High levels of the other major male gonadotropin, DHT (dihydrotestosterone), is strongly associated with abdominal obesity. It does also slowly decline with age from a peak value around 45 pmol/L postpuberty to around 28 in octogenarians. The DHT/FT ratio is fairly constant between 0.15 to 0.18 in healthy adult men.(1)
Andra bloggar om CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, bukfetma, testosteron, dihydrotestosteron androgener.
_________________
(1) Starka L, Pospisilova H, Hill M. Free testosterone and free dihydrotestosterone throughout the life span of men. Journal of Steroid Biochemistry & Molecular Biology 116:118–120, 2009.
Showing posts with label androgens. Show all posts
Showing posts with label androgens. Show all posts
Friday, February 19, 2010
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.
CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, nokturi, trängningar, enteric, gender immune dimorphism, immunity, Th1/Th2, androgens, estrogens, nocturia, seasonality.
______________________
(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.
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.
CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, nokturi, trängningar, enteric, gender immune dimorphism, immunity, Th1/Th2, androgens, estrogens, nocturia, seasonality.
______________________
(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.
CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, nokturi, trängningar, androgens, erection, estrogens, nocturia, testosterone.
CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, nokturi, trängningar, androgens, erection, estrogens, nocturia, testosterone.
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.
_______________________
(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.
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.)
Andra bloggar om CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, nokturi, trängningar, sömn, testosteron, androgener
___________________
(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.
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.)
Andra bloggar om CPPS, prostatit, kroniskt bäckenbottensmärtsyndrom, nokturi, trängningar, sömn, testosteron, androgener
___________________
(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.
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
__________________
(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.
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.)
Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, testosteron, androgener
____________________
(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.
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.)
Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, testosteron, androgener
____________________
(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.
Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, testosteron, androgener
_______________
(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.
"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.
Andra bloggar om CPPS, kroniskt bäckenbottensmärtsyndrom, testosteron, androgener
_______________
(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.
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