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.
Andra bloggar om immunity, adrenal, cytokines, Th1/Th2, estrogens, SHBG, IL-6, HPA axis, IDO, IL-10, IL-12, hypoactive adrenal medulla, low epinephrine excretors.
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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.
Showing posts with label SHBG. Show all posts
Showing posts with label SHBG. Show all posts
Wednesday, February 24, 2010
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)
Andra bloggar om CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, nokturi, trängningar, sömn, testosteron, androgener.
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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.
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)
Andra bloggar om CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, nokturi, trängningar, sömn, testosteron, androgener.
_______________________
(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.
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.
Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, testosteron, androgener, estrogener
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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.
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.
Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, testosteron, androgener, estrogener
__________________
(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.
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