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.

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.

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)

Andra bloggar om kronisk prostatit, kroniskt bäckenbottensmärtsyndrom, testosteron, prostatacancer
__________________
(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.

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.

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.