma etc) (see Peterlik and Cross, 2005, for references) and recent research has also shown that it promotes production of several anti-microbial peptides.(4-5) Especially cathelicidins(6), which also have been shown to protect the urinary tract against infection.(7)

It is also interesting that recent cancer research has shown that calcitriol regulates “the expression of genes involved in the metabolism of prostaglandins”. It significantly represses expression of COX-2 and EP2 and FP receptors, and also up-regulates 15-hydroxyprostaglandin dehydrogenase.(8)

Diseases correlated with D
Diseases thought to be, or proven to be related with low levels of D are many cancers (stomach, colorectal, liver, gall bladder, pancreas, lung(9), female breast, prostate,(10-11) bladder, kidney(12)), tubercolosis(13), multiple sclerosis,(14-15), rheumatoid arthritis (16) (Merlino, Curtis et al.), diabetes type 1/ insulin resistance (Hypponen, Laara et al.), hyperparathyroidism,(17) systemic lupus erythematosus, osteoarthritis, ankylosing spondylitis and, possibly, fibromyalgia, SAD, schizophrenia,(18-19) Crohn’s disease, ulcerative colitis, irritable bowel syndrome, periodontitis and genigivitis,(20) and colorectal cancer.(21) Epidemiological studies (corrected for other factors) indicate that these diseases are more common and severe the more north you live.

The immune conditions above (RA, SLE, MS, IBS and diabetes) are thought to be caused by too low calcitriol (a vitamin D metabolite) levels to prevent a “pathological activation of Th-1 responses” (Peterlik and Cross, 2005).

Some of these diseases and activation of Th1 (cellular) immunity are also correlated to and overlap with CPPS and other urological problem.

Prostate cancer and D
Prostate cancer (Hanchette and Schwartz, Tuohimaa) is e.g. one of the cancers following the latitudinal pattern and D-vitamin has shown to be effective against pre-cancerous cells (Nonn et al.). The vitamin D receptor (VDR) is present in the prostate.

Muscle pain, weakness and depression
It is interesting to note that D-vitamin deficiency may manifest itself as pain and fatigue (ATP-deficiency), which also is characteristic for fibromyalgia and myofascial syndrome. A study found that people with less than 40 nmol/l walked more slowly and had more problems rising from chairs than people with more than 90 nmol/l.(22) Vitamin D has been proven effective for treating musculoskeletal pain.(23) D-vitamin insufficiency is a known cause of tiredness and depression (especially SAD).


Approximate vitamin D levels in sufferers of various diseases and conditions. Levels at the end of winter (march) and early fall (september), and lifeguards and multiple sclerosis treatedment (24) added for comparison.(25)

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Additional information on vitamin D
Vitamin D council
Grassroots health

References
(1) Humble M. D-vitaminbrist kanske vanligare än vi trott. Prevention och behandling skulle kunna ge oanade folkhälsoeffekter. [Vitamin D deficiency probably more common than earlier apprehended. Prevention and treatment could result in unexpected public health effects]. Läkartidningen 104(11):853-857, 2007. Article in Swedish.)
(2)van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol. 97(1-2):93-101, 2005.
(3) Peterlik M, Cross HS. Dysfunction of the vitamin D endocrine system as common cause for multiple malignant and other chronic diseases. Anticancer Res 26(4A):2581-2588, 2006.
(4) Cannell JJ, Vieth J, Umhau C, Holick MF, Grant B, Madronich S, Garland CF, Giovannucci E. Epidemic influenza and vitamin D. Epidemiology and Infection 136:1129-1140, 2006.
(5) Weber G, Ståhle M Vitamin D induces the antimicrobial protein hCAP18 in human skin. J Invest Dermatol 124(5):1080-1082, 2005.
(6) ”Cathelicidins have a very broad spectrum of activity, and promote wound healing and re-epthelialization of breaks in the skin: they are absent in chronic (non-healing) ulcers. [Heilborn JD, Nilsson MF, Kratz G, et al., The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. J Invest Dermatol. 120(3): 379-89, 2003] Cathelicidins have activity against intracellular bacteria; this has been demonstrated in Mycobacterium tuberculosis [Liu PT, Stenger S, Li H, Wenzel L. et al., Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006 Mar 24;311(5768):1770-3] Cathelicidins are active in the innate defence system of the gut, lining the mucosa and preventing attachment by epithelial-adherent bacterial pathogens. [Dann SM, Eckmann L. Innate immune defenses in the intestinal tract. Curr Opin Gastroenterol. 2007 Mar;23(2):115-20.] Cathelicidins are active in vitro against Herpes Simplex Virus and cathelicidin deficiency has been found in persons with eczema herpeticum. [Howell MD, Wollenberg A, Gallo RL. et al., Cathelicidin deficiency predisposes to eczema herpeticum. J Allergy Clin Immunol. 2006 Apr;117(4):836-41.]” (http://www.davidwheldon.co.uk/vit_D.html.)
(7) Chromek M, Gallo RL The antimicrobial cathelicidin protects the urinary tract against invasive bacterial infection. Nature Medicine 12:636-641, 2006.
(8) Moreno J, Krishnan AV, Swami S, Nonn L, Peehl DM, Feldman D. Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Res 65(17):7917-7925, 2005.
(9) Porojnicu AC, Robsahm TE, Dahlback A, Berg JP, Christiani D, Bruland OS, Moan J. Seasonal and geographical variations in lung cancer prognosis in Norway. Does Vitamin D from the sun play a role? Lung Cancer. 55(3):263-270, 2007.
(10) Lagunova Z, Porojnicu AC, Dahlback A, Berg JP, Beer TM, Moan J. Prostate cancer survival is dependent on season of diagnosis. Prostate 67(12):1362-1370, 2007.
(11) Schwartz GG, Hanchette CL. UV, latitude, and spatial trends in prostate cancer mortality: all sunlight is not the same (United States). Cancer Causes Control. 17(8):1091-1101, 2006.
(12) Tuohimaa P, Pukkala E, Scélo G, Olsen JH, Brewster DH, Hemminki K, Tracey E, Weiderpass E, Kliewer EV, Pompe-Kirn V, McBride ML, Martos C, Chia KS, Tonita JM, Jonasson JG, Boffetta P, Brennan P. Does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancers: Vitamin D as a possible explanation. Eur J Cancer 43(11):1701-12, 2007.
(13) People with D-vitamin deficiency are much easier infected, and an increase in active D in the body helps fight the infection (remember the sanatorium treatments with lots of “fresh air”, i.e. sunlight !)
(14) There is also concern that nutritional factors help promote MS. Like: cereals, legumes, dairy products, too little Omega-3 and too much Omega-6, antioxidant deficiencies and low fibre (from fruits and vegetables) consumption (A Embry, http://www.direct-ms.org).
(15) Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296(23):2832-2838, 2006.
(16) Cutolo M, Otsa K, Laas K, Yprus M, Lehtme R, Secchi ME, Sulli A, Paolino S, Seriolo B. Circannual vitamin d serum levels and disease activity in rheumatoid arthritis: Northern versus Southern Europe. Clin Exp Rheumatol. 24(6):702-704, 2006.
(17) Chronic vitamin-D insufficiency or deficiency may cause any of the parathyroid glands to become “stuck in high gear” while trying to keep calcium levels in the body within “safe” limits, which may cause a lot of problems when you really do get D-vitamin see www.parathyroid.com for more info.
(18) Carrión-Baralt JR, Fuentes-Rivera Z, Schmeidler J, Silverman JM. A case-control study of the seasonality effects on schizophrenic births on a tropical island. Schizophr Res. 71(1):145-53, 2004
(19) Carrión-Baralt JR, Smith CJ, Rossy-Fullana E, Lewis-Fernández R, Davis KL, Silverman JM. Seasonality effects on schizophrenic births in multiplex families in a tropical island. Psychiatry Res 142(1):93-7, 2006
(20) Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence? BJN 89:552-572, 2003.
(21) Garland C, Shekelle RB, Barrett-Connor E, Criqui MH, Rossof AH, Paul O. Dietary vitamin D and calcium and risk of colorectal cancer: a 19 year prospective study in men. Lancet 1:307-309, 1985.
(22) Dawson-Hughes B. Vitamin D, how much is enough and why. 5th International Symposium on Nutritional Aspects of Osteoporosis. Lausanne, May 14-17, 2003.
(23) Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, non-specific muscoloskeletal pain. Mayo Clinic Proc. 78(12):1463-1470, 2003.
(24) Kimball SM, Ursell MR, O'Connor P, Vieth R. Safety of vitamin D3 in adults with multiple sclerosis. Am J Clin Nutr 86:645–5, 2007.
(25) From left to right: Chronic pain/fibromyalgia, pain in general, rickets, osteporosis/osteopaenia, respiratory tract infection/ILI, connective tissue disease, polymyalgia rheumatica/giant cell arteritis, inflammatory arthritis/rheumatism in general, osteoarthritis, propensity of falling, general muscle weakness, fatigue, melanoma stage IV, breast cancer, cardio-vascular disease, diabetes mellitus, multiple sclerosis, CPPS (hypothetical), march levesl found in many people living in Europe and northern USA, september levels found in people tanning or moving about a lot in the sun, americam life-guards, people in MS remission due to vitamin D treatment.

Saturday, March 13, 2010

Cold-induced diuresis (CID)

As CPPS micturition problems worsen in winter and cold it may be of interest to know that diuresis can be induced by cold weather (<10-15 C) or cold water (<18-23 C). CPPS sufferers seem to have a more easily induced CID. This may be indicative of low AVP levels, as the reflex can be blocked by administration of AVP or a synthetic analogue (e.g. desmopressin). Murine experiments have also shown that “genetic AVP deficiency abolishes cold-induced diuresis but does not attenuate cold-induced hypertension” and that acute CID is due to AVP reduction, while chronic CID is due to suppression of renal V2 receptors and the associated AQP-2 water channels, rather than inhibition of AVP release.(1)

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(1) Sun Z. Genetic AVP deficiency abolishes cold-induced diuresis but does not attenuate cold-induced hypertension. Am J Physiol Renal Physiol.290(6):F1472-7, 2006.

Cold and CPPS

Two interesting facts have been reported by a Finnish study(1). The authors found that prevalence of prostatitis was higher in married men, which could mean that a causal agent could be found in female pathogens. But, they also found that symptoms were worst from November through March (63% of the men, self-reported) and in northern Finland 14% of the men were diagnosed compared to 5-9% in central and southern Europe.

A Swedish study corroborates this data: “Nearly every other man stated that the disease had started in association with a specific event, which for 15 men (31%) included exposure to cold. Forty men (83%) reported that cold caused symptom aggravation and/or induced a relapse. Thirty men (63%) stated that taking a hot bath and 22 (46%) reported that spending time in a hot climate decreased the symptoms.”(2)

This is very interesting as it indicates a cold related factor (as the authors also suggest) or a sun-related problem (like D-vitamin deficiency) or both. The latter is also indicated by a Korean study(3). that found that increased exposure to sunlight decreased CPPS symptoms. The Koreans did not find any correlation with temperature.

Why may cold aggravate symptoms? One obvious cause is muscular tension, another less obvious may be that cold seems to slightly stimulate the immune system. The acute effect of (severe) chilling is a suppression of parts of the cellular and humoral immune response and the induction of heat shock proteins(4). But afterwards levels of proinflammatory cytokines (especially IL-6), natural killer cells, leukocytes, catecholamines and stress hormones are raised. Possibly due to the increased metabolic rate and effort to keep the core body temperature stable (peripheral vasoconstriction, shivering etc).(5-7)

But there is also the possibility of a correlation with blood viscosity and clotting propensity. Cold increases blood viscosity (makes it "thicker" and "less runny"). Viscosity is also higher in the morning, which anecdotally sees worse CPPS problems. Inflammation / infection is also correlated with increased viscosity and clotting propensity.(8) Curiously many treatments (I will discuss those later this year) decreases viscosity and clotting.

Another point of interest is that vitamin D levels are at their lowest in march. And accumulating evidence indicates that infection risk and immune dysregulation increases with lower D levels. Of wich I'll talk in my next installment.

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20100314 edited the vitamin D - Korea paras and clarified the viscosity note.

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(1) Mehik A, Hellstrom P, Lukkarinen O, Sarpola A, Jarvelin M. Epidemiology of prostatitis in finnish men: a population based cross-sectional study. BJU Int 86(4):443-448, 2000.
(2) Hedelin H, Jonsson K. Chronic prostatitis/chronic pelvic pain syndrome: Symptoms are aggravated by cold and become less distressing with age and time. Scand J Urol Nephrol. 2007 Jun 21;:1-5 [Epub ahead of print]
(3) Ku JH, Kim ME, Lee NK, Park YH. Influence of environmental factors on chronic prostatitis-like symptoms in young men: results of a community based survey. Urology, 58(6):853-858, 2001.
(4) Shephard RJ, Shek PN. Cold exposure and immune function. Can J Physiol Pharmacol. 76(9):828-836, 1998.
(5) Janskyl L, Pospiilova D, Honzova S, Uliny B, Ramek P, Zeman V, Kamnikova J. Immune system of cold exposed and cold adapted humans. European Journal of Applied Physiology. 72(5-6):445-450, 1996.
(6) Walsh NP, Whitham M. Exercising in environmental extremes: a greater threat to immune function? Sports Medicine 36(11):941-976, 2006.
(7) Brenner IKM, Castellani JW, Gabaree C, Young AJ, Zamecnik J, Shepard RJ, Shek PN. Immune changes in humans during cold exposure: effects of prior heating and exercise. J Appl Physiol 87:699-710, 1999.
(8) Pop GAM, Duncker DJ, Gardien M, Vranckx P, Versluis S, Hasan D, Slager CJ. The clinical significance of whole blood viscosity in (cardio)vascular medicine. Neth Heart J. 10(12):512–516, 2002.

Wednesday, March 3, 2010

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.

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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.

Wednesday, February 24, 2010

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.

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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.

Friday, February 19, 2010

The immune-brain-gut-endocrine axis

This is the third installment of my short review of immune function. For part one (basics) see here and part two (vitamin D) see here. A discussion of CPPS and immunity and some other related topics will follow within the next days.

While the existence of communication between the immune system and other bodily organs may seem an obvious proposition it was not so not long ago. It is only during the last 30 years that it has been appreciated that the immune system and especially the brain (or rather certain parts of the brain) and the immune system “talk” with each other. The exchange of information modulates behavioral and physiological responses to immune insults and immune responses to conscious and semi-conscious behavioral responses to environmental stressors.

Two pathways link the brain and the immune system: signaling through nerves (e.g. neocortical-sympathetic axis and brainstem-vagus pathway) of the autonomic nervous system (ANS), and “neuroendocrine humoral outflow via the pituitary” (that is: substances transported by/in blood, lymph, saliva etc) or rather under HPA axis control. The major ANS component involved in this is the sympathetic nervous system (SNS). This connection has also been evidenced by the alteration of immune function through behavioral conditioning (e.g. that stress both can drive a pro- and anti-inflammatory response) and specific brain lesions.

The ANS is further divided in three sub-systems: the sympathetic (or noradrenergic) nervous system, the parasympathetic (or cholinergic) nervous system and the (semi-autonomous) enteric nervous system that lies entirely within the wall of the gastrointestinal tract (a sort of second brain in the belly) and that connects to both the SNS and PSNS (via e.g. the vagus nerve).(1)

During immune challenge (or cellular damage for any reason) or stress (work, social etc) the immune system is similarly activated. Levels of norepinephrine (noradrenalin), CRH, vasopressin and other substances change inducing immune activation. The the individual differences in activation are dependant both on early-life events and genes.(2)

Pro-inflammatory cytokines activate the HPA axis which induces increased plasma concentrations of CRH, vasopressin, ACTH and cathecolamines (e.g. epinephrine and noreepinephrine). Activation of the immune system does also induce fever (not always) and sickness behaviour. That immune cytokines cause sickness behaviour has been amply demonstrated due to cytokine therapy of cancer patients, as the symptoms almost immediately disappear upon discontinuation of treatment. It may be interesting to note that “full blown” sickness behaviour is caused by IL-2 and/or IFN-alpha(3). Of special interest is that the fatigue and irritability, commonly seen in CPPS is “caused” by IFN-alpha (which btw, in conjunction with IFN-beta, is central to anti-viral immune response).

An overactive HPA-axis with concomitant hypercortisolemia, is commonly seen in (cytokine-induced) depression. Some anti-depressants have been shown to induce cytokine suppression (and thus immune suppression and regulation), which is interesting in view of the use of anti-depressants against over-active bladder and other micturition disorders. The exact mechanisms are not fully known.

Other cytokine-“antagonists” used in micturition disorders are etanercept and infliximab (both are TNF-alpha-antagonist). (4)

Human visceral obesity is associated with HPA alterations. Cause and effect are still unclear though, but low testosterone and high glucocorticoids result in increased fat. As visceral fat increases it will suppress testosterone and enhance cortisol. (5)

Other substances affecting the immune system are e.g. prolactin, TSH, GH, GNRH and IGF-1. Hyperprolactinemia has e.g. been observed in 20% of SLE sufferers. Low IGF-1 is associated with cognitive decline and sickness behaviour, and low GH with anxiety and depression. IGF-1 is interesting as excercise increases its ratio visavi pro-inflammatory cytokines. Maybe a reason (in addition to the ussal endorphins) why CPPS sufferers (and others) feel better after excercise?(6)

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(1) Elenkov IJ, Wilder RL, Chrousos GP, Vizi S. The sympathetic nerve-an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52(4):595-638, 2000.
(2) Anisman H. Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. [2008 CCNP Heinz Lehman Award Paper]. J Psychiatry Neursci 34(1):4-20, 2009.
(3) IFN-beta causes fatigue, depression and “mental fog”. TNF-alpha fatigue and anorexia. IL-2 fatigue, anhedonia (listlessness), dysphoria (depression, anxiety, irritability, restlessness) and “mental fog”. IFN-alpha fatigue, depression, psychomotor slowing, anxiety, social withdrawal, irritability, anorexia and “mental fog”.
(4) Schiepers OJG, Wichers MC, Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry. 29(2):201-217, 2005.
(5) Nieuwenhuizen AG, Rutters F. The HPA axis in the regulation of energy balance.
(6) Kelley KW, Weigent DA, Kooijman R. Protein hormones and immunity. Brain Behav Immun 21:384-292, 2007.

Dihydrotestosterone

High levels of the other major male gonadotropin, DHT (dihydrotestosterone), is strongly associated with abdominal obesity. It does also slowly decline with age from a peak value around 45 pmol/L postpuberty to around 28 in octogenarians. The DHT/FT ratio is fairly constant between 0.15 to 0.18 in healthy adult men.(1)

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(1) Starka L, Pospisilova H, Hill M. Free testosterone and free dihydrotestosterone throughout the life span of men. Journal of Steroid Biochemistry & Molecular Biology 116:118–120, 2009.

Sunday, February 14, 2010

Conclusions about sleep in CPPS

The following is speculative, but sleep deprivation caused by nocturia and sleep disturbances due to CPPS effects on the enteric nervous system (and thus in the end on the HPA axis and on sickness behaviour) is probably an important cause of the severe discomfort and psychological effects seen in CPPS. Especially in non-retired individuals who cannot recover lost sleep during daytime because of work duties. The exact directionality of effects is likely complicated. Are the problem driven by HPA axis disturbances or enteric effects, mediated by the vagus nerve, or by the sleep disturbance caused by nocturia. Regardless of the ultimate cause it is well worth finding strategies for getting a good nights sleep. Strategies such as avoiding caffeinated products, chocolate, alcohol, strawberries and other products know to be diuretic. Especially in the evening and late afternoon.

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The importance of sleep

While this may seem an off topic it is not. Disrupted sleep is a common feature in CPPS and other disease. Why is sleep important? Because regular and normal sleep is important for immunocomptence. In an elegant study it was shown that: “Species that have evolved longer sleep durations appear to be able to increase investment in their immune system an be better protected from parasites” and “suggest that sleep has a much wider role in disease resistance than is currently appreciated”.(1)

So undisturbed sleep is important for psychological, urological (2) and immunological health. This is also why elite athletes pay much attention to get regular and adequate (about 8 hours) sleep to keep at the top. You should take the same care.

While studies on sleep and immunity etc on humans are somewhat contradictory due to methodological differences and the complexity of the studies, some general associations have been shown.

Mild sleep deprivation is associated with increased activity of e.g the HPA axis and the autonomic sympatho-adrenal system. The first signs of alterations are changes in emotional perception. And there is a connection between disturbed sleep (i.e. apnoea) and psychiatric illness (e.g. ADHD, depression, schizophrenia). And conversely certain disease, notably chronic inflammatory diseases, is associated with sleep disturbances.(3-8)

Well known cytokines in sleep and health are IL-1 and IL-6. Sleep deprivation increases diurnal levels of IL-6, IL-1 and TNF-alfa and decreases cortisol levels thus causing daytime sleepiness, fatigue, disrupted concentration and other problems. IL-6 peaks during normal sleep (and promotes slow wave sleep, aka stage 3 and 4 sleep). (9-10) But too much will cause bad sleep.

As aspirin decreases IL-6 (11) it may both improve sleep during infection and likely worsen sleep in healthy individuals if taken in the evening. (IL-6 peaks around 1900 and 0500, and is at its lowest around 0800 and 2100.) Other cytokines do also affect sleep.

Vagus nerve signaling is important for activation of the immune system, and insults to vagus nerve afferents may activate the immune system in the absence of verifiable infection / pathogens and cause sleep disruption. Severing of the nerve diminishes this response. (12-13)

Obesity, metabolic syndrome and diabetes are associated with increased risk of sleep disturbances and obstructive sleep apnea.

Effects of sleep disruption differ depending on amount of disruption and if it occurs during deep sleep (also called restorative sleep, slow wave sleep, stage 3 and 4) or during REM sleep. A few days of sleep deprivation has been shown to increase viable bacteria in blood and lymphatic systems. Early (14) and slow wave sleep (SWS) is correlated with a shift towards Th1 immunity and late and REM sleep with a Th2 / immunosuppressive shift. Frequent arousals are correlated with increased cortisol, epinephrine (adrenaline) and norepinephrine (noradr…) levels. (15)

During infection time in SWS is increased, while duration of REM slep is decreased in “severe inflammatory states” (chronic fatigue, cancer and auto-immune disease). Shift work is associated with increased infection and prolonged sleep loss in military is associated with changes in “hormonal patterns”.(16)

(See by the way the site www.cfs-recovery.org, if it is still on line, where a chronic fatigue sufferer tells his tale of years of failed attempts to get a diagnosis (wow he must have been a hypochondriac… [this is a sarcasm]) and appropriate treatment, before finally testing himself for sleep apnoea, despite no snoring!! After which he fast recovered… Especially notice the many odd symptoms and problems he got!)

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(1) Preston BT, Capellini I, McNamara P, Barton RA, Nunn CL. Parasite resistance and the adaptive significance of sleep. BMC Evol Biol 9:7, 2009 jan 9
(2) Nolan TE, Metheny WP, Smith RP. Unrecognized association of sleep disorders and depression with chronic pelvic pain. South Med J. 1992 Dec;85(12):1181-3.
(3) Chang PP, Ford DE, Mead LA, Cooper-Patrick L, Klag MJ. Insomnia in young men and subsequent depression. The Johns Hopkins Precursors Study. Am J Epidemiol. 146(2):105-14, 1997.
(4) Plante DT, Winkelman JW. Sleep disturbance in bipolar disorder: therapeutic implications. Am J Psychiatry. 165(7):830-43, 2008.
(5) Peppard PE, Szklo-Coxe M, Hla KM, Young T. Longitudinal association of sleep-related breathing disorder and depression. Arch Intern Med. 166(16):1709-15, 2006.
(6) Ellenbogen JM, Hulbert JC, Jiang Y, Stickgold R. The sleeping brain's influence on verbal memory: boosting resistance to interference. PLoS ONE. 2009;4(1):e4117. Epub 2009 Jan 7.
(7) Meerlo P, Sgoifo A, Suchecki D. Restricted and disrupted sleep: effects on autonomic function, neuroendocrine stress systems and stress responsivity. Sleep Med Rev 12(3):197-210, 2008.
(8) Schroder CM, O'Hara R. Depression and Obstructive Sleep Apnea (OSA). Ann Gen Psychiatry. 2005 Jun 27;4:13.
(9) Opp MR. Cytokines and sleep. Sleep Med Rev 9:355-364, 2005.
(10) Kapsimalis F, Basta M, Varouchakis G, Gourgoulianis K, Vgontzas A, Kryger M. Cytokines and pathological sleep. Sleep Med 9(6):603-614, 2008.
(11) von Känel R, Kudielka BM, Metzenthin P, Helfricht S, Preckel D, Haeberli A, Stutz M, Fischer JE. Aspirin, but not propranolol, attenuates the acute stress-induced increase in circulating levels of interleukin-6: a randomized, double-blind, placebo-controlled study. Brain Behav Immun. 22(2):150-157, 2008.
(12) Johnston GR, Webster NR. Cytokines and the immunomodulatory function of the vagus nerve. Br J Anaesth. 102(4):453-462, 2009
(13) Van Der Zanden EP, Boeckxstaens GE, de Jonge WJ. The vagus nerve as a modulator of intestinal inflammation. Neurogastroenterol Motil. 21(1):6-17, 2009.
(14) Refers to the first 1-3 hours of sleep, while late refers to the following 3-5 hours.
(15) Lorton D, Lubahn CL, Estus C, Millar BA, Carter JL, Wood CA, Bellinger DL. Bidirectional communication between the brain and the immune system: implications for physiological sleep and disorders with disrupted sleep. Neuroimmunomodulation 13:357-374, 2006.
(16) Majde JA, Krueger JM. Links between the innate immune system and sleep. J Allergy Clin Immunol 116:1188-1198, 2005.