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Prostate ...
- Thread starter Michael Scally MD
- Start date
A team of researchers has identified a key mechanism behind aggressive prostate cancer. The study shows that two lncRNAs (PRNCR1 and PCGEM1) activate androgen receptors, circumventing androgen-deprivation therapy. In their active state, these receptors turn on genes that spur growth and metastasis, making these cancers highly treatment-resistant. The study illustrates how prostate cancer can thrive, even when deprived of hormones, and provides tempting targets for new therapies.
Yang L, et al. LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs. Nature. 2013. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs : Nature : Nature Publishing Group
Although recent studies have indicated roles of long non-coding RNAs (lncRNAs) in physiological aspects of cell-type determination and tissue homeostasis1, their potential involvement in regulated gene transcription programs remains rather poorly understood. The androgen receptor regulates a large repertoire of genes central to the identity and behaviour of prostate cancer cells2, and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy3. Here we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 (also known as PCAT8) and PCGEM1, bind successively to the androgen receptor and strongly enhance both ligand-dependent and ligand-independent androgen-receptor-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the carboxy-terminally acetylated androgen receptor on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the androgen receptor amino terminus that is methylated by DOT1L. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited pygopus 2 PHD domain enhances selective looping of androgen-receptor-bound enhancers to target gene promoters in these cells. In ‘resistant’ prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full-length androgen receptor, causing ligand-independent activation of the androgen receptor transcriptional program and cell proliferation. Conditionally expressed short hairpin RNA targeting these lncRNAs in castration-resistant prostate cancer cell lines strongly suppressed tumour xenograft growth in vivo. Together, these results indicate that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumours.
Gene regulation: Long RNAs wire up cancer growth
Gene regulation: Long RNAs wire up cancer growth : Nature : Nature Publishing Group
Yang L, et al. LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs. Nature. 2013. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs : Nature : Nature Publishing Group
Although recent studies have indicated roles of long non-coding RNAs (lncRNAs) in physiological aspects of cell-type determination and tissue homeostasis1, their potential involvement in regulated gene transcription programs remains rather poorly understood. The androgen receptor regulates a large repertoire of genes central to the identity and behaviour of prostate cancer cells2, and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy3. Here we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 (also known as PCAT8) and PCGEM1, bind successively to the androgen receptor and strongly enhance both ligand-dependent and ligand-independent androgen-receptor-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the carboxy-terminally acetylated androgen receptor on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the androgen receptor amino terminus that is methylated by DOT1L. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited pygopus 2 PHD domain enhances selective looping of androgen-receptor-bound enhancers to target gene promoters in these cells. In ‘resistant’ prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full-length androgen receptor, causing ligand-independent activation of the androgen receptor transcriptional program and cell proliferation. Conditionally expressed short hairpin RNA targeting these lncRNAs in castration-resistant prostate cancer cell lines strongly suppressed tumour xenograft growth in vivo. Together, these results indicate that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumours.
Gene regulation: Long RNAs wire up cancer growth
Gene regulation: Long RNAs wire up cancer growth : Nature : Nature Publishing Group
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What can we now conclude about the use of finasteride for prevention? The safest conclusion is that it has no short- or long-term effect on all-cause mortality, so we cannot recommend its use to prolong life. For men who choose regular prostate-cancer screening, the use of finasteride meaningfully reduces the risk of prostate cancer and thus the morbidity associated with treatment of the disease. Whether the use of the drug has either a positive or a negative effect on prostate-cancer–specific mortality remains unknown, but either way the effect is probably very small and does not result in any difference in life expectancy.
Thompson IM, Goodman PJ, Tangen CM, et al. Long-Term Survival of Participants in the Prostate Cancer Prevention Trial. New England Journal of Medicine 2013;369(7):603-10. MMS: Error
BACKGROUND - In the Prostate Cancer Prevention Trial (PCPT), finasteride significantly reduced the risk of prostate cancer but was associated with an increased risk of high-grade disease. With up to 18 years of follow-up, we analyzed rates of survival among all study participants and among those with prostate cancer.
METHODS - We collected data on the incidence of prostate cancer among PCPT participants for an additional year after our first report was published in 2003 and searched the Social Security Death Index to assess survival status through October 31, 2011.
RESULTS - Among 18,880 eligible men who underwent randomization, prostate cancer was diagnosed in 989 of 9423 (10.5%) in the finasteride group and 1412 of 9457 (14.9%) in the placebo group (relative risk in the finasteride group, 0.70; 95% confidence interval [CI], 0.65 to 0.76; P<0.001). Of the men who were evaluated, 333 (3.5%) in the finasteride group and 286 (3.0%) in the placebo group had high-grade cancer (Gleason score, 7 to 10) (relative risk, 1.17; 95% CI, 1.00 to 1.37; P=0.05). Of the men who died, 2538 were in the finasteride group and 2496 were in the placebo group, for 15-year survival rates of 78.0% and 78.2%, respectively. The unadjusted hazard ratio for death in the finasteride group was 1.02 (95% CI, 0.97 to 1.08; P=0.46). Ten-year survival rates were 83.0% in the finasteride group and 80.9% in the placebo group for men with low-grade prostate cancer and 73.0% and 73.6%, respectively, for those with high-grade prostate cancer.
CONCLUSIONS - Finasteride reduced the risk of prostate cancer by about one third. High-grade prostate cancer was more common in the finasteride group than in the placebo group, but after 18 years of follow-up, there was no significant between-group difference in the rates of overall survival or survival after the diagnosis of prostate cancer. (Funded by the National Cancer Institute.)
Thompson IM, Goodman PJ, Tangen CM, et al. Long-Term Survival of Participants in the Prostate Cancer Prevention Trial. New England Journal of Medicine 2013;369(7):603-10. MMS: Error
BACKGROUND - In the Prostate Cancer Prevention Trial (PCPT), finasteride significantly reduced the risk of prostate cancer but was associated with an increased risk of high-grade disease. With up to 18 years of follow-up, we analyzed rates of survival among all study participants and among those with prostate cancer.
METHODS - We collected data on the incidence of prostate cancer among PCPT participants for an additional year after our first report was published in 2003 and searched the Social Security Death Index to assess survival status through October 31, 2011.
RESULTS - Among 18,880 eligible men who underwent randomization, prostate cancer was diagnosed in 989 of 9423 (10.5%) in the finasteride group and 1412 of 9457 (14.9%) in the placebo group (relative risk in the finasteride group, 0.70; 95% confidence interval [CI], 0.65 to 0.76; P<0.001). Of the men who were evaluated, 333 (3.5%) in the finasteride group and 286 (3.0%) in the placebo group had high-grade cancer (Gleason score, 7 to 10) (relative risk, 1.17; 95% CI, 1.00 to 1.37; P=0.05). Of the men who died, 2538 were in the finasteride group and 2496 were in the placebo group, for 15-year survival rates of 78.0% and 78.2%, respectively. The unadjusted hazard ratio for death in the finasteride group was 1.02 (95% CI, 0.97 to 1.08; P=0.46). Ten-year survival rates were 83.0% in the finasteride group and 80.9% in the placebo group for men with low-grade prostate cancer and 73.0% and 73.6%, respectively, for those with high-grade prostate cancer.
CONCLUSIONS - Finasteride reduced the risk of prostate cancer by about one third. High-grade prostate cancer was more common in the finasteride group than in the placebo group, but after 18 years of follow-up, there was no significant between-group difference in the rates of overall survival or survival after the diagnosis of prostate cancer. (Funded by the National Cancer Institute.)
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No he wont do anything for my test levels because i had prostrate cancer.when they stopped my ADT shots and i finished my radiation treatments i started Nolvadex on my own because i got gyno from the ADT. My PSA dropped from 11.4 to 0.1 after the treatments were done.I was on ADT for 6 months while being treated for the cancer,my last ADT shot was in DEC 2012 and my test level still is at castration level.This is after the Nolvadex and then 3 weeks of HCG shots and Adex to surpress estrogen while i was using the HCG.Right now i am taking 20 mg Nolvadex and 25 mg of Clomid daily on my own to try to get my system restarted,i will be tested in 4 weeks for test level and TSH and T4 levels.
The reason for the ADT was to shrink my prostrate for radiation seed implants and 25 external radiation treatments 2 months after the seed implants,I started the ADT 2 months before the seed implants to shrink the prostrate,and it continued untill i finished the radiation treatments.I was on ADT for about 6 months.ADT is also used as a sole treatment for prostrate cancer without radiation treatments,some men cant get the seed implants so they get 40 external radiation treatments without implants.Some men have other issues and cant be treated like i was which was the best treatments with the best outcome of 95% sucess rate. I think IADT is for men that cant have implants or have problems with radiation treatments,it is suppose to slow or stop the growth of the cancer and prolong their life.My PSA was 0.1 after treatments,i am 67 and not going to live without at least a normal level of testerone.i will have PSA test done every 6 monthsas long as it stays low i should not have any problems.
Back On track for the rumor I heard about Dutasteride (Avodart) soon to be earning a Black Box Warning due to the increased risk for MORE INCIDENCE of High Grade Prostate cancers once finally diagnosed. So a recent post got me looking again... (and I am gathering that this issue is now basically inclusive of Finasteride as well..)
So I have attached the latest Prescribing info as of late 2012... I have some notes here...
FIRST- here is a publication from the FDA. You can actually denote the title reads, "5-alpha reductase inhibitors (5-ARIs): Label Change - Increased Risk of Prostate Cancer
Drugs in the 5-ARI class include finasteride and dutasteride. These drugs are marketed under the brand-names Proscar, Propecia, Avodart, and Jalyn
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258529.htm
If you read the Dutasteride Prescribing info, you can note -
5 WARNINGS AND PRECAUTIONS
(5.1) Effects on Prostate-Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection In clinical trials, AVODART reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. This decrease was predictable over the entire range of PSA values in subjects with symptomatic BPH, although it may vary in individuals. VODART may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men taking AVODART, a new PSA baseline should be established at least 3 months after
starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on AVODART may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5 lphareductase inhibitor. Noncompliance with AVODART may also affect PSA test results. To interpret an isolated PSA value in a man treated with AVODART for 3 months or more, the PSA value should be doubled for comparison with normal values in untreated men. The free-to-total PSA ratio (percent free PSA) remains constant, even under the influence
of AVODART. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving AVODART, no adjustment to its value appears necessary. Coadministration of dutasteride and tamsulosin resulted in similar changes to serum PSA
as dutasteride monotherapy.
TRANSLATION - The overall sedating effect of the physical condition of the prostate will artificially REDUCE production of PSA to the point that a cancer may go on to prosper which would otherwise be diagnosed earlier. IN FACT, I speculate that NOT ONLY does the PSA decrease from use, but it might even be more difficult to diagnose a cancer with a DRE as resulting LOCAL inflammation may be kept down EVEN in the presence of an active physical cancer....
5.2 Increased Risk of High-Grade Prostate Cancer
In men aged 50 to 75 years with a prior negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/mL and 10.0 ng/mL taking AVODART in the 4-year Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, there was an increased incidence of Gleason score 8-10 prostate cancer compared with men taking placebo (AVODART 1.0% versus placebo 0.5%) [see Indications and Usage (1.3), Adverse Reactions (6.1)]. In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR), similar results for Gleason score 8-10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%). 5 alpha-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5 alpha-reductase inhibitors to reduce prostate volume or trial related
factors impacted the results of these trials has not been established.
TRANSLATION - Like I said....
5.6 Effect on Semen Characteristics
The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal volunteers aged 18 to 52 (n = 27 dutasteride, n = 23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reductions from
baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all semen parameters at all time-points remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), 2 subjects in the dutasteride group had decreases in sperm count of greater than 90%
from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of dutasteride’s effect on semen characteristics for an individual patient’s fertility is not known.
TRANSLATION - Hmmm - Not good... And all fer some flow. I hope not to prevent hair loss as vanity..
Long-Term Treatment (Up to 4 Years):
High-Grade Prostate Cancer: The REDUCE trial was a randomized, double-blind, placebo-controlled trial that enrolled 8,231 men aged 50 to 75 years with a serum PSA of 2.5 ng/mL to 10 ng/mL and a negative prostate biopsy within the previous 6 months. Subjects were randomized to receive placebo (N = 4,126) or 0.5-mg daily doses of AVODART(N = 4,105) for up to 4 years. The mean age was 63 years and 91% were Caucasian. Subjects underwent protocol-mandated scheduled prostate biopsies at 2 and 4 years of treatment or had “for-cause biopsies” at non-scheduled times if clinically indicated. There was a higher incidenceof Gleason score 8-10 prostate cancer in men receiving AVODART (1.0%) compared with men on placebo (0.5%) [see Indications and Usage (1.3), Warnings and Precautions (5.2)]. In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg,PROSCAR), similar results for Gleason score 8-10 prostate cancer were observed (finasteride1.8% versus placebo 1.1%). No clinical benefit has been demonstrated in patients with prostate cancer treated with AVODART.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of AVODART. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to acombination of their seriousness, frequency of reporting, or potential causal connection to
AVODART.
Immune System Disorders: Hypersensitivity reactions, including rash, pruritus, urticaria, localized edema, serious skin reactions, and angioedema.
Neoplasms: Male breast cancer.
Psychiatric Disorders: Depressed mood.
Reproductive System and Breast Disorders: Testicular pain and testicular swelling.
TRANSLATION: This SHIT IS HAPPENING. But we are not really interested in running too many studies to see how often. But our corporate legal has determined that it is advisable to mention that "we heard it"... LOL
7.3 Calcium Channel Antagonists
Coadministration of verapamil or diltiazem decreases dutasteride clearance and leads to increased exposure to dutasteride. The change in dutasteride exposure is not considered to be clinically significant. No dose adjustment is recommended [see Clinical Pharmacology (12.3)].
TRANSLATION: This is related (somewhat) to animal body electrical pathways (which we really don't even hint to in this statement) and NOTS TO BE FUKED WITH. We don't even BEGIN to broach the implications of this statement...
12.3 Pharmacokinetics
Distribution: Pharmacokinetic data following single and repeat oral doses show that dutasteride has a large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha-1 acid glycoprotein (96.6%). In a trial of healthy subjects (n = 26) receiving dutasteride 0.5 mg/day for 12 months, semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) at 12 months and, similar to serum, achieved steady-state concentrations at 6 months. On average, at 12 months 11.5% of serum dutasteride concentrations partitioned into semen.
TRANSLATION - Loooook - Albumin has a purpose after all. In fact, they may even be hinting that this drug could POSSIBLY involve itself with LH & FSH... Not only there appears to be a relationship to semen involvement.
13.2 Animal Toxicology and/or Pharmacology
Central Nervous System Toxicology Studies: In rats and dogs, repeated oral administration of dutasteride resulted in some animals showing signs of non-specific, reversible, centrally-mediated toxicity without associated histopathological changes at exposures 425- and 315-fold the expected clinical exposure (of parent drug), respectively.
Translation - Again on the electrical. And while the ACTION may be stopped (slickly stated as "reversible"), the DAMAGE is untold and UNCLEAR - at least to us...
Effect on Maximum Urine Flow Rate:
A mean peak urine flow rate (Qmax) of ?15 mL/sec was required for trial entry. Qmax was approximately 10 mL/sec at baseline across the 3 pivotal trials. Differences between the 2 groups were statistically significant from baseline at Month 3 in all 3 trials and were maintained through Month 12. At Month 12, the mean increase in Qmax across the 3 trials pooled was 1.6 mL/sec for AVODART and 0.7 mL/sec for placebo; the mean difference (dutasteride minus placebo) was 0.8 mL/sec (range: 0.7 to 1.0 mL/sec in each of the 3 trials, P<0.001). At Month 24, the mean increase in Qmax was 1.8 mL/sec for dutasteride and 0.7 mL/sec for placebo, with a mean difference of 1.1 mL/sec (range: 1.0 to 1.2 mL/sec in each of the 3 trials, P<0.001). See Figure 5. The increase in maximum urine flow rate seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open label extension trials.
TRANSLATION - All this just to piss 15-25% faster... Did ya really have that much more to do?? LOL
17.3 Exposure of Women—Risk to Male Fetus
Physicians should inform patients that AVODART Capsules should not be handled by a woman who is pregnant or who could become pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a pregnant woman or woman of childbearing potential comes in contact with leaking AVODART Capsules, the contact area should be washed immediately with soap and water [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].
Translation - Look Bitchez. This shit is so potent, you run the risk of fukin up you unborn son for almost just looking at a single pill. So if you husband is a spoiled baby shitass. Don't even think about handling this one to put on his plate. The funny part is how they make reference to DAMAGE to unborn MALE fetuses. WHEREAS, THEY SEEM TO OMIT THAT FEMALE FETUSES REQUIRE ANDROGENS IN THE DEVELOPMENTAL STAGES TOO. Again though, screw the cattle...
But no apparent "Black Box Warning" as of yet. So time goes on..
Yes, I felt like playing a devil's advocate tonight. Still so much is left unsaid to even analyze or be critical of...
FURTHER NOTES:
More on FDA Warning...:
Safety Announcement
[6-9-2011] The U.S. Food and Drug Administration (FDA) is informing healthcare professionals that the Warnings and Precautions section of the labels for the 5-alpha reductase inhibitor (5-ARI) class of drugs has been revised to include new safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer). This risk appears to be low, but healthcare professionals should be aware of this safety information, and weigh the known benefits against the potential risks when deciding to start or continue treatment with 5-ARIs in men.
The new safety information is based on FDA’s review of two large, randomized controlled trials––the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial––which evaluated daily use of finasteride 5 mg versus placebo for 7 years and daily use of dutasteride 0.5 mg versus placebo for 4 years, respectively, for the reduction in the risk of prostate cancer in men at least 50 years of age. The trials demonstrated an overall reduction in prostate cancer diagnoses with finasteride 5 mg and dutasteride treatment (see Data Summary below). This overall reduction was due to a decreased incidence of lower risk forms of prostate cancer. However, both trials showed an increased incidence of high-grade prostate cancer with finasteride and dutasteride treatment.
So Glaxo APPEARS reserved in NOT BOASTING this diminished PC count for those under 50 on the drug. But a the same time, what are the statistics of guys with BPH getting prostate cancer. I seem to see the opposite in real world reviews. As, men with BPH, and especially long term would seem to have lower rates of PC ANYWAY. I wonder where that study/those stats are. Seems to me you either have BPH by the age of 60 and dont get PC, or MAY have BPH or NOT, and then get BPH..
So does BPH indicate a higher androgen activity in the prostate and thus indicate hormonal receptors in that area are more occupied with androgen occupation, as opposed to estrogen interaction/population. Are estrogens the root of PC..?!? Is there any reason they state "no benefit or protection from PC?" Really? Take the stats of men with BPH that get diagnose with PC. And then take the stats of men with no or minimal BPH - and GUESS which group will statistically have a higher PC rate in the end. My money is on the ones with no swollen pisser...:drooling:
Am I missing something
So I have attached the latest Prescribing info as of late 2012... I have some notes here...
FIRST- here is a publication from the FDA. You can actually denote the title reads, "5-alpha reductase inhibitors (5-ARIs): Label Change - Increased Risk of Prostate Cancer
Drugs in the 5-ARI class include finasteride and dutasteride. These drugs are marketed under the brand-names Proscar, Propecia, Avodart, and Jalyn
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258529.htm
If you read the Dutasteride Prescribing info, you can note -
5 WARNINGS AND PRECAUTIONS
(5.1) Effects on Prostate-Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection In clinical trials, AVODART reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. This decrease was predictable over the entire range of PSA values in subjects with symptomatic BPH, although it may vary in individuals. VODART may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men taking AVODART, a new PSA baseline should be established at least 3 months after
starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on AVODART may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5 lphareductase inhibitor. Noncompliance with AVODART may also affect PSA test results. To interpret an isolated PSA value in a man treated with AVODART for 3 months or more, the PSA value should be doubled for comparison with normal values in untreated men. The free-to-total PSA ratio (percent free PSA) remains constant, even under the influence
of AVODART. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving AVODART, no adjustment to its value appears necessary. Coadministration of dutasteride and tamsulosin resulted in similar changes to serum PSA
as dutasteride monotherapy.
TRANSLATION - The overall sedating effect of the physical condition of the prostate will artificially REDUCE production of PSA to the point that a cancer may go on to prosper which would otherwise be diagnosed earlier. IN FACT, I speculate that NOT ONLY does the PSA decrease from use, but it might even be more difficult to diagnose a cancer with a DRE as resulting LOCAL inflammation may be kept down EVEN in the presence of an active physical cancer....
5.2 Increased Risk of High-Grade Prostate Cancer
In men aged 50 to 75 years with a prior negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/mL and 10.0 ng/mL taking AVODART in the 4-year Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, there was an increased incidence of Gleason score 8-10 prostate cancer compared with men taking placebo (AVODART 1.0% versus placebo 0.5%) [see Indications and Usage (1.3), Adverse Reactions (6.1)]. In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR), similar results for Gleason score 8-10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%). 5 alpha-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5 alpha-reductase inhibitors to reduce prostate volume or trial related
factors impacted the results of these trials has not been established.
TRANSLATION - Like I said....
5.6 Effect on Semen Characteristics
The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal volunteers aged 18 to 52 (n = 27 dutasteride, n = 23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reductions from
baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all semen parameters at all time-points remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), 2 subjects in the dutasteride group had decreases in sperm count of greater than 90%
from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of dutasteride’s effect on semen characteristics for an individual patient’s fertility is not known.
TRANSLATION - Hmmm - Not good... And all fer some flow. I hope not to prevent hair loss as vanity..
Long-Term Treatment (Up to 4 Years):
High-Grade Prostate Cancer: The REDUCE trial was a randomized, double-blind, placebo-controlled trial that enrolled 8,231 men aged 50 to 75 years with a serum PSA of 2.5 ng/mL to 10 ng/mL and a negative prostate biopsy within the previous 6 months. Subjects were randomized to receive placebo (N = 4,126) or 0.5-mg daily doses of AVODART(N = 4,105) for up to 4 years. The mean age was 63 years and 91% were Caucasian. Subjects underwent protocol-mandated scheduled prostate biopsies at 2 and 4 years of treatment or had “for-cause biopsies” at non-scheduled times if clinically indicated. There was a higher incidenceof Gleason score 8-10 prostate cancer in men receiving AVODART (1.0%) compared with men on placebo (0.5%) [see Indications and Usage (1.3), Warnings and Precautions (5.2)]. In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg,PROSCAR), similar results for Gleason score 8-10 prostate cancer were observed (finasteride1.8% versus placebo 1.1%). No clinical benefit has been demonstrated in patients with prostate cancer treated with AVODART.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of AVODART. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to acombination of their seriousness, frequency of reporting, or potential causal connection to
AVODART.
Immune System Disorders: Hypersensitivity reactions, including rash, pruritus, urticaria, localized edema, serious skin reactions, and angioedema.
Neoplasms: Male breast cancer.
Psychiatric Disorders: Depressed mood.
Reproductive System and Breast Disorders: Testicular pain and testicular swelling.
TRANSLATION: This SHIT IS HAPPENING. But we are not really interested in running too many studies to see how often. But our corporate legal has determined that it is advisable to mention that "we heard it"... LOL
7.3 Calcium Channel Antagonists
Coadministration of verapamil or diltiazem decreases dutasteride clearance and leads to increased exposure to dutasteride. The change in dutasteride exposure is not considered to be clinically significant. No dose adjustment is recommended [see Clinical Pharmacology (12.3)].
TRANSLATION: This is related (somewhat) to animal body electrical pathways (which we really don't even hint to in this statement) and NOTS TO BE FUKED WITH. We don't even BEGIN to broach the implications of this statement...
12.3 Pharmacokinetics
Distribution: Pharmacokinetic data following single and repeat oral doses show that dutasteride has a large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha-1 acid glycoprotein (96.6%). In a trial of healthy subjects (n = 26) receiving dutasteride 0.5 mg/day for 12 months, semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) at 12 months and, similar to serum, achieved steady-state concentrations at 6 months. On average, at 12 months 11.5% of serum dutasteride concentrations partitioned into semen.
TRANSLATION - Loooook - Albumin has a purpose after all. In fact, they may even be hinting that this drug could POSSIBLY involve itself with LH & FSH... Not only there appears to be a relationship to semen involvement.
13.2 Animal Toxicology and/or Pharmacology
Central Nervous System Toxicology Studies: In rats and dogs, repeated oral administration of dutasteride resulted in some animals showing signs of non-specific, reversible, centrally-mediated toxicity without associated histopathological changes at exposures 425- and 315-fold the expected clinical exposure (of parent drug), respectively.
Translation - Again on the electrical. And while the ACTION may be stopped (slickly stated as "reversible"), the DAMAGE is untold and UNCLEAR - at least to us...
Effect on Maximum Urine Flow Rate:
A mean peak urine flow rate (Qmax) of ?15 mL/sec was required for trial entry. Qmax was approximately 10 mL/sec at baseline across the 3 pivotal trials. Differences between the 2 groups were statistically significant from baseline at Month 3 in all 3 trials and were maintained through Month 12. At Month 12, the mean increase in Qmax across the 3 trials pooled was 1.6 mL/sec for AVODART and 0.7 mL/sec for placebo; the mean difference (dutasteride minus placebo) was 0.8 mL/sec (range: 0.7 to 1.0 mL/sec in each of the 3 trials, P<0.001). At Month 24, the mean increase in Qmax was 1.8 mL/sec for dutasteride and 0.7 mL/sec for placebo, with a mean difference of 1.1 mL/sec (range: 1.0 to 1.2 mL/sec in each of the 3 trials, P<0.001). See Figure 5. The increase in maximum urine flow rate seen during the first 2 years of double-blind treatment was maintained throughout an additional 2 years of open label extension trials.
TRANSLATION - All this just to piss 15-25% faster... Did ya really have that much more to do?? LOL
17.3 Exposure of Women—Risk to Male Fetus
Physicians should inform patients that AVODART Capsules should not be handled by a woman who is pregnant or who could become pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a pregnant woman or woman of childbearing potential comes in contact with leaking AVODART Capsules, the contact area should be washed immediately with soap and water [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].
Translation - Look Bitchez. This shit is so potent, you run the risk of fukin up you unborn son for almost just looking at a single pill. So if you husband is a spoiled baby shitass. Don't even think about handling this one to put on his plate. The funny part is how they make reference to DAMAGE to unborn MALE fetuses. WHEREAS, THEY SEEM TO OMIT THAT FEMALE FETUSES REQUIRE ANDROGENS IN THE DEVELOPMENTAL STAGES TOO. Again though, screw the cattle...
But no apparent "Black Box Warning" as of yet. So time goes on..
Yes, I felt like playing a devil's advocate tonight. Still so much is left unsaid to even analyze or be critical of...
FURTHER NOTES:
More on FDA Warning...:
Safety Announcement
[6-9-2011] The U.S. Food and Drug Administration (FDA) is informing healthcare professionals that the Warnings and Precautions section of the labels for the 5-alpha reductase inhibitor (5-ARI) class of drugs has been revised to include new safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer). This risk appears to be low, but healthcare professionals should be aware of this safety information, and weigh the known benefits against the potential risks when deciding to start or continue treatment with 5-ARIs in men.
The new safety information is based on FDA’s review of two large, randomized controlled trials––the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial––which evaluated daily use of finasteride 5 mg versus placebo for 7 years and daily use of dutasteride 0.5 mg versus placebo for 4 years, respectively, for the reduction in the risk of prostate cancer in men at least 50 years of age. The trials demonstrated an overall reduction in prostate cancer diagnoses with finasteride 5 mg and dutasteride treatment (see Data Summary below). This overall reduction was due to a decreased incidence of lower risk forms of prostate cancer. However, both trials showed an increased incidence of high-grade prostate cancer with finasteride and dutasteride treatment.
So Glaxo APPEARS reserved in NOT BOASTING this diminished PC count for those under 50 on the drug. But a the same time, what are the statistics of guys with BPH getting prostate cancer. I seem to see the opposite in real world reviews. As, men with BPH, and especially long term would seem to have lower rates of PC ANYWAY. I wonder where that study/those stats are. Seems to me you either have BPH by the age of 60 and dont get PC, or MAY have BPH or NOT, and then get BPH..
So does BPH indicate a higher androgen activity in the prostate and thus indicate hormonal receptors in that area are more occupied with androgen occupation, as opposed to estrogen interaction/population. Are estrogens the root of PC..?!? Is there any reason they state "no benefit or protection from PC?" Really? Take the stats of men with BPH that get diagnose with PC. And then take the stats of men with no or minimal BPH - and GUESS which group will statistically have a higher PC rate in the end. My money is on the ones with no swollen pisser...:drooling:
Am I missing something
I never had BPH,even when using steroids for 30 years.My prostrate was not enlarged even when i was diagosed with Pca. My cancer was grade 8,very high grade.PSA is good to screen for Pca,but ultrasound and biopsy is only way to tell if its cancer.
Screening guideline is not reactionary, doesn’t dismiss PSA
Screening guideline is not reactionary, doesn’t dismiss PSA | Urology Times
Screening guideline is not reactionary, doesn’t dismiss PSA | Urology Times
Yea, no surprise and thanks for the input. The real issue is the HISTORICAL STIGMA regarding a visit to the finger doc is going to limit past available information as to WHO really ever suffered BPH historically. Let alone I wonder the number of men that would have even known what was "going on with their pisser" and said nothing other than "DAMN" for a few days...
So really, I wonder what the statistics are...?
1. PERCENTAGE of men who have suffered BPH to VARYING/WHAT Degrees, and then eventually turned up with PC.?
2. PERCENTAGE of men who RARELY or NEVER suffered BPH and turn up with PC..?
Skimming the surface of the mind, one would initially believe that all men must suffer benign BPH throughout life after 40, and therefore the odds of PC diagnoses (say age 50 and up) would have had some pretty good BPH over the years. But you have to wonder with consideration of past ignorance and stigma.
NOW - Move the age up to 60 and up, and then 70 and up, and what do you have? I'm guessing a lot more BPH than PC. So now you have to start to wonder:
- WHAT ARE ALL OF THE CAUSES OF BPH?!?
- Is it possibly also related to an IMMUNE RESPONSE?
- Could BPH be a local biological fight against early cancer, or even UNKNOWN CAUSES.? Clearly, BPH can occur with general bacterial infection. Why should women be the only group with a high maintenance organ down there. Hell, just look at a vagina wrong and it will start spittin bacteria at ya.. LOL.
- What REALLY Causes PC?!!? Its common medical knowledge that it does not take a biological contaminant, genetic failure, or particular illness to result in cancer. A dentist can tell you if you bite your cheek enough times over the years you would wind up with a cancer diagnosis just from the local prolonger physicial tissue aggravation.
- And forget about viral (the unspeakable). I wont even go there..
- What is the REAL Reason for the likelihood of a higher grade PC cancer diagnosis (if ever realized) with patients using drugs like Dutasteride? Clearly the information says that drug drops PSA about 50% QUICKLY with continued use. Is it possible that these drugs are blocking a normal and natural HEALTHY biological fight against PC and/or its potential cause - be it infection or what..?!!
So I guess my overall question is - Does higher incidence of BPH correlate with lower incidence of PC?
So really, I wonder what the statistics are...?
1. PERCENTAGE of men who have suffered BPH to VARYING/WHAT Degrees, and then eventually turned up with PC.?
2. PERCENTAGE of men who RARELY or NEVER suffered BPH and turn up with PC..?
Skimming the surface of the mind, one would initially believe that all men must suffer benign BPH throughout life after 40, and therefore the odds of PC diagnoses (say age 50 and up) would have had some pretty good BPH over the years. But you have to wonder with consideration of past ignorance and stigma.
NOW - Move the age up to 60 and up, and then 70 and up, and what do you have? I'm guessing a lot more BPH than PC. So now you have to start to wonder:
- WHAT ARE ALL OF THE CAUSES OF BPH?!?
- Is it possibly also related to an IMMUNE RESPONSE?
- Could BPH be a local biological fight against early cancer, or even UNKNOWN CAUSES.? Clearly, BPH can occur with general bacterial infection. Why should women be the only group with a high maintenance organ down there. Hell, just look at a vagina wrong and it will start spittin bacteria at ya..
LOL.- What REALLY Causes PC?!!? Its common medical knowledge that it does not take a biological contaminant, genetic failure, or particular illness to result in cancer. A dentist can tell you if you bite your cheek enough times over the years you would wind up with a cancer diagnosis just from the local prolonger physicial tissue aggravation.
- And forget about viral (the unspeakable). I wont even go there..
- What is the REAL Reason for the likelihood of a higher grade PC cancer diagnosis (if ever realized) with patients using drugs like Dutasteride? Clearly the information says that drug drops PSA about 50% QUICKLY with continued use. Is it possible that these drugs are blocking a normal and natural HEALTHY biological fight against PC and/or its potential cause - be it infection or what..?!!
So I guess my overall question is - Does higher incidence of BPH correlate with lower incidence of PC?
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I started using steroids in 1980,since then i have done over 30 cycles that i have documented.I did 3 cycles in 2009 and 3 cycles in 2010.They included 600mg test E,600 mg EQ weekly and 50mg tren A every day and i even threw in some Masteron in one of those cycles.. I never had BPH while on.I was 64 and 65 when i did the cycles.The only reason they found my PSA was high is when i went for a check up in 2012,and i had no enlarged prostrate then. It increased from 7.7 Jan to 11.4 in June and still no enlarged prostrate.
Penney KL, Stampfer MJ, Jahn JL, et al. Gleason Grade Progression Is Uncommon. Cancer Research 2013;73(16):5163-8. Gleason Grade Progression Is Uncommon
Gleason grade is universally used for pathologic scoring of the differentiation of prostate cancer. However, it is unknown whether prostate tumors arise well differentiated and then progress to less differentiated forms or if Gleason grade is an early and largely unchanging feature. Prostate-specific antigen (PSA) screening has reduced the proportion of tumors diagnosed at advanced stage, which allows assessment of this question on a population level. If Gleason grade progresses as stage does, one would expect a similar reduction in high-grade tumors.
We studied 1,207 Physicians' Health Study and Health Professionals Follow-up Study participants diagnosed with prostate cancer from 1982 to 2004 and treated with prostatectomy. We compared the distribution of grade and clinical stage across the pre-PSA and PSA screening eras. We re-reviewed grade using the ISUP 2005 revised criteria. The proportion of advanced stage tumors dropped more than six-fold, from the earliest period (12/1982–1/1993), 19.9% stage ?T3, to the latest (5/2000–12/2004), 3% stage T3, none T4. The proportion of Gleason score ?8 decreased substantially less, from 25.3% to 17.6%. A significant interaction between stage and diagnosis date predicting grade (P = 0.04) suggests that the relationship between grade and stage varies by time period.
As the dramatic shift in stage since the introduction of PSA screening was accompanied by a more modest shift in Gleason grade, these findings suggest that grade may be established early in tumor pathogenesis. This has implications for the understanding of tumor progression and prognosis, and may help patients diagnosed with lower grade disease feel more comfortable choosing active surveillance.
Gleason grade is universally used for pathologic scoring of the differentiation of prostate cancer. However, it is unknown whether prostate tumors arise well differentiated and then progress to less differentiated forms or if Gleason grade is an early and largely unchanging feature. Prostate-specific antigen (PSA) screening has reduced the proportion of tumors diagnosed at advanced stage, which allows assessment of this question on a population level. If Gleason grade progresses as stage does, one would expect a similar reduction in high-grade tumors.
We studied 1,207 Physicians' Health Study and Health Professionals Follow-up Study participants diagnosed with prostate cancer from 1982 to 2004 and treated with prostatectomy. We compared the distribution of grade and clinical stage across the pre-PSA and PSA screening eras. We re-reviewed grade using the ISUP 2005 revised criteria. The proportion of advanced stage tumors dropped more than six-fold, from the earliest period (12/1982–1/1993), 19.9% stage ?T3, to the latest (5/2000–12/2004), 3% stage T3, none T4. The proportion of Gleason score ?8 decreased substantially less, from 25.3% to 17.6%. A significant interaction between stage and diagnosis date predicting grade (P = 0.04) suggests that the relationship between grade and stage varies by time period.
As the dramatic shift in stage since the introduction of PSA screening was accompanied by a more modest shift in Gleason grade, these findings suggest that grade may be established early in tumor pathogenesis. This has implications for the understanding of tumor progression and prognosis, and may help patients diagnosed with lower grade disease feel more comfortable choosing active surveillance.
I find it amazing that i used steroids at high doses when i was 64 and 65 and didnt have an enlarged prostrate or even have any pissing problems.It would seem an older guy like me would be more sensitive to high testosterone levels and have a large prostrate since its normal for the prostrate to get larger as you age anyway......When they do the seed implant they do ADT to shrink your prostrate for at least 3 months,but they went ahead and did the implants after only 2 month of ADT and they said mine was small already.Like i said i have never had any prostrate issues even will on steroids......My gleason score was 8 after the biopsy,i went on ADT the next month after the biopsy.
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Khera M, Crawford D, Morales A, Salonia A, Morgentaler A. A New Era of Testosterone and Prostate Cancer: From Physiology to Clinical Implications. European Urology. A New Era of Testosterone and Prostate Cancer: From Physiology to Clinical Implications
Context Decades-old beliefs regarding androgens and prostate cancer (PCa) have undergone dramatic shifts in light of modern evidence and new theoretical constructs, but considerable confusion remains on this topic, particularly with regard to the use of testosterone therapy in men with any history of PCa.
Objective To review current literature regarding the relationship of serum testosterone on PCa and in particular the effect of testosterone therapy on PCa progression and recurrence.
Evidence acquisition A Medline search was conducted to identify all original and review articles assessing the effect of androgens on the prostate and the use of testosterone in men with a history of treated and untreated PCa.
Evidence synthesis Contrary to traditional teaching, high endogenous serum testosterone does not increase the risk of developing PCa, and low serum testosterone does not protect against PCa. Although limited in size and duration, current studies similarly fail to indicate any increased risk of PCa in men receiving testosterone therapy. These results indicate a finite ability of androgens to stimulate PCa growth (the saturation model). A majority of studies demonstrate an association between low serum testosterone and poor prognostic features of PCa, including high-grade disease, advanced pathologic stage, and increased risk of biochemical recurrence following radical prostatectomy. The prostate-specific antigen-to-testosterone ratio predicted PCa risk in several biopsy studies. Multiple reports of testosterone therapy in men after treatment for localized PCa have shown low or absent recurrence rates. Some men with untreated PCa have received testosterone therapy without evidence for PCa progression.
Conclusions The long-held belief that PCa risk is related to high serum androgen concentrations can no longer be supported. Current evidence indicates that maximal androgen-stimulated PCa growth is achieved at relatively low serum testosterone concentrations. It may therefore be reasonable to consider testosterone therapy in selected men with PCa and symptomatic hypogonadism.
Context Decades-old beliefs regarding androgens and prostate cancer (PCa) have undergone dramatic shifts in light of modern evidence and new theoretical constructs, but considerable confusion remains on this topic, particularly with regard to the use of testosterone therapy in men with any history of PCa.
Objective To review current literature regarding the relationship of serum testosterone on PCa and in particular the effect of testosterone therapy on PCa progression and recurrence.
Evidence acquisition A Medline search was conducted to identify all original and review articles assessing the effect of androgens on the prostate and the use of testosterone in men with a history of treated and untreated PCa.
Evidence synthesis Contrary to traditional teaching, high endogenous serum testosterone does not increase the risk of developing PCa, and low serum testosterone does not protect against PCa. Although limited in size and duration, current studies similarly fail to indicate any increased risk of PCa in men receiving testosterone therapy. These results indicate a finite ability of androgens to stimulate PCa growth (the saturation model). A majority of studies demonstrate an association between low serum testosterone and poor prognostic features of PCa, including high-grade disease, advanced pathologic stage, and increased risk of biochemical recurrence following radical prostatectomy. The prostate-specific antigen-to-testosterone ratio predicted PCa risk in several biopsy studies. Multiple reports of testosterone therapy in men after treatment for localized PCa have shown low or absent recurrence rates. Some men with untreated PCa have received testosterone therapy without evidence for PCa progression.
Conclusions The long-held belief that PCa risk is related to high serum androgen concentrations can no longer be supported. Current evidence indicates that maximal androgen-stimulated PCa growth is achieved at relatively low serum testosterone concentrations. It may therefore be reasonable to consider testosterone therapy in selected men with PCa and symptomatic hypogonadism.
Researchers Link Early Hair Loss and Prostate Cancer
According to a few new studies, men who lose their hair early in life have a greater risk of developing prostate cancer—especially African American men.
Although researchers have long suspected a link between baldness and prostate cancer, earlier studies have been inconclusive—and sometimes conflicting. (JNCI reported on the potential link in the early 1970s.)
In October 2008, researchers from the Division of Cancer Epidemiology and Genetics at the National Cancer Institute published “Androgen and Prostate Cancer: Is the Hypothesis Dead?” in Cancer Epidemiology, Biomarkers, and Prevention. They said that although data from animal, clinical, and prevention studies support the role of androgen in prostate cancer growth, proliferation, and progression, “results from serum-based epidemiologic studies in humans have been inconclusive, and . . . showed no association between serum androgen and prostate cancer risk.”
That same year, a study from Istanbul, Turkey, amplified this conclusion. Published in volume 11 of Informa Healthcare, their study of 152 patients found no correlation between pattern of baldness and androgen levels in the blood.
However, researchers from the European Georges Pompidou Hospital in Paris, France, reached a different conclusion. Reporting on a study of 669 subjects in the Aug. 22, 2011, issue of Annals of Oncology, they found that patients with prostate cancer were twice as likely to have male pattern baldness, or androgenic alopecia (AA), at age 20 years.
Why the inconsistency?
Beyond the possibility of faulty memories of study participants filling out questionnaires, Steven Freedland, M.D., associate professor of surgery at Duke University Medical Center in Durham, N.C., believes he knows why. “To me, the androgen hypothesis is not wrong; it just means we’ve been looking in the wrong place. We should be examining the tissue, not serum levels, which doesn’t accurately reflect what’s going on in the prostate.”
Freedland cowrote one of the new studies, which examined 312 healthy control subjects, 167 men with prostate cancer, and 229 men without prostate cancer at a Veterans Affairs Hospital. Participants self-described their hair patterns at ages 30 and 40 years. “We tested the association between hair pattern—overall, vertex, or frontal—and prostate cancer status by using logistic regression analysis adjusting for multiple clinical features,” Freedland said.
In relation to controls, the researchers found that a younger age of AA onset was statistically significantly
MF: This is correct as is. associated with increased prostate cancer risk.
The study noted similar patterns for frontal, but not vertex, balding. “Overall balding was associated with greater than twofold increase in high-grade disease,” Freedland said. “Although our study was not specifically African American men, they comprised nearly 50% of the cohort.” The study appeared in the March 26, 2013, issue of Cancer Causes and Control.
A study dealing specifically with African American men found that advanced prostate cancer increased with younger age and type of baldness. Conducted by researchers at the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania in Philadelphia, the study consisted of 318 men with prostate cancer and 219 control subjects enrolled in the Study of Clinical Outcomes, Risk, and Ethnicity (SCORE) between 1998 and 2010. Lead researcher Charnita Zeigler-Johnson, Ph.D., research assistant professor at the University of Pennsylvania, said that this study is the first to examine these associations in an all– African American sample and one of a few studies to examine results by age groups.
In the study, which appeared in the March 2013 Cancer Epidemiology, Biomarkers, and Prevention, the researchers determined age-stratified associations of baldness with prostate cancer occurrence and severity defined by high stage (T3/T4) or high-grade Gleason scores (7+.) Bald men, regardless of hair loss type, had a 69% greater risk of prostate cancer, and young men with frontal hair loss were six times more likely than those without such baldness to get advanced prostate cancer by age 60 years. Frontal hair loss was also associated with higher cancer risk than vertex baldness.
Zeigler-Johnson said that the link between male pattern baldness and prostate cancer is believed to be tied to dihydrotestosterone, which is linked to benign and cancerous growth of the prostate gland and contributes to hair follicle shrinkage, which can cause hair thinning. “It remains unclear if this is the only biological link or if other hormonal or inflammatory pathways involved in baldness may also contribute to carcinogenesis of the prostate gland. More research of underlying mechanisms particularly related to African Americans is needed.”
Men who are not bald may thus have less risk for prostate cancer, Zeigler-Johnson said. Their results indicate that “nonbald men are less likely to report a history of early-onset baldness.”
These findings also apply to people who aren’t black. After reviewing seven case–control studies totaling 8,994 patients, researchers from the Hair Center at the Department of Dermatology at the Cleveland Clinic in Ohio found that vertex pattern AA was associated with a statistically significantly increased risk of prostate cancer, but “any pattern” AA did not show a statistically significant increase in risk of prostate cancer. The study appeared in the Feb. 7, 2013, Journal of the American Academy of Dermatology. Also, researchers from the Cancer
Epidemiology Centre at the Cancer Council of Victoria, Australia, assessed whether AA at ages 20 and 40 years was associated with risk of prostate cancer. Of the 9,448 men studied, researchers identified 476 prostate cancer cases. They concluded that vertex AA at age 40 years might indicate increased risk of early-onset prostate cancer. “If confirmed, these results suggest that the apparently conflicting findings of previous studies might be explained by failure to adequately model the age-varying nature of the association between AA and prostate cancer.” This study also appeared in the March 2013 Cancer Epidemiology, Biomarkers, and Prevention.
Daniel S. Blumenthal, M.D., former director of the Cancer Group at Morehouse School of Medicine in Atlanta and president-elect of the American College of Preventive Medicine, said that although the studies are interesting, the conclusions are unlikely to affect clinical practice much. “This is especially true since the studies are inconsistent with each other as far as types of baldness. Also, I think that hair loss is too variable a phenomenon to be useful clinically in an individual patient.”
Zeigler-Johnson said that the differences between types of baldness are duly noted and need to be reconciled. “Still, all these recent findings are exciting and novel, and no doubt need to be confirmed by additional research.”
Fillon M. Researchers Link Early Hair Loss and Prostate Cancer. Journal of the National Cancer Institute. Researchers Link Early Hair Loss and Prostate Cancer
According to a few new studies, men who lose their hair early in life have a greater risk of developing prostate cancer—especially African American men.
Although researchers have long suspected a link between baldness and prostate cancer, earlier studies have been inconclusive—and sometimes conflicting. (JNCI reported on the potential link in the early 1970s.)
In October 2008, researchers from the Division of Cancer Epidemiology and Genetics at the National Cancer Institute published “Androgen and Prostate Cancer: Is the Hypothesis Dead?” in Cancer Epidemiology, Biomarkers, and Prevention. They said that although data from animal, clinical, and prevention studies support the role of androgen in prostate cancer growth, proliferation, and progression, “results from serum-based epidemiologic studies in humans have been inconclusive, and . . . showed no association between serum androgen and prostate cancer risk.”
That same year, a study from Istanbul, Turkey, amplified this conclusion. Published in volume 11 of Informa Healthcare, their study of 152 patients found no correlation between pattern of baldness and androgen levels in the blood.
However, researchers from the European Georges Pompidou Hospital in Paris, France, reached a different conclusion. Reporting on a study of 669 subjects in the Aug. 22, 2011, issue of Annals of Oncology, they found that patients with prostate cancer were twice as likely to have male pattern baldness, or androgenic alopecia (AA), at age 20 years.
Why the inconsistency?
Beyond the possibility of faulty memories of study participants filling out questionnaires, Steven Freedland, M.D., associate professor of surgery at Duke University Medical Center in Durham, N.C., believes he knows why. “To me, the androgen hypothesis is not wrong; it just means we’ve been looking in the wrong place. We should be examining the tissue, not serum levels, which doesn’t accurately reflect what’s going on in the prostate.”
Freedland cowrote one of the new studies, which examined 312 healthy control subjects, 167 men with prostate cancer, and 229 men without prostate cancer at a Veterans Affairs Hospital. Participants self-described their hair patterns at ages 30 and 40 years. “We tested the association between hair pattern—overall, vertex, or frontal—and prostate cancer status by using logistic regression analysis adjusting for multiple clinical features,” Freedland said.
In relation to controls, the researchers found that a younger age of AA onset was statistically significantly
MF: This is correct as is. associated with increased prostate cancer risk.
The study noted similar patterns for frontal, but not vertex, balding. “Overall balding was associated with greater than twofold increase in high-grade disease,” Freedland said. “Although our study was not specifically African American men, they comprised nearly 50% of the cohort.” The study appeared in the March 26, 2013, issue of Cancer Causes and Control.
A study dealing specifically with African American men found that advanced prostate cancer increased with younger age and type of baldness. Conducted by researchers at the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania in Philadelphia, the study consisted of 318 men with prostate cancer and 219 control subjects enrolled in the Study of Clinical Outcomes, Risk, and Ethnicity (SCORE) between 1998 and 2010. Lead researcher Charnita Zeigler-Johnson, Ph.D., research assistant professor at the University of Pennsylvania, said that this study is the first to examine these associations in an all– African American sample and one of a few studies to examine results by age groups.
In the study, which appeared in the March 2013 Cancer Epidemiology, Biomarkers, and Prevention, the researchers determined age-stratified associations of baldness with prostate cancer occurrence and severity defined by high stage (T3/T4) or high-grade Gleason scores (7+.) Bald men, regardless of hair loss type, had a 69% greater risk of prostate cancer, and young men with frontal hair loss were six times more likely than those without such baldness to get advanced prostate cancer by age 60 years. Frontal hair loss was also associated with higher cancer risk than vertex baldness.
Zeigler-Johnson said that the link between male pattern baldness and prostate cancer is believed to be tied to dihydrotestosterone, which is linked to benign and cancerous growth of the prostate gland and contributes to hair follicle shrinkage, which can cause hair thinning. “It remains unclear if this is the only biological link or if other hormonal or inflammatory pathways involved in baldness may also contribute to carcinogenesis of the prostate gland. More research of underlying mechanisms particularly related to African Americans is needed.”
Men who are not bald may thus have less risk for prostate cancer, Zeigler-Johnson said. Their results indicate that “nonbald men are less likely to report a history of early-onset baldness.”
These findings also apply to people who aren’t black. After reviewing seven case–control studies totaling 8,994 patients, researchers from the Hair Center at the Department of Dermatology at the Cleveland Clinic in Ohio found that vertex pattern AA was associated with a statistically significantly increased risk of prostate cancer, but “any pattern” AA did not show a statistically significant increase in risk of prostate cancer. The study appeared in the Feb. 7, 2013, Journal of the American Academy of Dermatology. Also, researchers from the Cancer
Epidemiology Centre at the Cancer Council of Victoria, Australia, assessed whether AA at ages 20 and 40 years was associated with risk of prostate cancer. Of the 9,448 men studied, researchers identified 476 prostate cancer cases. They concluded that vertex AA at age 40 years might indicate increased risk of early-onset prostate cancer. “If confirmed, these results suggest that the apparently conflicting findings of previous studies might be explained by failure to adequately model the age-varying nature of the association between AA and prostate cancer.” This study also appeared in the March 2013 Cancer Epidemiology, Biomarkers, and Prevention.
Daniel S. Blumenthal, M.D., former director of the Cancer Group at Morehouse School of Medicine in Atlanta and president-elect of the American College of Preventive Medicine, said that although the studies are interesting, the conclusions are unlikely to affect clinical practice much. “This is especially true since the studies are inconsistent with each other as far as types of baldness. Also, I think that hair loss is too variable a phenomenon to be useful clinically in an individual patient.”
Zeigler-Johnson said that the differences between types of baldness are duly noted and need to be reconciled. “Still, all these recent findings are exciting and novel, and no doubt need to be confirmed by additional research.”
Fillon M. Researchers Link Early Hair Loss and Prostate Cancer. Journal of the National Cancer Institute. Researchers Link Early Hair Loss and Prostate Cancer
Doctors Who Profit From Radiation Prescribe It More Often, Study Finds
http://www.nytimes.com/2013/08/19/u...tion-prescribe-it-more-often-study-finds.html
http://www.nytimes.com/2013/08/19/u...tion-prescribe-it-more-often-study-finds.html
From the article primer as published in this thread...:
NOTES:
(1) EVERY MAN can remember the day he first went BALD...!
(2) Note above in RED, Me LIKES the way he thinks....
*** You can further denote the, "it just means we’ve been looking in the wrong place". Talk about a FAILURE of hyperfocused GROUPTHINK of an ENTIRE INDUSTRY admitted.. There's the proof..
ITS ABOUT FUKING TIME>>>!
NOTES:
(1) EVERY MAN can remember the day he first went BALD...!
(2) Note above in RED, Me LIKES the way he thinks....
*** You can further denote the, "it just means we’ve been looking in the wrong place". Talk about a FAILURE of hyperfocused GROUPTHINK of an ENTIRE INDUSTRY admitted.. There's the proof..
ITS ABOUT FUKING TIME>>>!
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That was part of the treatment i had for PCa along with radiation seed implants.There were patients there that were only able to get the IMRT because they were not candidates for the seed implants. They pretty much threw the kitchen sink at my cancer and the results were a drop in my PSA from 11.4 to 0.1 after treatments. Was the IMRT necessary,maby not but why chance it.
Kumagai J, Hofland J, Erkens-Schulze S, et al. Intratumoral conversion of adrenal androgen precursors drives androgen receptor-activated cell growth in prostate cancer more potently than de novo steroidogenesis. Prostate. Intratumoral conversion of adrenal androgen precursors drives androgen receptor-activated cell growth in prostate cancer more potently than de novo steroidogenesis - Kumagai - 2013 - The Prostate - Wiley Online Library
BACKGROUND: Despite an initial response to hormonal therapy, patients with advanced prostate cancer (PC) almost always progress to castration-resistant disease (CRPC). Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in prostate tissue of eugonadal men. These levels could originate from intratumoral conversion of adrenal androgens and/or from de novo steroid synthesis. However, the relative contribution of de novo steroidogenesis to AR-driven cell growth is unknown.
METHODS: The relative contribution of androgen biosynthetic pathways to activate androgen receptor (AR)-regulated cell growth and expression of PSA, FKBP5, and TMPRSS2 was studied at physiologically relevant levels of adrenal androgen precursors and intermediates of de novo androgen biosynthesis in human prostate cancer cell lines, PC346C, VCaP, and LNCaP.
RESULTS: In PC346C and VCaP, responses to pregnenolone and progesterone were absent or minimal, while large effects of adrenal androgen precursors were found. VCaP CRPC clones overexpressing CYP17A1 did not acquire an increased ability to use pregnenolone or progesterone to activate AR. In contrast, all precursors stimulated growth and gene expression in LNCaP cells, presumably resulting from the mutated AR in these cells.
CONCLUSIONS: Our data indicate that at physiological levels of T precursors PC cells can generally convert adrenal androgens, while de novo steroidogenesis is not generally possible in PC cells and is not able to support AR transactivation and PC growth.
BACKGROUND: Despite an initial response to hormonal therapy, patients with advanced prostate cancer (PC) almost always progress to castration-resistant disease (CRPC). Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in prostate tissue of eugonadal men. These levels could originate from intratumoral conversion of adrenal androgens and/or from de novo steroid synthesis. However, the relative contribution of de novo steroidogenesis to AR-driven cell growth is unknown.
METHODS: The relative contribution of androgen biosynthetic pathways to activate androgen receptor (AR)-regulated cell growth and expression of PSA, FKBP5, and TMPRSS2 was studied at physiologically relevant levels of adrenal androgen precursors and intermediates of de novo androgen biosynthesis in human prostate cancer cell lines, PC346C, VCaP, and LNCaP.
RESULTS: In PC346C and VCaP, responses to pregnenolone and progesterone were absent or minimal, while large effects of adrenal androgen precursors were found. VCaP CRPC clones overexpressing CYP17A1 did not acquire an increased ability to use pregnenolone or progesterone to activate AR. In contrast, all precursors stimulated growth and gene expression in LNCaP cells, presumably resulting from the mutated AR in these cells.
CONCLUSIONS: Our data indicate that at physiological levels of T precursors PC cells can generally convert adrenal androgens, while de novo steroidogenesis is not generally possible in PC cells and is not able to support AR transactivation and PC growth.
Chang KH, Li R, Kuri B, et al. A Gain-of-Function Mutation in DHT Synthesis in Castration-Resistant Prostate Cancer. Cell 2013;154(5):1074-84. Cell - A Gain-of-Function Mutation in DHT Synthesis in Castration-Resistant Prostate Cancer
Growth of prostate cancer cells is dependent upon androgen stimulation of the androgen receptor (AR). Dihydrotestosterone (DHT), the most potent androgen, is usually synthesized in the prostate from testosterone secreted by the testis. Following chemical or surgical castration, prostate cancers usually shrink owing to testosterone deprivation. However, tumors often recur, forming castration-resistant prostate cancer (CRPC). Here, we show that CRPC sometimes expresses a gain-of-stability mutation that leads to a gain-of-function in 3beta-hydroxysteroid dehydrogenase type 1 (3betaHSD1), which catalyzes the initial rate-limiting step in conversion of the adrenal-derived steroid dehydroepiandrosterone to DHT. The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumulation. Whereas dehydroepiandrosterone conversion to DHT is usually very limited, expression of 367T accelerates this conversion and provides the DHT necessary to activate the AR. We suggest that 3betaHSD1 is a valid target for the treatment of CRPC.
Growth of prostate cancer cells is dependent upon androgen stimulation of the androgen receptor (AR). Dihydrotestosterone (DHT), the most potent androgen, is usually synthesized in the prostate from testosterone secreted by the testis. Following chemical or surgical castration, prostate cancers usually shrink owing to testosterone deprivation. However, tumors often recur, forming castration-resistant prostate cancer (CRPC). Here, we show that CRPC sometimes expresses a gain-of-stability mutation that leads to a gain-of-function in 3beta-hydroxysteroid dehydrogenase type 1 (3betaHSD1), which catalyzes the initial rate-limiting step in conversion of the adrenal-derived steroid dehydroepiandrosterone to DHT. The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumulation. Whereas dehydroepiandrosterone conversion to DHT is usually very limited, expression of 367T accelerates this conversion and provides the DHT necessary to activate the AR. We suggest that 3betaHSD1 is a valid target for the treatment of CRPC.
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