Wednesday, December 23, 2009

Concluding remark about the urodynmic findings

Urodynamic and ecographic studies have shown a high prevalence of urodynamic abnormalities. Are these under-diagnosed in male urologic patients? The problem with any of the above conditions is: what came first? In some cases physiological changes may be the obvious precursor, in other case they may be caused by the subsequent chronic inflammation. Urography and trans-rectal ultrasound should be performed to rule out these problems.

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Tuesday, December 22, 2009

Varicocele and hemorrhoids

A higher prevalence of varicocele (=varicose veins in the scrotum) has been found in “chronic prostatitis syndrome” (sorry the category is from the study, but I guess NIH-III can be assumed) patients. About 15% were affected compared to 5% of the asymptomatic controls.(1-2)

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(1) Pavone C, Caldarera E, Liberti P et al. Correlation between chronic prostatitis syndrome and pelvic venous disease: a survey of 2554 urologic outpatients. Eur Urol 37(4):400-403 2000
(2) Lotti F, Corona G, Mancini M, Biagini C, Colpi GM, Innocenti SD, Filimberti E, Gacci M, Krausz C, Sforza A, Forti G, Mannucci E, Maggi M. The Association between Varicocele, Premature Ejaculation and Prostatitis Symptoms: Possible Mechanisms. J Sex Med. 2009 Aug 11. [Epub ahead of print]

Monday, December 21, 2009

Concretions / calculi / calcifications

These are hardened grains that can form in the bladder, prostate or ductus deferens and ejaculatorius. The composition of prostatic calculi indicates that they too are caused by reflux.(1) Small concretions occur in healthy men, but men with many or larger ones have shown improvement upon elimination of those.(2-3)

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(1) http://www.prostatitis.org/stones.html
(2) Geramoutsos I, Gyftopoulos K, Perimenis P, Thanou V, Liagka D, Siamblis D et al. Clinical correlation of prostatic lithiasis with Chronic Pelvic Pain Syndromes in Young Adults. Eur Urol 45(3):333-338, 2004.
(3) Shoskes DA, Lee CT, Murphy D, Kefer J, Wood HM. Incidence and significance of prostatic stones in men with chronic prostatitis/chronic pelvic pain syndrome. Urology 70(2):235-238, 2007.

Sunday, December 20, 2009

Urodynamic problems and intraprostatic pressure

An often overlooked factor seems to be screening for physiological and mechanical and fluid dynamical causes related to bladder, prostate and seminal vesicles. Studies have found physical abnormalities, and a transrectal ultrasonography study found physical (urological) abnormalities or other conditions in as many as 70% of the patients ! (1)

The most common cause of pathology is reflux(2), or urine flow up into the canalicoli (i.e. prostate) is caused by urethral strictures (due to trigonitis or urethral stenosis, both uncommon in men, or muscular hypertonus or physical abnormalities(3)) or sclerosis/dysectasia of the bladder neck (cervicis vesicae) affecting normal defluition (“deflux”) of urine (micturition). Non-infectious epidydimitis may also occur for the same reasons. Reflux is thought to cause inflammation by the presence of purine and pyrimidine (uric acid) in the urine. (Aside: high values of uric acid in blood causes gout.) Another possible cause of inflammation could be turbulent flow of the urine damaging urethral tissues.(4)

A recent ultrasound study of the bladder neck area found differences of: prostate volume, hypoechoic periurethral zone volume, posterior prostate lip thickness, bladder neck thickness and bladder muscle (detrusor) thickness between CPPS patients and controls. No differences in calcifications were found.(5)

A study indicated that NIH-IIIa patients have significantly higher intraprostatic pressure than IIIb or BPH patients(6), This may be caused by strictures, as mentioned above, muscular tension or concretions, or by tissue damage caused by blood pressure and other problems affecting interstitial tissue pressure.(7) This latter would also be consistent with the presence of inflammation markers.

Fall et al. concluded that: “Urodynamic studies [of prostatitis patients] demonstrate decreased urinary flow rates, incomplete relaxation of the bladder neck and prostatic urethra, as well as abnormally high urethral closure pressure at rest. The relaxation of the external urethral sphincter during urination is normal”.

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(1) Nicolai M, De Thomasis R, Di Federico G, Palmerio A, Iantorno R, Tenaglia R. [Role of transrectal echography in the evaluation of obstructive seminal vesicle pathology in prostatitis syndrome] Arch Ital Urol Androl. 68 (5 Suppl):101-4, 1996.
(2) Mehik A, Leskinen MJ, Hellström P Mechanisms of pain in CPPS: influence of prostatic inflammation. World J urol 21:90-94, 2003
(3) Hochreiter WW Zbrun S CPPS and voiding dysfunction. Curr Urol Rep 5(4):300-304, 2004
(4) Martinez-Borges AR Turbulent urinary flow in the urethra could be a causal factor for benign prostatic hyperplasia. Medical hypothesis 67(4):871-875 2006
(5) Dellabella M, Milanese G, Muzzonigro G. Ultrasound evaluation of bladder neck complex alterations in CP/CPPS. 2005 EAU meeting, Istanbul. (Also published in J Urol 176:112-118, 2006. Correlation between…)
(6) Mehik A, Hellstrom P, Nickel JC et al The CP/CPPS can be characterized by prostatic tissue pressure measurements. J Urol 167(1):137-140, 2002
(7) Mehik A, Leskinen MJ, Hellström P Mechanisms of pain in CPPS: influence of prostatic inflammation. World J urol 21:90-94, 2003

Nocturia and quality of life

A couple of months ago I discussed how nocturia affects neurological health. Below follows a diagram presented at the EAU 2009 in Stockholm (based on Tikkinen et al poster presented at ICS 2008, abstract 434). It illustrates well how even one nocturnal void affects quality of life (QoL).



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Vitamin D and immune seasonality

Many diseases show an increased incidence with less sun exposure (i.e. living in the north) which may be correlated insufficient levels vitamin D. Does vitamin D affect immune regulation? Yes, an increasing amount of evidence shows that vitamin D and individual vitamin D receptor polymorphism (“gene variants”) are very important for immune regulation. The VDR is present in almost every cell in the body. Much of the basic research has been done with so called VDR null (3) mice and it indicates that VDR differences in vitamin D deficiency cause different risk for respiratory diseases, stomach ulcers, auto-immunity, cancers (breast, skin, colon, prostate, pancreas etc), hypertension, IBS, diabetes, increased thrombogenicity (“clot forming”), thyroid disturbances, rheumatic disease, MS (4) (which “is essentially unknown at the equator”), osteoporosis, diffuse muscular pain, ostearthrosis, connective tissue disorders, caries, skin disorders (including acne), rickets, SLE, myopathy (“weak muscles”), schizophrenia and on and on and on.

Main ways of action of vitamin D (or rather its metabolites) are immuno-regulatory. It regulates immunity by suppressing the proliferation of immunoglobulin, inhibit differentiation of dendritic cells (“the most potent of antigen presenting cells”), slowing B cell differentiation and inhibit Th1 cell proliferation (innate, cellular response) thus decreasing e.g. IFN-gamma and IL-2 productiion. It may also increase Treg and IL-4, 5 and 10 production thus in sum inducing a more Th2 (adaptive, humoral) biased response and attenuating any excessive Th1 inflammatory response.. It does also regulate and inhibit Th17 response. Innate immunity is also enhanced by expression of antimicrobial peptides (AMPs, e.g. cathelicidin and defensins). Innate (cellular) immunity is important for epithelial integrity of e.g. lungs, gengiva, bladder, skin (epidermis) and intestine. VDR-driven immune response is strongly impaired in vitamin D deficiency. Other effects are anti-neoplastic (regulation of cell growth and differentiation) and inhibition of angiogenesis (growth of new blood vessels, especially into tumors). Influenza and auto-immune disease are typically worsening (exacerbating / flaring) in winter (3) and spring, and improving in summer and fall.(4-12)

125 micrograms vitamin D per day reach steady state at about 150 nmol/l 25(OH)D after 3 months and 250 micrograms at about 200 nmol/l after 3 months (starting point was 70 nmol).(13) Intoxication has been observed at levels above 375 nmol/l (50000 IU/day). Skin production of vitamin D is self-limiting so intoxication is not possible by tanning. Hyperthyroidism increases 25(OH)D metabolism rates. (Holick)
Useful amounts of vitamin D are only present in certain wild fat fish. E.g. fresh *wild* salmon that contains 600-1000 IU per 100 grams. Darkskinned African skin equals approximately a sun protection factor 15 sun screen (Holick).

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(1) Caveat: murine immune system differs from human in certain important aspects.
(2) In a trial reported by J Burton, at the 2009 meeting of American Academy of Neurology, vitamin D supplementation for, on average, 14000 IU/day induced remission and about a halved relapse rate.
(3) Immune response is upregulated during winter to counter environmental adversities. In the wild the net effect is a relative immune suppression (due to limited energy availability / high energy expense), but in laboratory conditions this may not be the case.
(4) Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, Lieben L, Mathieu C, Demay M. Vitamon D and human health: lesosn from vitamin D receptor null mice. Endocr Rev 29(6):726-776, 2008.
(5) Cantorna MT. Vitamin D and its role in immunology: multiple sclerosis and inflammatory bowel disease. Prog Biophys Mol Biol. 92(1):60-64, 2006.
(6) Lips P. Vitamin D physiology. Prog Biophys Mol Biol. 92(1):4-8, 2006.
(7) Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 81:353-373, 2006.
(8) Holick MF. Vitamin D deficiency. NEJM 357(3):266-281, 2007.
(9) Mouyis M, Ostor AJK, Crisp AJ, Ginawi A, Halsall DJ, Shenker N, Poole KES. Hypovitaminosis D among rheumatology outpatients in clinical practice. Rheumatology 47:1348-1351, 2008.
(10) Nelson RJ. Seasonal immune function and sickness response. Trends Immunol 25(4):187-192, 2004.
(11) Bikle D. Nonclassic actions of vitamin D. J Clin Endocrinol Metab 94(1):26-34, 2009.
(12) White JH. Vitamin D signaling, infectious diseases and regulation of innate immunity. Inf Immun 76(9):3837-3843, 2008.
(13) Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 77:204-210, 2003.

Saturday, December 19, 2009

The immune system (enteric, gender, seasonality)

The following blog posts will discuss basic immune function and the possible connections with CPPS.

The immune system is divided in two arms: innate and adaptive. Both of which contain cellular (macrophages, natural killer cells etc) and humoral (antibodies) immune components. Cellular immunity protects mainly against intracellular bacteria, protozoans, fungi and many viruses), while humoral immunity protects against multicellular parasites, extracellular bacteria, certain viruses, ceratin toxins and allergens. A popular concept of immunity is the Th1/Th2/Th17-hypothesis.(1-3) In additon to these two arms, an oft forgotten an very important part of the immune system is the enteric immune system.

Not only does the gut have a massive nervous system (see below), it is also the biggest immune system in the body. The gut-associated lymphoid tissue comprises about 70 percent of the mucosal barrier (most of the rest protects the lungs). And that is not suprising as the gut has to withstand an endless stream of pathogens and occasional toxins. Not only invaders from outside the body but also the about over 100 trillion organisms that live in the gut. The maternal intestinal microbiota (both organisms and a large number of “intestinally derived bacterial components”, N.B. not antibodies, but genetic material) is passed to the newborn trough the breast milk.(4) Ingested probiotics may modulate intestinal pain and the immune system by normalizing cytokine ratios.(5)

The brain and the viscera communicate with each other to coordinate behavior and emotional responses (due to evolutionary reasons like territorial marking, not stop to pee while hunted, panic, anxiety, and so on).and visceral activity. Pathological changes (e.g. bacterial infection, tissue damage, distension of the colon and others) in the viscera affect the forebrain.

Immune activity shows a circadian rhythm with cellular/Th1 prevalence during sleep (maximum activity coincides with nocturnal cortisol maximum) and humoral/Th2 prevalence during daytime. Diseases more common / worse during daytime are e.g. stroke, arrhythmias, seizures, sepsis and asthma.

A seasonal pattern of increased immune activity during winter with humoral bias, to counter wintertime stress induced immune suppression, and cellular bias during summer is also postulated.(6,7) Children (and especially foetuses) are more humoral/Th2 biased than adults (8) (and sex differences are minimal before puberty). Adult men generally have a more Th1-biased response, due to high androgen levels, that gets more Th2-biased with age as testosterone levels decrease. Female response is generally more Th2-biased due to the high levels of estrogens that are both pro-inflammatory (a pro-fibrotic response) and “immunosupportive”. Thus the same infectious (or adjuvant) insult may cause a stronger anti-inflammatory response in men.(9)

Estrogens correlate with increased incidence of depression, axiety and auto-immune disorders (women are 2-9 times more likely to suffer from pain disorders, RA and SLE). Female immune response varies with the different phases of the menstrual cycle, pregnancy and contraceptive usage.(10)

Much confusion casued by animals studies arises from the fact that acute and chronic phase response are not distinguished. These differences between acute and chronic phases and phases of the menstrual cycle are seldom considered in general research even if sex differences have been accounted for (which in itself is not done as much as it should).

Nocturia induced sleep disruption and androgen alterations may both lead to immune changes worsening CPPS and explain the sickness behaviour seen in CPPS sufferers. Also the fact that CPPS generally remits during summer (when sun-stimulated vitamin D production shift the immune response towards an anti-inflammatory response), may indicate that CPPS is an immune related disorder. Possibly a disorder of Th1-driven (cellular) inflammatory immunity.

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(1) Steinman L. A rush to judgment on Th17. J Exp Med 205(7): 1517–1522, 2008.
(2) Kidd P. Th1/Th2 balance: The hypothesis, its limitations, and implications for health and disease. Altern Med Rev 8(3):223-246, 2003
(3) Steinman L. A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell–mediated tissue damage. Nature medicine 13(2):139-145, 2007
(4) Perez PF, Dore J, Leclerc M, Levenez F, Benyacoub J, Serrant P, Segira-Roggero I, Schiffrin EJ, Donnet-Hughes A. Bacterial imprinting on the neonatal immune system: lessons from maternal cells? Pediatrics 119(3):E724-732, 2007.
(5) Marchesi J, Shanahan F. The normal intestinal microbiota. Curr Opin Infect Dis 20:508-513, 2007.
(6) Nelson RJ, GE Demas GE, Klein SL, Kriegsfeld LJ. Seasonal Patterns of Stress, Immune Function, and Disease. Cambridge University Press, 2002.
(7) Nelson RJ. Seasonal immune function and sickness responses Trends in Immunology 25(4):187-192, 2004.
(8) Petrovsky N. Towards a unified model of neuroendocrine–immune interaction. Immunol Cell Biol 79:350–357, 2001
(9) Fairweather D, Frisancho-Kiss S, Rose NR. Sex differences in autoimmune disease from a pathological perspective. Am J Pathol 173:600-609, 2008.
(10) Darnall BD, Suarez EC. Sex and gender in psychoneurimmunology research: past, present and future. Brain Behav Immun 23:595-604, 2009.

Some final words on androgens

As androgens, and especially testosterone, are important for male health they are an interesting field of research. Unfortunately the research is scant on the relation between androgens and CPPS. But it is definitively a good idea to try to minimize androgen disruption by trying to get enough sleep. Especially due to the fact that nocturia disrupts sleep in CPPS. A possible solution could be very small doses of desmopressin, to see if sleep improves leading to improved wellbeing and vigour. It would also be interesting to research thyroid and gonadal-pituitary function.

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Friday, November 27, 2009

Androgens and other hormones in CPPS

As earlier mentioned good studies are lacking, but there is agreement that total/free testosterone levels are lower than in comparable healthy men. There is little data but Dimitrakov et al.(1) measured levels of various hormones and androgens in a small study (27 patients, 29 controls). The data was pretty disparate but the following was found (unless otherwise noted all values are medians):

Progesterone (ref 13-97) varied greatly between individuals with a median value of 26 ng/dl (controls were <3).

Corticosterone (ref 100-700) was significantly lower. 40 ng/dl with 75% <75 (yes it is a correct transcription). Controls 141.

Aldosterone (ref 20-90) was also significantly lower. 18 pg/ml with 75% <64. Controls 61. It did also correlate with NIH-CPSI pain scores.

11-deoxycortisol (20-130) was lower. 12 ng/dl, although controls also were pretty low at 31.

Androstenedione (50-250) was higher. 126 ng/dl vs. 73.

Total testosterone (260-1000) was low. 60 ng/dl (25-75 percentile was 37 and 79) as has previously been reported.

Unfortunately no free testosterone and SHBG is given so we do not know if free testosterone also is low. The control group was hypogonadal unless the reported median (8, 25 percentile 1!! and 75th percentile 402) is wrong. The authors then draw an unwarranted conclusion that the testosterone value is significantly higher, which gives the wrong impression that it is normal instead of hypogonadal. The problem is their controls, why have some almost zero testosterone? Did some have prostate cancer?

Other measured hormones show no difference (DHEA, DHEAS, estradiol, cortisol, 17-dehydrocortisol). LH, FSH, SHBG, prolactin were not measured. Although a new study show blunted adrenocorticotropin response compared with controls.(2) The authors suggest the values indicate reduced activity of CYP21A2 (p450c21) and non-classical congenital adrenal hyperplasia. It would surely be very interesting if they also tested the subjects genes for CYP21 polymorphisms.(5) (Is acne more common in CPPS sufferers? A possible but controversial causality has been suggested.(4))

Regarding cortisol levels another small study showed small differences in awakening response between CPPS patients and controls. CPPS patients had a slightly slower drop-off -- lesser slope and thus a greater area under the curve from the awakening peak until about three hours after. Increased cortisol is associated with pain (or stress) so this may just indicate that the CPPS patients have pain, are stressed in general by the condition or by some incidental cause (e.g. social situation or undiagnosed rheumatic condition). As patients and controls were not fully comparable in education and socioeconomic status (e.g. 5 controls out of 20 had never married vs 18 CPPS, 1 control was divorced vs 5 CPPS, 1 control was on disability or unemployed and not student vs 7 CPPS) the finding may have been spurious and not related to CPPS as the authors concluded.(3)

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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.
(2) Anderson RU, Orenberg EK, Morey A, Chavez N, Chan CA. Stress induced HPA axis responses and disturbances in psychological profiles in men with CP/CPPS. J Urol, Sep 15, 2009 epub ahead of print.
(3) Anderson RU, Orenberg EK, Chan CA, Morey A, Flores V. Psychometric profiles and HPA axis function in men with CP/CPPS. J Urol 179:956-960, 2008.
(4) Thalmann S, Meier CA. Acne and ‘Mild’ Adrenal Hyperplasia. Dermatology 213:277-278, 2006.
(5) Admoni O, Israel S, Lavi I, Gur M, Tenenbaum-Rakover Y. Hyperandrogenism in carriers of CYP21 mutations: the role of genotype. Clin Endocrinol (Oxf). 64(6):645-51, 2006.
NCAH review: Speiser PW. Nonclassic adrenal hyperplasia. Rev Endocr Metab Disord. 2009 Mar;10(1):77-82.

Testosterone and sleep

This is very interesting for CPPS sufferers. As sleep is very important for health and for feeling well. And sleep disturbance is common in CPPS due to the need to void once or twice at night. Which can affect testosterone levels deeply.

Sleep is very important for testosterone levels. This is regardless of when you sleep as long as it is a good undisturbed period of about eight hours.(1) Shorter sleep in old age may be a cause of lower testosterone levels. Bad sleep, especially loss of REM sleep, will depress testosterone levels, but paradoxically high testosterone levels may cause bad sleep too by inducing apnea.(2) A vicious circle!

Individuals with obstructive sleep apnea (OSA) are an extreme example.(3) Sleep disruption will disturb all sleep-controlled endocrine rhythms, not only testosterone. "In conclusion, testosterone increased during sleep and fell during waking, whereas circadian effects seemed marginal. Individual differences were pronounced."(4) "During fragmented sleep, nocturnal testosterone rise was observed only in subjects who showed REM episodes. Our findings indicate that the sleep-related rise in serum testosterone levels is linked with the appearance of first REM sleep. Fragmented sleep disrupted the testosterone rhythm with a considerable attenuation of the nocturnal rise only in subjects who did not show REM sleep."(5)

As nocturia is a common cause of disrupted sleep addressing nocturia in CPPS patients is an important issue. The figure below shows normal sleep (no nightly awakenings) and disrupted sleep (nightly awakenings indicated by blue bars).





The following diagram shows normal nightly testosterone rise (left: A,C) and absence with disrupted rem sleep (right: B, D). Time zero is from onset of melatonin (upper: A,B) and start of sleep (lower: C,D). (Luboshitzky et al, 2001.)



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(1) Axelsson J, Ingre M, Åkerstedt T, Holmbäck U. Effects of acutely displaced sleep on testosterone. J Clin Endocrinol Metab 90:4530-4535, 2005.
(2) Saaresranta T, Polo M. Sleep-disordered breathing and hormones. Eur Respir J 22:161-172, 2003.
(3) Luboshitzky R, Aviv A, Hefetz A, Herer P, Shen-Orr Z, Lavie L, Lavie P. Decreased pituitary-gonadal secretion in men with obstructive sleep apnea. J Clin Endocrin Metab 87(7):3394-3398, 2002.
(4) Axelsson J, Ingre M, Åkerstedt T, Holmbäck U. Effects of Acutely Displaced Sleep on Testosterone. J Clin Endocrin Metab 90(8):4530-4535, 2005.
(5) Luboshitzky R, Zabari Z, Shen-Orr Z, Herer P, Lavie P. Disruption of the nocturnal testosterone rhythm by sleep fragmentation in normal men. J Clin Endocrin Metab 86(3):1134-1139, 2001.

Does testosterone cause prostate cancer?

A very good question and not likely related to CPPS, but there is a dicussion if there is a correlation. The association between testosterone and cancer is currently in doubt due to the following. Men dying from prostate cancer are all castrated (zero testosterone) due to treatment. Huggins assertion that testosterone causes cancer is based on equivocal results from one patient!! No modern studies during the last 25 years have managed to prove that prostate cancer cells grow with extra testosterone.(1) Prostate cancer increases with age, while testosterone decrease with age. Aggressive cancer is correlated with low testosterone.(2) As is recurrence. Morgentaler calls the high testosterone cancer connection a myth.(3) Recent research indicates that vitamin D deficiency may increase the risk of developing prostate cancer.(4)

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(1) Endogenous Hormones and Prostate Cancer Collaborative Group, Roddam AW, Allen NE, Appleby P, Key TJ. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. JNCI 100(3):170-183, 2008.
(2) C Schulman, Testosteron treatment and and prostate risk, EUA Congress 2009
(3) Morgentaler A. Testosterone and prostate cancer: an historical perspective on a modern myth. Eur Urol 50(5):935-939, 2006.
(4) Schwartz GG. Vitamin D and intervention trials in prostate cancer: from theory to therapy. Ann Epidemiol. 19(2):96-102, 2009.

Wednesday, November 18, 2009

Sex hormone binding globulin

SHBG or sex hormone binding globulin is the most important variable when assessing testosterone status as increased levels of it decreaseas available bioactive and free testosterone. Total testosterone levels without measuring SHBG may be meaningless as high levels of SHGB lead to higher total testosterone levels than would normally be present, while at the same time causing low levels of free testosterone. Low SHBG leads to the opposite findings.

Low SHBG is associated with obesity (high aromatase levels), diabetes (hyperinsulinemia), nephrotic syndrome, hypothyroidism, glucorticoids, high testosterone, hGH excess and progestins.

High SHBG levels with hepatic cirrhosis / liver disease, increased estrogen levels (correlates with chronic inflammation, autoimmune disease, rheumatism), hyperthyroidism / thyrotoxicity, porphyria and low testosterone. Notice that TSH levels may be within the normal range in the latter case, so SHBG levels out of the normal range should be followed up.

It must be noted though that in men with a normally functioning HPG axis lowered free testosterone will, through feedback, lead to increased LH and (total) testosterone to compensate for the low free-T, and thus keeping the free T levels “normal”. Only when the HPG feedback cannot compensate free-T will also start to decrease.

High SHBG will also bind estrogen (E2) and cause low levels of free-E2, which may be a cause of osteopeania in men.(1)

In practice this means that E2 also should be measured to determine testosterone status and HPG axis status. If free T is less than free E2 as a percentage of total T values “all systems are go” so to speak. E.g. about 40% free compared to total T and 60% E2 at 80 nmol/l SHBG or 50% free T and 70% E2 at 40 nmol/l SHBG.

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(1) de Ronde W, van der Schouw YT, Muller M, Grobbee DE, Gooren LJ, Pols HA, de Jong FH. Associations of Sex-Hormone-Binding Globulin (SHBG) with Non-SHBG-Bound Levels of Testosterone and Estradiol in Independently Living Men J Clin Endocrinol Metab. 90(1):157-162, 2005.

Testosterone levels

Testosterone declines slowly as men age after peaking in early adulthood.(1) Young men have a higher nightly production (approximate minimum, 500-600 ng/dl, around 20.00 hours, maximum, 550-750, around 06.00), than older men (min, 300-500 ng/dl, around 20.00 hours, max, 350-550, around 06.00). No circadian variation at all is seen in hypogonadal men (<300).(2) At high age levels may be deficient and cause a lower quality of life.

Studies of seasonal testosterone level variations are contradictory though. A large Norwegian study indicates that levels are higher in winter and lower in summer.(3) It has been speculated if this is due to longer time spent awake or lower melatonin levels in summer, due to the longer hours of light. It would be interesting to see if men borne and living in the tropics or in temperate zones, with less cold than Norway, but still marked seasonal variation in insolation, show similar seasonal testosterone variation.

REM sleep is important in nightly production. See coming post for details.

Testosterone levels do also seem to be slightly higher in “western” men than others, but it is unclear whether this reflects nutrition, socio-economic status, disease incidence, selection bias etc. Additional information is found in “Prevalence of Symptomatic Androgen Deficiency in Men”,(4) but do also see the BACH survey.(5)

Low levels cause depression, diminished cognitve abilities, lowered aggressiveness, visceral obesity, lowere libido, osteoporosis, dry skin, anemia, loss of muscle mass, cardio-vascular disease, pain, headcahes, reumatoid arthritis etc.(6) On average libido and vigour start to noticeably wane at around <15 (total testosterone level), visceral obesity to be notable at around <12 nmol, depression, sleep disturbances, loss of concentration, diabetes type 2, waist circumference >102 cm at about <10 nmol, hot flushes, erectile dysfunction at around <8 nmol. These changes are independent of age and there are notable individual and daily differences.(7) This condition is usually called hypogonadism in developed stages. The more general term testosterone deficiency syndrome has also been suggested.

For practical reasons free testosterone should be measured as that is more indicative due to great intraindividual variation SHBG levels. (See following post.)

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(1) Yeap BB. Testosterone and ill-health in aging men. Nature Clinical Practice Endocrinology & metabolism. 5(2):113-121, 2009.
(2) Gupta et al. Modeling of circadian testosterone. J Clin Pharmacol 40:731-738, 2000.
(3) Svartberg J, Jorde R, Sundsfjord J, Böna, KH, Barrett-Connor E. Seasonal variation of testosterone and waist to hip ratio in men: the Tromsö study. J Clin Endocrinol Metab 88(7):3099-3104, 2006.
(4) Araujo AB, Esche GR, Kupelian V, O'donnell AB, Travison TG, Williams RE, Clark RV, McKinlay JB. Prevalence of Symptomatic Androgen Deficiency in Men. J Clin Endocrinol Metab. Aug 14 2007. [Epub ahead of print]
(5) Araujo AB, Esche GR, Kupelian V, O’Donnell AB, Travison TG, Williams RE, Clark RV, McKinlay JB. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab 92(11):4241-4247, 2007.
(6) Bain J. The many faces of testosterone. Clinical Interventions in Aging 2(4):567-576, 2007.
(7) M Zitzmann, Testosterone deficiency and mens' health, EAU Congress 2009.

Saturday, October 10, 2009

Testosterone and androgens in male health

Unfortunately effect of, or variation in, testosterone and other sex hormone levels has not been well studied in relation to CP/CPPS. A few studies indicate that levels are lower than normal relative to age and lifestyle. The problem with all these studies is that they commonly do not publish any data on albumin, prolactin, estradiol, LH, FSH or SHBG levels making interpretation very difficult.(1) In the following a general overview is given of how androgens and sex hormone affect male health.

"Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immune-suppressors."(2) Testosterone deficiency also leads to low levels of ATP, which causes tiredness, higher incidence of osteoporosis (especially with estradiol deficiency), worsen rheumatoid arthritis (both total and free testosterone and SHBG are lower than in healthy subjects), abdominal obesity, increased diabetes risk, low libido, erectile dysfunction, depression, coronary artery disease and other problems.

Coagulation factors are increased in low levels of (free?) testosterone, which may explain some of the features of CPPS and why some of the treatments (that have anti-thrombotic effect) lead to improvement.

Abdominal obesity is due to visceral fat building up. Visceral fat inhibits testicular function, secretes pro-inflammatory cytokines (TNF-alpha, IL-6, IL-8), but also IL-10. It also secretes leptin (affects GnRH and HPA axis regulation of LH/FSH, which in turn affects testo production), PAI-1 (simply explained: a "blood coagulant"), acute phase proteins and so on. A downward spiral.

There is also research (3) that indicate a possible hypothalamic testosterone lowering pathway independent of luteinizing hormone-releasing hormone, possibly mediated by pro-inflammatory cytokines released in the brain and by alcohol. "In addition, this pathway may play a role in androgen-dependent functions that are unrelated to fertility, such as cardiovascular, renal and immunological activity, muscle mass, behavior and cognitive abilities. These are usually considered genomic effects of androgens. In addition, testosterone exerts many very rapid, non-genomic effects as varied as airway smooth muscles reactivity, as well as reward, learning and analgesia."(4)

Additionally testosterone / gonadal function is affected by systemic disease. The following is summarised from Karagiannis and Harsoulis.(5) Acute disease and stress is associated with reversible impairment of gonadotropin and testosterone secretion. Severe starvation likewise (and can lead to hyperestrogenism and refeeding gynecomastia when relieved). In chronic disease gonadotropins are increased while testosterone is suppressed. In most cases of hypogonadism Leydig cell function is impaired.

Liver cirrhosis is associated with hypogonadism due to endocrine disruption. In alcoholics the symptoms are worsened by alcohol effects on the testes. Alcohol per se (without liver disease) can cause hypogonadism due to disruption of the HPA axis and other effects.

Hemochromatosis causes damage due to pituitary and testicular "poisoning" by accumulation of excess iron. Which leads to hypogonadism.

Chronic renal disease causes "major [negative] effects on the male reproductive system" due to its severe effects on the organism. The changes occur early in renal disease and do not improve by treatment or dialysis, rather worsen.

Metabolic syndrome cause decreased total testosterone and SHBG levels, gonadotropin secretion disturbances and aromatase production by fat cells that further depress testosterone etc.

Hypogonadism is also associated with rheumatic and autoimmune disease like RA and SLE. Some anti-rheumatic drugs can also irreversibly damage testicular function.

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(1) If FSH and LH are elevated the testicular production of testosterone is impaired. If low then it may be caused by pituitary adenoma (elevated prolactin) or Cushings (aberrant cortisol) or hemochromatosis (elevated transferrin).
(2) Cutolo M, Capellino S, Sulli A, Serioli B, Secchi ME, Villaggio B, Straub RH. Estrogens and autoimmune diseases. Ann N Y Acad Sci 1089:538-547, 2006.
(3) James, P.J., Rivier, C., Lee, S. Presence of corticotropin-releasing factor and/or tyrosine hydroxylase in cells of a neural brain-testicular pathway that are labelled by a transganglionic tracer. J. Neuroendocrinol. 20:173-181, 2008 (and research by Riviers et al referenced therein.)
(4) http://pblcr.salk.edu/08_testosterone.html accessed 2009-03-08 at 1613 GMT.
(5) Karagiannis A, Harsoulis F. Gonadal dysfunction in systemic disease. Eur J Endocrin 152:501-513, 2005.

Sunday, October 4, 2009

Sexual health-concluding remark

Erectile dysfunction (ED) and ejaculatory dyssynergia (EDS) strongly affect quality of life in some CPPS sufferers. Why these occur and how many men that are affected is not clear. Research in ED and EDS is in my opinion lacking in standardized procedures and useful measurables (the 2-minute limit is not a good parameter-it is in fact ridiculous). The fact that circumcised and normal men are not distinguished is also a confounding factor. Lack of detailed information on thyroid and gonadal function (prolactin, SHBG, DHEA etc) is yet another.

Saturday, October 3, 2009

Infertility in CPPS

Prostatitis is an indicator of infertility risk (e.g. if epidydimial infection / inflammation or zinc or magnesium abnormalities are present). It has been estimated that somewhere between 35-90% of men seeking for help with infertility has had or has some prostatitis-like disease or symptoms (including STD’s)(1). Notice that inflammation or abnormalities in any of the: testicles, prostate, epididymis, seminal vescicles, vas deferens, ampollae, Cowper’s gland and the glands of Littre affect fertility! (There are of course other causes, but the above are prostatitis-related.)

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(1) Colpi GM (ed.). Male infertility today, nr 4, 2004. Imprimatur: fotolito e stampa grafiche gelmini, Milano.

Friday, October 2, 2009

Ejaculate (semen) abnormalities in CPPS

Ejaculate is comprised of sperm, prostatic fluid (watery, 15-30%), urethral (Littre’s) and bulbourethral (Cowper’s) gland fluids (viscous, clear) and seminal vesicle fluid (gelatinous, 50-70% of volume). About 1.5-5 milliliters is the average. Anecdotal evidence indicates that semen gets yellowish and thicker or too watery and having a non-homogenous appearance in CPPS, especially during flares. Is this because of abnormal proportions of the various fluids or other causes ?

Ejaculate is slightly alkaline: pH 7.3-8.5 (variation is due to methodology and values as low as about 6.5 can be found in the literature). Higher pH is indicative of infection and too low pH impairs sperm motility. Some CPPS sufferers have high pH.

A small study has found that ejaculate citrate levels are depressed in NIH-II, IIIa and IIIb patients compared to controls. Interestingly NIH-II and IIIa sufferers had very similar levels 3.32 +/- 0.79 mg/ml and 3.41 +/- 0.88 (controls 8.55 +/- 1.20) indicating commonality. IIIb sufferers have intermediate values (4.37 +/- 0.77).(1)

Analyses have also shown decreased levels of magnesium, zinc, fructose(2), spermine, prostate anti-microbial factor (PAF) and other substances. There are also conflicting studies on seminal microflora. There is a case report of CPPS in conjunction with the presence of uric acid in the ejaculate.(3)

Ejaculate main composition: Zinc 0.352 ± 0.048 g/liter; Magnesium 0.120 ± 0.060 g/liter; Calcium 1.200 ± 0.080 g/liter; Citric acid 4.80 ± 26.9 g/liter; Cholesterol 0.078 ± 0.013 g/liter; Spermine 0.243 ± 0.025 g/liter; Lysozyme 0.021 ± 0.006 g/liter; Acid phosphatase 2.56 million IU per liter.(4)

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(1) Chen J, Xu Z, Zhao H, Jiang X. Citrate in expressed prostatic secretions has the feasibility to be used as a useful indicator of category IIIB prostatitis. Urol Int 78(3):230-234, 2007. The essentially same article was also published as Chen J, Zhao HF, Xu ZS, The prostate has secretory dysfunction for category IIIA and IIIB prostatitis in J Urol 177(6):2166-2169, 2007.
(2) Engeler DS, Hauri D, John H. Impact of prostatitis NIH IIIB (prostatodynia) on ejaculate parameters. Eur Urol 44(5):546-548, 2003.
(3) Motrich RD, Olmedo JJ, Molina R, Tissera A, Minuzzi G, Rivero VE. Fertility and Sterility 85(3):751, 2006.
(4) Sexually transmitted diseases, Holmes KK, Mårdh P-A, Sparling PF, Weisner PJ, Cates W Jr, Lemon SM, et al., eds.

Thursday, October 1, 2009

Magnesium and zinc in the prostate

CP/CPPS is currently not connected with magnesium or zinc insufficiency, but the prostate is the most zinc and magnesium-rich organ in the body (up to 20 times higher concentration than in other organs). Magnesium is essential for seminal fluid quality and sperm "survival" and uro-genital health. A study (1) has shown that magnesium levels were significantly decreased in the seminal plasma of normozoospermic chronic prostatitis sufferers. But other studies have shown no such correlation(2). Zinc is essential for sperm quality, prostate and uro-genital health in general (3,4) and also for health in general.

Plasma zinc levels are below normal in patients with malignancies (decreased about 60-70%), but above normal in patients with benign hyperplasia and chronic prostatitis(5). Levels in controls is 94.5±10.38 µg/100 ml; with benign diseases of the prostate between 145 and 173 µg/100 ml (highest in BPH) and patients with malignancy 59.6±3.08 µg/100 ml(6).

It is unclear if the raised zinc levels are causing the illness or are an effect thereof(7). Anecdotal data suggest zinc supplementation may improve semen abnormalities.
Both minerals are tightly regulated in the body and not stored (if one does not include the skeleton).

(Curiously MgCl was suggested in France before WWII as an effective diuretic and uro-prostatic function "corrector" [J. Favier, "Equilibre mineral et sante", Librairie Le François, 1951]. Which is popular to mention on self-help and altmed sites.)

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(1) Edorh AP, Tachev K, Hadou T, Gbeassor M, Sanni A, Creppy EE, Le Faou A, Rihn BH. Magnesium content in seminal fluid as an indicator of chronic prostatitis. Cell Mol Biol (Noisy-le-grand). 2003;49 Online Pub:OL419-23.
(2) Colleen S, Mårdh PA, Schytz A. Magnesium and zinc in seminal fluid of healthy males and patients with non-acute prostatitis with and without gonorrhoea. Scand J Urol Nephrol 9:192-197, 1975.
(3) "Zinc: a key urological element" by IM Bush et al., presentation at the 1974 AMA annual meeting, Chicago, USA
(4) Yan M, Song Y, Wong CP, Hardin K, Ho E. Zinc deficiency alters DNA damage response genes in normal human prostate epithelial cells. J Nutr 138:667-673, 2008.
(5) Goel and Sankwhar, Comparative study of zinc levels in benign and malignant lesions of the prostate, Scand J Urol Nephrol, 108-12, 2006
(6) Goel T, Sankhwar S. Comparative study of zinc levels in benign and malignant lesions of the prostate. Scand J of Urology and Nephrology, 40(2):108-112, 2006.
(7) Antibacterial effect of intraprostatic zinc injection in a rat model of chronic bacterial prostatitis by YH Cho et al., Int J Antimicrob Agents 19:576-582, 2002

Wednesday, September 30, 2009

Prostate related findings

Inflammation in bacterial prostatitis is characterized by the "presence of polymorphonuclear leukocytes and macrophages in the glandular ducts, epithelium and/or adjacent stroma" around the acini or ducts. Stromal involvement depends on intraluminal inflammation (1, 2). Other findings are: abnormal glandular ducts, epithelial atrophy, metaplasia and dysplasia, and hyperchromasia ("with polymorphism of the epithelial cell nuclei and cytoplasmic basophilia"). Changes that may be misinterpreted as cancerous. If palpated the prostate is often enlarged and "soft" in bacterial prostatitis while never in CPPS.

In CP/CPPS "glandular atrophy with stromal fibrosis, accompanied by a mild residual inflammatory reaction" is commonly observed(3). But only 5% of biopsies show significant inflammation(4). Although variation between studies is high up to 100% (5) prevalence has been found. The variation is obviously due to the varying (read: poor!) selection criteria of the studies. There is minimal correlation between histopathology and visible/clinical symptoms, but histological findings increase with age and are more commin in infertile men.

It is unclear whether some minimal inflammation of the prostate is normal or not, so if this is of any clinical use remains to be seen.

The recent REDUCE trial involving 5597 subjects has shown that no "clinically meaningful" difference is present between healthy subjects and CP/CPPS sufferers.(6) PSA levels are insignificantly elevated in CPPS (NIH III) and slightly to highly elevated in NIH IV. CPPS sufferers with elevated levels should be screened for cancer and BPH.(7)

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(1) Mehik A, Leskinen MJ, Hellström P Mechanisms of pain in CPPS: influence of prostatic inflammation. World J urol 21:90-94, 2003
(2) Dellabella M, Milanese G, Sigala S, d’Anzeo G, Arrighi N, Bodei S, Muzzonigro G. The role of prostatic stroma in CP/CPPS. Inflamm Res. 2009 Sep 11 Epub ahead of print.
(3) Mehik A, Leskinen MJ, Hellström P Mechanisms of pain in CPPS: influence of prostatic inflammation. World J urol 21:90-94, 2003
(4) True LD, Berger RE, Rothman I, Ross SO, Krieger JN. Prostate histopathology and CP/CPPS: a prospective biopsy study. J Urol 162:2014-2018, 1999.
(5) PHF Schatteman, L Hoekx, J J Wyndaele, W Jeuris, E van Marck. Inflammation in prostate biopsies of men without prostatic malignancy or clinical prostatitis. Eur Urol 37:404-412, 2000
(6) Nickel JC, Roehrborn CG, O'Leary MP, Bostwick DG, Somerville MC, Rittmaster RS. Examination of the Relationship Between Symptoms of Prostatitis and Histological Inflammation: Baseline Data From the REDUCE Chemoprevention Trial. J Urol. Jul 13 2007.
(7) Nadler RB, McNaughton Collins M, Propert KJ, Mikolajczyk SD, Knauss JS, Landis JR, Fowler JE jr, Schaeffer AJ, Alexander RB. PSA test in diagnostic evaluation of CP/CPPS. Urology 67:337-342, 2006.

Friday, September 25, 2009

Post-ejaculatory pain

Regarding sexual activity advice goes both ways. It stands to reason that if you have pain during or after intercourse it may not be so smart to proceed with it. But some men’s symptoms (pain, epidydimitis) get relieved by ejaculation (see Treatment below). (Local application of anti-inflammatory and pain relieving medications may help. But check with your doctor first.)

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CPPS and ejaculation

Premature ejaculation / “failed” / “unexpected” ejaculation

Both anecdotal evidence and some research show that ejaculation is un-coordinated in men with CPPS. Problems vary but common problems is ejaculation before climax ("premature ejaculation, PE), no climax and ejaculation (anejaculation/anorgasmia), painful (often sort of “stumbling”) ejaculation and “weak” ejaculation. An Italian study has shown that about 50% of patients with ejaculatory problems had chronic bacterial prostatitis .(1)

A Turkish study showed that over 75% of patients with CP/CPPS had ejaculatory problems .(2) In both cases no other pathology could be found, but in hyperthyroid patients with premature ejaculation ejaculation normalizes after euthyroidism (thyroid hormones within normal range) is attained(3-4). An interesting finding as there seems to be little research on this in CPPS. Could some CPPS patients have undiagnosed thyroid disorder?

Research on ejaculation is, in my opinion, in some regards plain stupid as any ejaculation within two minutes is regarded as premature/abnormal, regardless of how it is experienced or if foreskin is normal or removed. It is also very focussed on "end" results and not the underlying (reflex) dyssynergia.

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(1) Screponi E, Carosa E, Di Stasi SM, Pepe M, Carruba G, Jannini EA. Prevalence of chronic prostatitis in men with premature ejaculation. Urology. 58(2):198-202, 2001.
(2) Gonen M, Kalkan M, Cenker A, Ozkardes H. Prevalence of premature ejaculation in Turkish men with chronic pelvic pain syndrome. J Androl. 26(5):601-603, 2005.
(3) Krassas GE, Tziomalos K, Papadopoulou F, Pontikides N, Perros P. Erectile dysfunction in patients with hyper- and hypothyroidism: how common and should we treat? J Clin Endocrinol Metab 93(5):1815-9, 2008.
(4) Cihan A, Demir O, Demir T, Aslan G, Comlekci A, Esen A. The relationship between premature ejaculation and hyperthyroidism. J Urol 181(3):1273-1280, 2009.

Physiology of ejaculation

Ejaculation requires exquisite coordination and timing of various muscles and glands. Thus minimal differences in timing cause disruption. Also non-neurological disturbances caused by enlarged prostate (constricting the urether and ejaculatory ducts) and constipation (generalized pressure on the lower abdominopelvic cavity) affect ejaculation.

Ejaculation is divided in two phases: emission and ejaculation proper.

Emission is under control of the sympathetic nervous system, while the ejaculatory phase is under control of a spinal reflex. Emission begins with sperm travelling along the vas deferens (spermatic cord a 30 centimeter long structure that loops over the pelvic bone ! one of these evolutionary trade-offs we carry) and entering the ejaculatory ducts and being mixed with fluids from the seminal vesicles, prostate and bulbourethral glands. The resulting fluid is called semen.

Ejaculation proper consists of approximately 5-15 rhythmic contractions of the bulbospongiosus muscle ejecting the semen through the urethra and out. Total duration of the process is about 15 seconds. (Females differ slightly as they have up to 20-30 contractions and shorter refractory period, i.e. time before next attempt can be made. Women having Skene’s glands may experience orgasm by indirect stimulation of the gland,(1) the so called G-spot. )

N.B. ejaculation is not necessarily concomitant with orgasm or vice versa.

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Wolters JP, Hellstrom WJG. Current Concepts in Ejaculatory Dysfunction. Rev Urol 8(Suppl 4):S18-S25, 2006.
(1) Gravina GL, Brandetti F, Martini P, Carosa E, Di Stasi SM, Morano S, Lenzi A, Jannini EA. Measurement of the thickness of the urethrovaginal space in women with or without vaginal orgasm. J Sex Med. 2008 5(3):610-8.

Sunday, September 6, 2009

Patient reported frequency and severity of urological symptoms

Presenting symptoms (described by patients and recorded by urologists) in 1074 patients with prostatitis.(1)

SymptomN (%)
Frequency689 (64.2)
Obstructive voiding675 (62.8)
Perineal pain or discomfort630 (58.7)
Suprapubic pain or discomfort492 (45.8)
Penile pain or discomfort360 (33.5)
Premature ejaculation305 (28.4)
Malaise229 (21.3)
Urethral discharge220 (20.5)
Inguinal pain or discomfort216 (20.1)
Erectile dysfunction205 (19.1)
Haematospermia169 (15.7)
Voiding difficulties162 (15.1)
Fever159 (14.8)
Purulent urine150 (14.0)
Abnormal seminal fluid 97 (9.0)
Myalgia 64 (6.0)
Abnormal urine (mucus) 61 (5.7)
Haematuria 46 (4.3)


Mean (sd) score
frequencyseverity
Penile pain or discomfort55.2 (386/699)1.3 (1.4)3.1 (2.7)
Perineal pain or discomfort81.6 (666/816)2.2 (1.3)4.5 (2.5)
Suprapubic pain or discomfort74.6 (561/779)2.0 (1.4)4.3 (2.5)
Ejaculatory pain or discomfort63.9 (461/721)1.4 (1.3)3.3 (2.4)
Testicular pain or discomfort43.9 (302/688)0.9 (1.2)2.5 (2.5)
Lumbar/inguinal/thigh pain35.4 (240/678)0.8 (1.3)2.3 (2.8)
or discomfort
Incomplete bladder emptying72.8 (541/743)1.8 (1.4)3.7 (2.7)
Burning during micturition81.7 (652/798)2.0 (1.3)4.2 (2.5)
Urgency72.4 (514/710)1.7 (1.4)3.9 (2.8)
Urinary frequency86.4 (717/830)2.4 (1.4)5.0 (2.7)

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(1) Rizzo M, Marchetti F, Travaglini F, Trinchieri A, Nickel JC. Prevalence, diagnosis and treatment of prostatitis in Italy: a prospective urology outpatient practice study. BJU Int 92(9):955-959, 2003.

Saturday, September 5, 2009

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.

Saturday, August 29, 2009

Erectile dysfunction and the physiology of erection

Impotence or erectile dysfunction is reported in CPPS, but information on prevalence is highly variable, although rates are higher than in controls, especially in young CPPS sufferers. It is most likely caused by underlying testosterone deficiency, diabetes and obesity and/or stress/fear induced reactions. See discussion on testosterone, nocturia and sleep for causes of testosterone deficiency in CPPS.

Erection is a complex "neurovascular" event "modulated by psychological and hormonal factors" leading to increased blood flow into and decreased flow out of the penis (so called tumescence). Murine (rats and mice) studies indicate that selenium, vitamin E and vitamin C insufficiency may be involved.(1)

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(1) Priviero FBM, Leite R, Webb RC, Teixeira CE. Neurphysiological basis of penile erection. Acta Pharmacol Sin 28(6):751-755, 2007 (this is a concise review).

Sexual health in CPPS

There are a lot of sexual problems associated with CPPS, which is one cause why Freudians have had a field day with CPPS (and other urogenital disorders). Careful anamnesis will show that sexual problems evolve slowly over many years in CPPS sufferers. And it is when those interfere too much in normal life that they are brought to the doctor’s attention. Due to this there is an obvious possibility of many a CPPS sufferer consulting a psychiatrist (or "sexologists") rather than a urologist.

Problems are those mentioned below and also: penis / glans pain / discomfort (not associated with urination); penile numbness / insensitivity to "friction" (obviously more noticeable in non-circumcised men); and, discoloration (bluish-whitish-pinkish mottled hue) of glans.

Sufferers have less sexual interest and erectile function(1-2). This is hardly surprising and a well described and known fact as it is both part of the pathology and of sickness behavior (the bodily reactions to pain, illness and infection which cause androgen down-regulation, impaired spermatogenesis, depression etc). The only interesting fact in the study by Aubin et al. (one of many on the subject) is the usage of an adapted form of the BSFQ (brief sexual functioning questionnaire), that, while highly subjective, is useful indicating CPPS sexual symptom severity. About 36% of the CPPS subjects had never had epi- or post-coital pain. 51% occasionally and 13 often or always. The rest of the study was pretty oxymoronic, such as proving that age and disease activity was significant for pain, sexual function and satisfaction… duh! (apologies for this rant).

In a german study of chronic pelvic pain (LUTS) about 30-40% up to 40 years old were affected of loss of libido and erectile dysfunction, and about 50-65% between 40 and 60 years, compared to about 5.5% and 9% respectively in controls. Above 60 years of age the differences vaned. The study also showed that premature ejaculation (defined as before or at the beginning of intercourse or without erection), was noticeably more common in all age groups. 4-10 times more common than in controls.(3)

Marital relations are normal, except in a few cases where it may precipitate a separation (4) (most likely do the mood swings affect an already compromised relationship).

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(1) Aubin S, Berger RE, Heiman JR, Ciol MA. The association between sexual function, pain and psychological adaption of men diagnosed with CPPS type III. J Sex Med 5:657-667, 2008.
(2) Davis SNP,Binik YM, Carrier S. Sexual dysfunction and pelvic pain in men: a male sexual pain disorder?. J Sex Marit Ther 35(3):182-205, 2009.
(3) Beutel ME, Weidner W, Brähler E. Der chronishe Beckenschmerz und seine Komorbidität. Der Urologe [A] 43:261-267, 2004. [Chronic pelvic pain and its comorbidity. In german.]
(4) Mehik A, Hellström P, Sarpola A, Lukkarinen O, Järvelin MR. Fears, sexual disturbances and personality features in men with prostatitis: a population-based cross-sectional study in Finland. BJU Int 88(1):35-38, 2001.

Micturition-concluding thought

Micturition troubles are a strong cause of worsened quality of life (QoL). There is no good explanation for those in CPPS, but the fact that many of the "irritants" affect vasopressin regulation and the pituitary is an indication of cause. Especially nocturia is very troublesome as it deeply affects daily life for persons with family and work. Improving nocturia by dietary changes and maybe additional small doses of vasopressin analogues would probably lead to much improved QoL for the average CPPS sufferer.

Wednesday, June 10, 2009

Pelvic tenderness

A study has shown that men with CPPS have more tenderness in the pelvic-pubic area. Internal and external "tender points" were examined.(1) How the tender points were selected and/or identified was not clear. The tender points bore no correlation to the fibromyalgia tender points.

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(1) Berger RE, Ciol MA, Rothman I, Turner JA. Pelvic tenderness is not limited to the prostate in CPPS… comparison of men with and without CPPS. BMC Urol 7:17-24, 2007.

Tuesday, June 9, 2009

Urinary nitrites

Urinary nitrites are higher in patients with enuresis (1) indicating a connection between nitric oxide (NO) regulation and enuresis ("over-active bladder"). "NO plays an important role in the micturition process and disorders [IC, cystitits, enuresis] of the lower urinary tract."(2) Some IC patients show significant improvement with decreasing bladder NO.(3)
Nitric oxide (NO) has been shown to be significantly higher in the prostatic urethra of NIH-IIIa patients, but not in NIH-IIIb patients.(4)

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(1) Al-Waili NS Increased urinary nitrite excretion in primary enuresis: effects of indomethacin treatment on urinary and serum osmolality and electrolytes, urinary volumes and nitrite excretion. BJU Int 90:294-301, 2002.
(2) Ho MH, Bhatia NN, Khorram O. Physiologic role of nitric oxide and nitric oxide synthase in female lower urinary tract. Curr Opin Obstet Gynecol 16(5):423-429, 2004.
(3) Hosseini A, Ehren I, Wiklund NP. Nitric oxide as an objective marker for evaluation of treatment response in patients with classic interstitial cystitis. J Urol 172(6 Pt 1):2261-2265, 2004.
(4) Hosseini A, Herulf M, Ehren I. Measurement of nitric oxide may differentiate between inflammatory and non-inflammatory prostatitis. Scand J Urol Nephrol 40(2):125-130, 2006.

Monday, June 8, 2009

Bladder lining findings

Many CPPS sufferers react with pain/discomfort on potassium instillations (a potassium ion containing fluid is injected into the bladder) in a manner similar to IC patients, but the so called potassium sensitivity test is not wholly reliable as both false negatives and positives are common. It is believed that the potassium sensitivity is caused by impaired “barrier function” of the bladder urothelium to irritants or cytotoxic substances in the urinary fluid. It is assumed that potassium influx into nerve and muscular cells causes abnormal nerve firing and muscular relaxation.

Sulfated polysaccharides, like heparin, are thought to lower adherence to the bladder and urethral etc mucosal wall, which would also improve urine flow dynamics. If adherence increases bacteria, molecules etc can attach to the surface, as well as flow become more turbulent.

Other research has shown that instillation with resinifera-toxin modulates nerve firing in such a way as to (permanently?) alleviate bladder related symptoms. See additional discussion under treatment.

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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

Sunday, May 31, 2009

Prostate findings

Bacterial prostatitis
Inflammation in bacterial prostatitis is characterized by the "presence of polymorphonuclear leukocytes and macrophages in the glandular ducts, epithelium and/or adjacent stroma" around the acini or ducts. Stromal involvement depends on intraluminal inflammation(1). Other findings are: abnormal glandular ducts, epithelial atrophy, metaplasia and dysplasia, and hyperchromasia ("with polymorphism of the epithelial cell nuclei and cytoplasmic basophilia"). Changes that may be misinterpreted as cancerous. If palpated the prostate is often enlarged and "soft" in bacterial prostatitis.

CP/CPPS
In CP/CPPS "glandular atrophy with stromal fibrosis, accompanied by a mild residual inflammatory reaction" is commonly observed(2). But only 5% of biopsies show significant inflammation(3). Although variation between studies is high up to 100% (4) prevalence has been found. The variation is obviously due to the varying (read: poor!) selection criteria of the studies. There is minimal correlation between histopathology and visible/clinical symptoms, but histological findings increase with age and are more common in infertile men. If palpated the prostate is never abnormal in CPPS.

It is unclear whether some minimal inflammation of the prostate is normal or not, so if this is of any clinical use remains to be seen. The recent REDUCE trial involving 5597 subjects has shown that no "clinically meaningful" difference is present between healthy subjects and CP/CPPS sufferers.(5)

PSA levels are insignificantly elevated in CPPS (NIH III) and slightly to highly elevated in NIH IV. CPPS sufferers with elevated levels should be screened for cancer and BPH.(6)

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(1) Mehik A, Leskinen MJ, Hellström P Mechanisms of pain in CPPS: influence of prostatic inflammation. World J urol 21:90-94, 2003
(2) Mehik A, Leskinen MJ, Hellström P Mechanisms of pain in CPPS: influence of prostatic inflammation. World J urol 21:90-94, 2003
(3) True LD, Berger RE, Rothman I, Ross SO, Krieger JN. Prostate histopathology and CP/CPPS: a prospective biopsy study. J Urol 162:2014-2018, 1999.
(4) PHF Schatteman, L Hoekx, J J Wyndaele, W Jeuris, E van Marck. Inflammation in prostate biopsies of men without prostatic malignancy or clinical prostatitis. Eur Urol 37:404-412, 2000
(5) Nickel JC, Roehrborn CG , O'Leary MP, Bostwick DG, Somerville MC, Rittmaster RS. Examination of the Relationship Between Symptoms of Prostatitis and Histological Inflammation: Baseline Data From the REDUCE Chemoprevention Trial. J Urol. Jul 13 2007.
(6) Nadler RB, McNaughton Collins M, Propert KJ, Mikolajczyk SD, Knauss JS, Landis JR, Fowler JE jr, Schaeffer AJ, Alexander RB. PSA test in diagnostic evaluation of CP/CPPS. Urology 67:337-342, 2006.

Saturday, May 30, 2009

Urodynamic findings

Coordination of voiding, sphincter and pelvic floor activity differs from controls. Average sphincter pressure is increased, while urine flow is decreased. Bladder neck and prostatic urethra may not be completely relaxed. Functional urethral length is increased and resting closure pressure may be higher than normal. Urethral sensitivity was increased, while the profile pattern is dysfunctional and/or obstructed. Cystometry is normal.(1)

It is unclear whether the muscular findings are causing the symptoms or an effect of an underlying pathology.

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(1) Zermann DH, Ishigooka M, Doggweiler R, Schmidt RA. Neurological insights into the etiology of genitourinary pain in men. J Urol 161(3):903-908.

Wednesday, May 27, 2009

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.

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(1) Holstege G. Micturition and the soul. J Comp Neurol 493:15-20, 2005

Sunday, May 17, 2009

Nocturia and neurological health

Two interesting studies by Asplund and Asplund et al. showed that self-reported poor somatic and mental health, pain, sick leave and visual impairement all increased with increasing nocturnal voids, while quality of life decreased.(1,2) This is very interesting in view of the importance of sleep for immune function (see below) and the possibility of neurological causes. Hypercalciuria has been implicated with nocturia in children and with concomitant hypokalemia also with diabetes insipidus, while in adults hypertension has been associated with nocturia. Sugaya et al. (7) have also shown that patients with nocturia have higher levels of serum catecholamines (adrenaline, noradrenaline and dopamine) which indicates that nocturia is stressful per se, or caused by a disorder of or affecting the adrenal gland. Other causes are: heart disease, sleep apnea, bladder and prostate problems, diabetes mellitus, HPA dysfunction (nocturnal polyuria and diabetes insipidus).

Nocturia is the leading cause of sleep disruption in adults. It is not a sickness of old age but afflicts young adults, 35+, too. "Nocturia patients are sleeping on average only 2-3 hours before waking for the first void." Traditionally nocturia has been indicated if two or more voids per night, but nocturia once a night is almost as disruptive as twice a night. Especially if the void occurs during slow wave sleep (during the first 4 hours of sleep).(3) "This results in disruption of the restorative sleep period with physiological consequences such as mood disturbance, cognitive and memory impairment and reduced performance at work. In addition, it is accountable for increased morbidity and mortality, increased risk of falling, cardiovascular disease, depression and lowered immune response." Sleep disruption also causes lowered testosterone and LH levels. Especially if disruption occurs during REM sleep.(8) It is more bothersome for younger people especially as they have work and families to care for and cannot take a nap or two during the day.(4) (Notice that lack of sleep causes daytime tiredness, mood disturbances, memory impairment, increased falling, accidents, more often sick, decreased life expectancy, depression, diabetes, obesity etc.) Nocturia affects QoL as much or even more as prostate cancer (except terminal cancer) and cardio-vascular disease regardless whether it is one or more nightly voiding.(5)

The preferred treatment for nocturia is desmopressin as it ensure the longest uninterrupted sleep period. Time to first void is on average 4-5 hours. Desmopressin increaes mean initial sleep period with about 100 minutes while indiplon and temazepam only with about 45-50 and 65-70 minutes.(6)

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(1) Asplund R, Marnetoft S-U, Selander J, Åkerström B. Nocturia in relation to somatic health, mental health and pain in adult men and women. BJU Int 95:816-819, 2005.
(2) Asplund R. Visual impairment, sleep and nocturia in the elderly. Arch Gerontol Geriatr. 41(1):61-67, 2005.
(3) N Stanley, Sleep, is it a waste of time and is nocturia causing relevant problems?, EUA 2009 Congress
(4) JP Norgaard, Nocturia: a disease or a natural consequence of ageing, EUA 2009 Congress
(5) T Holm-Larsen Why treat nocturia... EUA 2009 Congress
(6) van Kerrebroeck et al Eur Urol 52:221-229, 2007
(7) Sugaya K, Nishijima S, Miyazato M, Ogawa Y. Central nervous control of micturition and urine storage. J Smooth Muscle Res 41(3):117-132, 2005.
(8) In papers by Luboshitzky and Axelsson. Additional detail in post about testosterone.

Micturition frequency in CPPS

Disrupted urinary frequency is an important problem in CPPS. Causes are unknown, but vasopressin dysregulation or desensitization of the kidney vasopressin receptors is likely, as may also be detrusor dyssynergia (meaning the muscles controlling the bladder do not function as they should either due to neurological causes or localized muscular dysfunction). In addition to this muscles in the pelvis floor and urethra may be dysfunctional ("uncoordinated").
See posts on the physiology of micturition and on nocturia for additional detail.

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Sunday, May 10, 2009

Physiology of micturition

In very young children micturition has no circadian rhythm. A circadian rhythm with daily micturition and absence of nocturia (nightly vasopressin peak) will slowly assert itself during childhood and usually be mostly set by three years of age. Sporadical nocturia may though continue to occur for a few years. This situation is the essentially stable until old age. So it may safely be assumed that you should be able to undisturbed sleep for 6-8 hours and not need to immediately rush to micturate as soon as you wake up. (And certainly not to suddenly feel an overwhelming and even painful need to immediately micturate.) Normal average 24 hour diuresis is 1600 +/- 350 ml. Daytime average diuresis is about 1100 +/- 250 ml at age 30 and slightly lower in older people, about 800 +/- 150 ml.(1) (These figures vary somewhat and e.g. Raman et al. calculated 2200 ml as average normal diuresis.(2))

A healthy subject needs about 50 ml of liquid in the bladder, after a complete voiding, for some feeling of fullness. At about approximately 200 ml desire of voiding should start to occur, after which sensations of discomfort increase. At about 400 ml a strong urge to urinate is normally forcing an individual to void. (Stretch receptors in the detrusor signal the CNS, which leads to relaxation of the bladder neck, trigone, and urethra muscles.) During the day you should thus not need to micturate more than 3-5 times. Intervals between voidings should be longer than 2
hours with no feelings of urgency. (It should be noted that the Incontinence Society regards more than 8 voidings per 24 hours as an abnormal frequency a.k.a. an "overactive bladder".(3))

Regulation of micturition is very complex. It is an interplay between the HPA axis, the Pontine micturition center and neurological feedback from the bladder and pelvic floor. The bladder (detrusor muscle) is innervated by hypogastric (sympathetic nervous system) nerve fibres from the lumbar spinal region (control of storage) and pelvic (parasympathetic) nerve fibres from the sacral spinal region (to the ‘detrusor pelvic plexus’; control of voiding). Urethral smooth longitudinal and circular muscle are also innervated by hypogastric nerve fibres. The striated muscle of the urethral sphincter by pudendal nerve (somatic motor) fibres from the sacral spinal region. And the striated muscle of the pelvic floor by sacral nerve (somatic motor) fibres. The somatic fibres are involved in volitional micturition control (i.e. is under your "voluntary" control). Additional detail can be found in references 4-7.

Bladder filling is regulated by water homeostasis, especially the regulation of electrolyte levels (and then especially sodium) and blood volume (to avoid hypovolemia). This is in turn regulated by the release of vasopressin (AVP) and it’s binding to the type-2 receptor in renal principal cells. AVP production is regulated by specific regions of the hypothalamus and release by the pituitary. Regulation of AVP levels is also dependant on various hormones (PGE-2, bradykinin, dopamine, EGF etc). Vasopressin maximum occurs normally between approximately 1900 and 0700 hours. Nocturia may occure due to a shift of this interval.

Do notice that prostaglandin E2 levels are affected by many of the CPPS treatments, which may explaine their beneficial effect on diuresis/water balance (stimulates diuresis in the absence of AVP, otherwise it counteracts it). A full review of the current understanding can be found in Boone and Deen.(8)

A recent murine study (9) showed that partial bladder obstruction induced neurological sequelae (through locus coeruleus hyperactivity). It would have been interesting if the authors also had reported sleep patterns and changes in behaviour, to clarify if the causality was due to bladder distension or sleep disruption. Animal studies have shown that reduced serotonin levels trigger increased urinary frequency and detrusor overactivity. And in Europe duloxetine, a serotonin
norepinephrine reuptake inhibitor (anti-depressant) is approved for treatment of incontinence. A controversial treatment due to its adverse effects.

The "Musculo-Elastic Theory of anorectal function and dysfunction in the female" regarding "suspensory ligaments inactivating anorectal muscle forces" is also interesting as stress incontinence has been cured by surgical reinforcement of damaged ligaments correcting muscular dysfunction. An interesting overview is found in the journal of Pelviperineology.(10)

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(1) Asplund R. Nokturi och nattlig polyuri bland äldre [Nocturia and nocturnal polyuria in the elderly]. Läkartidningen 99(44):4370-4373, 2002. (In swedish).
(2) Raman A et al. Water turnover in 458 American adults 40-79 yr of age. Am J Physiol Renal Physiol 286: F394-F401, 2004
(3) Overactive bladder. ICS factsheet 2, july 2005.
(4) Andersson K-E, Hedlund P. Pharmacologic perspective on the physiology of the lower urinary tract. Urology 60(suppl 5A):13-21, 2002.
(5) Sugaya K, Nishijima S, Miyazato M, Ogawa Y. Central nervous control of micturition and urine storage. J Smooth Muscle Res 41(3):117-132, 2005.
(6) Birder LA, de Groat WC. Mechanisms of Disease: involvement of the urothelium in bladder dysfunction. Nature Clinical Practice Urology 4:46-54, 2007.
(7) Drake MJ. The Integrative Physiology of the Bladder. Ann R Coll Surg Engl. 89(6):580-585, 2007.
(8) Boone M, Deen PMT. Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption. Eur J Physiol 456:1005-1024, 2008.
(9) 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. Proc Natl Acad Sci USA. 105(30):10589-94, 2008.
(10) Pelviperineology Vol 27 N.3 September 2008.