Posted 4/15/2014 1:28 PM (GMT -5)
Doug,
It is not easy to find an answer to your question in the medical literature. In the past I tried to answer the question. What follows is a long answer after a search of what is available (that I could find):
The cause of prostate cancer has never been established. Although autopsy studies of younger men who experienced accidental deaths found cancer present on their fourth decade at a rate of 27% and on the fifth decade at 34%, some studies point to low testosterone in older men as a potential cause of prostate cancer. Morgentaler has addressed testosterone/PSA ratio as a potential marker for prostate cancer risk. This in spite of the fact that numerous studies cannot find a significant difference in testosterone levels among men diagnosed with prostate cancer. In simpler words, testosterone doesn’t seen to be the cause of prostate cancer either when high or low in men diagnosed with PCa.
In researching the medical literature I found evidence that there is a significant difference how testosterone is metabolized by benign and cancerous prostatic tissue. Studies in cell cultures and in patients demonstrate a marked difference:
J Steroid Biochem Mol Biol. 1994 Aug;50(3-4):151-9.
Smith CM, Ballard SA, Wyllie MG, Masters JR.
Comparison of testosterone metabolism in benign prostatic hyperplasia and human prostate cancer cell lines in vitro.
University College London, Institute of Urology, U.K.
Pathways of testosterone metabolism in tissue slices and cell suspensions of human benign hyperplastic prostate (BPH) tissue and human prostate cancer cell lines (DU145, HPC-36M, PC-3/MA2 and LNCaP) were investigated. Thin layer chromatography analysis was used to identify the following tritiated metabolites: testosterone, 5 alpha-dihydrostestosterone (DHT), 5 alpha-androstane-3 alpha/3
beta-17 beta-diol (androstanediols), 4-androstene-3,17-dione (androstenedione)and 5 alpha-androstanedione. The predominant pathway for testosterone metabolism in BPH was via 5 alpha-reductase producing 5 alpha-dihydrotestosterone (71% and
75% total metabolites in slices and suspensions incubated for 24 h,
respectively). The cancer cell lines DU145 and HPC-36M resembled BPH by metabolizing testosterone predominantly to DHT (68% and 82% total metabolites, respectively), although the rate of metabolism was much lower in the cell lines (0.099 and 0.05 pmol testosterone/mg protein/h in DU145 and HPC-36M) compared to
the BPH cell suspensions (6.4 pmol testosterone/mg protein/h). In contrast, PC-3/MA2 contained high 17 beta-HSD activity forming large amounts of 4-androstene-3,17-dione (84% total metabolites), converting testosterone at a rate faster (12.8 pmol testosterone/mg protein/h) than the BPH cell suspensions.
LNCaP rapidly converted testosterone exclusively to a glucuronide conjugate (7.4 pmol testosterone/mg protein/h), although after incubation with [3H]-4-androstene-3,17-dione, 5 alpha-reductase activity was demonstrated. LNCaP was the only cell line whose growth and colony-forming ability was stimulated by testosterone and DHT. BPH and all the cell lines tested had 5 alpha-reductase
activity, but only the prostate tissue and the cell lines DU145 and HPC-36M converted testosterone predominantly to DHT.
PMID: 7519439 [PubMed - indexed for MEDLINE]
Meikle AW, Smith JA, Stringham JD.
Production, clearance, and metabolism of testosterone in men with prostatic cancer. Prostate. 1987;10(1):25-31.
It was previously unknown whether the production and metabolism of testosterone was altered in men with prostatic cancer. We recently observed a familial influence on the plasma concentration of sex steroids in men with the cancer. We have now determined, by isotope dilution techniques, the blood testosterone production and clearance rates and testosterone metabolism to potent androgen
metabolites in men with prostatic cancer, their brothers, and unrelated controls. Nineteen men had a diagnosis of prostatic cancer before age 63 (probands), 23 were brothers of these index cases, and nine controls matched for age were selected randomly from the general population. None had received endocrine therapy. The plasma content of testosterone, dihydrotestosterone, sex hormone
binding globulin, apparent free testosterone concentration, follicle-stimulating hormone, and luteinizing hormone were not significantly different between the groups. The metabolic clearance rate of testosterone was significantly (P = .04) higher in probands (458 liters/day/body surface area, median) than in controls
(306 liters/day/body surface area). The conversion ratios of both testosterone (1.8%) and dihydrotestosterone (16.9%) to 3 alpha-androstanediol were significantly greater (P = .04 and P = .004, respectively) in probands than in controls (0.95%, 7.8%). These results indicate that men with prostatic cancer have elevated clearance rates of testosterone and an increased conversion ratio
of testosterone to its potent 5 alpha-reduced metabolites.
PMID: 3822917 [PubMed - indexed for MEDLINE]
Meikle AW, Smith JA, Stringham JD.
Estradiol and testosterone metabolism and production in men with prostatic cancer. J Steroid Biochem. 1989 Jul;33(1):19-24.
We recently observed a familial influence on the plasma concentration of sex-steroids and the metabolic clearance in men with prostatic cancer. We have now determined, by isotope dilution techniques, the blood estradiol and testosterone production and clearance rates in men with prostatic cancer and in unrelated controls. Thirty-eight men had a diagnosis of prostatic cancer before
the age of 63, and 22 controls matched for age were randomly selected from the general population. None of the patients or controls had received endocrine therapy. The plasma content of testosterone, dihydrotestosterone, estrone, estradiol, 3 alpha-androstanediol glucuronide, dehydroepiandrosterone sulfate,
sex-hormone binding globulin, apparent free testosterone concentration, follicle stimulating hormone and luteinizing hormone were not significantly different between the groups. The metabolic clearance and production rates of testosterone
were significantly (P = 0.008 and P = 0.013, respectively) higher in patients [447 +/- 26 L/day/body surface area(m2) and 2.21 +/- 0.17 mg/day/m2, n = 38] than in controls [346 +/- 20 L/day/m2 and 1.70 +/- 0.11 mg/day/m2, n = 22]. The PR and
MCR of estradiol were not significantly different between patients with prostatic cancer (n = 19) and controls (n = 12). These results indicate that men with prostatic cancer have elevated clearance and production rates of testosterone without an alteration of estradiol production or clearance.
PMID: 2761263 [PubMed - indexed for MEDLINE]
I also found studies that showed that once cancerous prostate glands were surgically removed from patients, patient’s testosterone levels were significantly increased:
1. Does Presence of Prostate Cancer Affect Serum Testosterone Levels in Clinically Localized Prostate Cancer Patients?
.
The relationships between serum level of testosterone (T) and prostate cancer (PCa) are complex. The present study evaluated whether presence of PCa alters serum T levels. Subjects were 125 patients with clinically localized PCa treated using radical prostatectomy (RP), for whom pretreatment T levels were recorded. We investigated clinical and pathological factors such as pretreatment serum T level, age, pretreatment prostate-specific antigen, Gleason score and pathological stage. Serum T and human luteinizing hormone (LH) levels before and after RP were then compared in 118 of the 125 patients. Mean pretreatment T level was significantly higher in patients with organ-confined PCa (pT2; 4.03+/- 1.50 ng ml(-1)) than in patients with nonorgan-confined cancer (pT3; 3.42+/-1.06 ng ml(-1); P=0.0438). No association existed between pretreatment serum T level and pathological Gleason score. After RP, serum T level (5.60+/-1.90 ng ml(-1) was significantly elevated compared to preoperative level (3.89+/-1.43 ng ml(-1); P<0.0001). In parallel, significant increases were seen in postoperative serum LH level (6.86+/-3.64 ng ml(-1)) compared to preoperative level (5.11+/-2.47 ng ml(-1); P=0.0001). In contrast, differences in serum T levels according to pathological stage disappeared postoperatively (P=0.5513). Significant increases in serum T and LH levels were seen after RP, compared to preoperative levels in parallel. This study suggests that serum T levels are altered by the presence of PCa, supporting the possibility that PCa may inhibit serum T levels with negative feedback in the hypothalamic-pituitary axis.
Imamoto T, Suzuki H, Yano M, Kawamura K, Kamiya N, Araki K, Komiya A, Naya Y, Shiraishi T, Ichikawa T.
PMID:18521100
INFLUENCE OF RADICAL PROSTATECTOMY ON SERUM HORMONE LEVELS
LESLIE R. MILLERa, ALAN W. PARTINa, DANIEL W. CHANa, DEBRA J. BRUZEKa, ADRIAN S. DOBSa, JONATHAN I. EPSTEINa and PATRICK C. WALSHa
J Urol. 1998 Aug;160(2):449-53.
Abstract
Purpose
The influence of radical prostatectomy on the hypothalamic pituitary axis has not been well studied. It is also unclear how alterations in serum androgen levels that result from surgical removal of the prostate might influence the recovery of libido and sexual function following radical prostatectomy. We determined the influence of radical prostatectomy on the hypothalamic pituitary testicular axis of 63 men with clinically localized prostate cancer treated only with radical prostatectomy.
Materials and Methods
A total of 63 healthy men 43 to 67 years old were enrolled in this prospective study. Phlebotomy was performed immediately before and 1 year following radical retropubic prostatectomy. Sera were stored frozen and analyzed as a group at the end of the study. We measured serum testosterone, percent free testosterone, dihydrotestosterone (DHT), estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone binding globulin and prolactin.
Results
Following radical prostatectomy there was a statistically significant increase in serum testosterone, free testosterone, estradiol, LH and FSH (p <0.0001), and statistically significant decrease in serum DHT (p <0.0001). No difference was noted in serum sex hormone binding globulin or prolactin levels. There was no statistically significant correlation between any serum hormone and sample storage time, patient age or prostate volume that could limit potential bias in study design. Serum hormone changes did not correlate with pathological stage or histological grade for this group of patients.
Conclusions
Radical prostatectomy influences the hypothalamic pituitary axis by increasing serum testosterone, percent free testosterone, estradiol, LH and FSH while decreasing serum DHT levels. These findings suggest that the sexual dysfunction associated with radical prostatectomy cannot be explained by androgen deficiency alone. These data further suggest that the normal prostate and/or prostate neoplasm could secrete a substance or substances that give negative feedback control to pituitary gonadotropin secretion. Further investigation is warranted to identify this substance or substances.
3. Impact of radical prostatectomy and TURP on the hypothalamic-pituitary-gonadalhormone axis. Madersbacher S, Schatzl G, Bieglmayer C, Reiter WJ, Gassner C, Berger P, Zidek T, Marberger M. Department of Urology, University of Vienna, Vienna, Austria.
OBJECTIVES: To assess the impact of prostate cancer (PCa) and benign prostatic hyperplasia (BPH) on the hypothalamic-pituitary hormone axis, we determined the endocrine changes after radical prostatectomy (RP) and transurethral resection of the prostate (TURP) for BPH and in a group of men with BPH followed up conservatively. METHODS: Patients with PCa before RP (n = 49), those who underwent TURP for BPH (n = 51), and men with lower urinary tract symptoms for whom a wait-and-see strategy was chosen (n = 46) were included. Serum levels of total testosterone, luteinizing hormone, and follicle-stimulating hormone were determined at baseline and 6 and 12 months later in all patients. RESULTS: No significant endocrine changes were observed in the wait-and-see and TURP groups 6 and 12 months after baseline. In contrast, luteinizing hormone increased from 5.2 to 8.9 mIU/mL (P = 0.0004) and follicle-stimulating hormone from 5.7 to 9.3 mIU/mL (P = 0.0003) 12 months after RP. The rise of total testosterone from 3.9 to 4.4 ng/mL failed to reach statistical significance (P = 0.18). Patients with Gleason score 2 to 6 PCa had higher testosterone values (4.2 ng/mL) at baseline than did those with Gleason score 7 to 10 PCa (2.2 ng/mL, P < 0.05). Although 12 months after RP no changes in testosterone were observed in the low Gleason score group, the testosterone levels more than doubled in those with high-grade tumors. The increases in luteinizing hormone and follicle-stimulating hormone at 12 months, however, were comparable in both groups. CONCLUSIONS: Our findings suggest a significant impact of PCa on the hypothalamic-pituitary axis that is more profound in high-grade cancer. Such an effect was not demonstrable for the transition zone in BPH.
PMID: 12429318 [PubMed - indexed for MEDLINE]
Given all these studies and ones below I have formulated a hypothesis. The cause of prostate cancer remains unknown, but if prostate cancer develops and with progression there is a trend for the cancer to become more and more aggressive (while occult and undiagnosed) and along with this there is a trend to lower levels of testosterone. The tumor load in mutating and growing increases the metabolic rate of testosterone resulting in more aggressive stages that create and consume more testosterone. Several studies have implied that low testosterone is a marker for advanced disease in newly diagnosed patients. It might as well be, but I therefore question the fact that low testosterone in such patients is rather a consequence of the disease rather than a promoter as reported by Morgentaler and others. In support of this a search revealed:
Serum testosterone as a prognostic factor in patients with advanced prostatic carcinoma. Iversen P, Rasmussen F, Christensen IJ. Department of Urology, Rigshospitalet, University of Copenhagen, Denmark.
In 245 patients with previously untreated advanced carcinoma of the prostate, serum concentrations of testosterone have been measured before androgen deprivation therapy, and patients were divided in quartiles according to their serum concentration. Pretreatment level
of serum testosterone was confirmed as having significant prognostic value on progression-free, overall, and cancer-specific survival, and the hazard ratios of lower quartiles compared to the upper quartile for these endpoints were 2.3, 2.1, and 2.0, respectively.However, correlations with symptomatology and other pretreatment parameters suggest that low serum testosterone merely is a consequence of the advanced malignancy rather than a causative factor in the pathogenesis of prostatic cancer. PMID: 7939452 [PubMed - indexed for MEDLINE]
Prostate. 1987;11(2):171-82. Serum hormone levels among patients with prostatic carcinoma or benign prostatic hyperplasia and clinic controls. Hulka BS, Hammond JE, DiFerdinando G, Mickey DD, Fried FA, Checkoway H, Stumpf WE, Beckman WC Jr, Clark TD. Department of Epidemiology, School of Public Health, University of NorthCarolina at Chapel Hill 27514.
This study sought to identify differences in serum hormone levels betweenprostatic cancer (CaP) patients, benign prostatic hyperplasia (BPH) patients, and clinic controls (CC). Serum testosterone, estradiol, and prolactin values were obtained from 35 CaP, 42 BPH, and 161 CC patients attending a single medical center between January 1984 and April 1985. Relative risk estimates adjusted for age and race were calculated to compare hormone values between each case group and the CC. The distributions of hormone values and the testosterone to estradiol (T/E) ratios were grouped into thirds with the lowest third forming the reference category. The relative risk estimates for BPH in the middle and high thirds of testosterone were greater than unity (1.26 and 2.10, respectively), whereas the relative risk estimates in the middle and high thirds of estradiol were less than unity (0.63 and 0.35, respectively). For the middle and high thirds of the T/E ratio, the relative risk estimates for BPH showed statistically significant three- to fourfold increases. Modest depression of serum testosterone and estradiol was noted for CaP patients compared to CC, although the differences were not statistically significant. This depression was interpreted to be a likely result of the malignant process rather than a cause of it, whereas the development of clinically evident BPH was felt to be a biologically plausible response to an elevated T/E ratio. PMID: 2444956 [PubMed - indexed for MEDLINE]
RalphV