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.

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)

CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, immune brain gut endocrine axis, enteric immune system, vagus nerve, immunity, cytokines.
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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.

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

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.