You can see there is an exponential rise in PSA starting at around 6/1/23, and doubling from PSA = 5 to 10 in about 8 months. My MRI at PSA = 10 showed a T3a tumor about 1.3 cm long (PIRADS 5). A subsequent targeted biopsy showed Gleason 3+4 in 4 cores, and 4+3 in one core. PSMA-PET showed no spread outside of the prostate.
After learning that prostate cancer cells only respond to dihydrotestosterone (DHT) and not to testosterone directly (DHT is made from testosterone), I decided to go on Dutasteride on 12/1/23. Since then, my PSA dropped to 5.5 in about 1.5 months, and then down to 3.3 after a total of 3 months from starting treatment. That's a 70% decrease in PSA, with no ADT therapy!
Dutasteride decreases DHT levels by more then 90%, which is why there is such a dramatic decrease in PSA levels. DHT is the fuel that feeds prostate cancer growth, not testosterone.
Dutasteride also shrinks the prostate by 25-50%, as well as reducing the risk of PCa by 20%.
Testosterone levels increase by about 20% on Dutasteride, because T is not getting converted to DHT. Estradiol levels also increase, as well, because T levels are increased.
I have two theories why the PSA has dropped 70% from the peak value of 10:
(1) the shrinking prostate size means that less PSA is being produced (fewer normal prostate cells);
and
(2) the tumor has either stopped growing, or is shrinking.
(I think I read that PCa cells produce more PSA than normal prostate cells. But, I need to confirm that is true.)
It's likely a combination of both effects. I will get a repeat MRI in 4-6 months to see if the tumor has actually shrunk.
I expect the PSA to continue to drop as the prostate (and, hopefully, the tumor) continues to shrink over the next 3-6 months.
I will post later two explanations of why the black label warning on Dutasteride is wrong, and should be disregarded.
Stay tuned!
Bob
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Bob - just curious - where did you find an MD willing to give the Dutasteride prescription, and they based that on? (Unless you're an MD or veterinarian or dentist and are prescribing yourself...) Just curious.. It's interesting to see someone experiment as you are.
I'm blessed to have a MD who's not only a family friend, but also an alternative type of integrative medicine doctor. He's also very interested in endocrine issues. He diagnosed my hypogonadism and put me on TRT, as well as finding my Hashimoto's Disease (low thyroid) and hyperprolactinemia (and put me on cabergoline). When I read that PCa doesn't feed off of testosterone, but, rather, off of DHT, I asked him to prescribe Dutasteride and he readily did. He's been a great support, and I'm grateful for him. We trust each other, after 20 years.
I am a doctor, but not an MD. I have a Ph.D in Nuclear Engineering...
I'm not nearly as informed as many here and perhaps do not fully understand but isn't the statement that, " After learning that prostate cancer cells only respond to dihydrotestosterone (DHT) and not to testosterone directly (DHT is made from testosterone)..." rather revolutionary? My docs have always told me that T is to PCa what Miracle Grow is to weeds; don't take T. Say a bit more if you will and talk about the relationship between growth in PCa and T. I have my annual uro apt at the end of the month and I want to discuss this with him.
I'm sorry that I don't have a reference handy that supports why and how PCa cells only respond to DHT and not to testosterone, but I can find it later.
Normally, about 10% of testosterone is converted to DHT by the enzyme "aromatase". The problem is that most doctors don't measure DHT (they say "it's small, unimportant, and in the noise.). So, the large databases for PCa patients don't have many measurements of DHT. But they have lots of data on testosterone. They could convert their testosterone measurements to DHT by the 10% rule, if they needed to. But, they don't because the doctors and professors all understand that when they say "testosterone" that it includes 10% of DHT. It's a given.
Overall, all of the papers and plots that show effects of testosterone are still valid and useful (even though DHT is the bad actor on a cellular level). So, to answer your question, increased testosterone does make PCa grow faster because 10% of the testosterone is converted to DHT. They go hand in hand. When one changes, the other changes the same amount. For example, if the testosterone increases by 50%, the DHT will also increase by 50%, and visa-versa.
One could easily convert the testosterone scales by dividing them by 10 to get the equivalent DHT level and everything would seem to be fine.
But, there is a problem with doing that. Some men take Dutasteride or Finesteride, which reduces the DHT level (but not the testosterone) by 95% on average. In fact, Dutasteride increases T by 20% on average (because less T is being converted to DHT, and, hence, there is more T available). So, this very large reduction in DHT breaks the 10% rule that I mentioned before by a very large amount.
The solution to this conundrum is to directly measure DHT and report those numbers in studies and trials, so that proper correlations can be made to the real DHT values, rather than relying on converting T to DHT via the simple 10% rule.
I checked your numbers and they appear correct. But, the overall percentage of DHT divided by testosterone is too high. It should be much lower...by about a factor of 10.
Are you taking 0.5 mg of Dutasteride every day?
Is there any chance you have the wrong units for DHT from you blood labs? Your table shows units of ng/mL for DHT, which is an odd unit. It would be worth a check to see what units the blood lab values are originally in.
My level of DHT on Dutasteride is 166 pg/mL, which is a more common unit of measure. 166 pg/mL converts to 16.6 ng/dL. My testosterone is 1060 ng/dL, so the percentage DHT to T ratio for me is (16.6/1060) x 100 = 1.57 % (which is about 4X too high...it should be down to about 0.4 %).
According to Clark (2004), a baseline value of DHT = 400 pg/mL. And, after 0.5 mg/day of Dutasteride the DHT level drops to 24 pg/mL, which is a 94% reduction from baseline.
Do you know what your baseline DHT was before you started Dutasteride?
But, as a retired engineer, I am serious about measurements, so I employ multiple labs to verify consistency across them. This one reports in pg/ml, but with a different reference range (250-990). Obviously, the two are coming from different analyzers and/or processes. Hence, my advice to you: Do NOT put blind faith to whatever you find published, like this Clark paper. Collect your personal data series and do your own analysis.
I'm a retired engineer, too. Ph.D in nuclear engineering from Univ. of Wisconsin (1982). Actually, I'm working full-time now as a patent agent for a law firm in Detroit. (I had a mid-career change from Nuc. Engineer to patent agent 24 years ago).
I'm sorry I can't explain why your DHT values appear to be 10 times too high. The Avodart should be reducing your DHT by 95% for a daily dose of 0.5 mg/day, according to Clark (2004).
Do you know what your baseline DHT was before you started Avodart?
The Clark paper seems very reasonable and well-documented, with good statistics. I have no reason to discount its findings.
The top samples of the posted DHT time series coincide with the start of taking said drug, so the baseline should be somewhere around there (no prior data). Dutasteride has a very long half life and it takes a couple of months to reach steady state serum concentration. This is in good agreement and demonstrable by the tT ramping up.
When you posted data in Greek (?), I thought it was from a different person or paper.
Are you living in Greece, or are you from there?
Every time I check your units, they come out OK.
If your DHT baseline was 0.32 or 0.297 ng/mL...then your 15 data point trend show that taking Dutasteride has had no significant reduction on your DHT levels at all.
Your % ratio of DHT/T is perfectly consistent with the published ranges of DHT:T , which range from 1:7 to 1: 15. In other words, DHT is normally about 10% of T.
Your ratios range from 3 % to 9 %, which is close to the average ratio of 10% (1:10). Maybe a factor of 2 different
No wonder your values are not consistent with Clark's paper!
Is there any chance the grapefruit juice is deactivating the Dutasteride? Just thinking outside of the box... Grapefruit juice is contraindicated in many medications.
Or, could you be that rare individual who simply doesn't respond to Dutasteride?
I am Greek living in Greece. Grapefruit is contraindicated because it facilitates the entry of a drug's active ingredient to the body a mechanism that may lead to overdosing. I have also tried for two weeks taking two tablets daily, but this didn't lower DHT any further. If you manage to lower your DHT 4.5 times more, then I may reconcider about the validity of the paper that you have made a Bible out of it. Until then there is this Greek proverbial phrase that goes like this: "Is the coastline crooked, or are we sailing wrongly?"
Turns out, by coincidence, my Urologist is the first author on a paper about the use of Dutasteride for PCa. I hope to talk to him about DHT levels, Dutasteride doses, effects on PCa, and your unusual DHT levels. He may have some ideas.
Electrical. Please also ask him whether the ratio of DHT/tT is the appropriate metric or the convenient one. I am putting forward such a skepticism because the bulk of tT binds with SHBG and becomes functionally non existent. A portion of the unbound T is the one that gets oxidised/hydrolyzed/whatever to become DHT. If so, there is the proportion/ratio of unbound to total, silently assumed as constant, while it is not. This may introduce an element of error.
I need to make an appointment with the Urologist. I thought I was done with him after the biopsy, but now I have lots to talk about with respect to Dustasteride.
I think SHBG goes up as we age. Mine did.
What you say about only free T being able to be converted to DHT makes sense. Plus, there's probably a protein-bound version of DHT and a free version of DHT, by analogy. Complicated.
I stumbled across this study that plotted the PSA values before and after using Dutasteride. I marked with a green arrow those 36 men who no (or small) drop in PSA, which indicates they are non-responders to Dutasteride. In the "Non-Malignent" group about 14% of them were non-responders, but in the "Prostate Cancer" group the percentage jumped up to 40% non-responders.
I forget if you have PCa or not, but if you do, there are significant odds that you won't respond to Dutasteride. This could explain why your DHT hasn't decreased very much. It's a possibility...
I am an average to good responder, in no need of any paper to theorize on the opposite. The FACT that my tT climbed from 800-900 to 1200-1500 upon starting Avodart is enough proof for me.
I was very surprised that the rate of non-PSA responders was so high. I would have expected it to be about 10% non-PSA responders for both groups.
While the statistics are poor (N=18 in the first group and n=15 in the second group), it was interesting that the non-PSA response rate was only about 10% in the no-cancer group, versus about 1/3 in the prostate cancer group. That implies that Avodart (Dutasteride) can be a hit-or-miss kind of treatment for men with PCa. Perhaps that's why it's not used more often?
One can see that there is a huge variability in the PSA response (before - after), ranging from [ -93% PSA drop to +12% PSA increase] for the non-malignant group, and ranging from [-80% PSA drop to +12% PSA increase] for the prostate cancer group. Some men are super-responders, while others have an increase in PSA when using Dutasteride. This lack of predictability may also be why Dutasteride is not used more often.
The average drop in the first group is about 50% (average PSA = 12.5 before and PSA=5.9 after), while the average drop is only about 40% in the second group (average PSA = 11 before and PSA=6.8 after).
The related question is what % of people have their DHT drop by at least 90% (as reported by Clark et. al) when on Dutasteride. I'm sure there's data out there that could be reported by someone. Perhaps clark has that data...
No need to apologize, as no offense was taken. On top of that, I appreciate your interest in my case, but, literally you are mixing apples with oranges. The cohort that makes up the paper, obviously, have their prostate. I don't. It is very well known that Avodart targets both cancerous and benign (if existing) prostate cells. My understanding is that it is more efficacious on the benign ones. As to your query, I don't have any data able to shed some light to it. Post RP my PSA was 0.02, three months later I started Avodart, PSA remained at 0.02 for another 3-4 months and consequently started to rise to 0.03 and beyond. My chart if you are interested:
You're right, Avodart does appear to be more beneficial (on average) for treating benign prostate cells than cancerous cells. The "Before/After" bar chart above supports this. Fortunately, 2/3 of men with PCa have a beneficial effect of Avodart treatment.
Avodart, (dutasteride), reduces PSA production from BPH, and perhaps some low grade cancers, which means to obtain the actual PSA value, you double the PSA value under Avodart to obtain the actual PSA level.
The speculation you are making is contrary to what has been observed.
Avodart MAY hold low grade cancers in check, but it will not prevent prostate cancer, and since it decreases the size of the prostate, your PSA value will decrease. Because of that prostate size decrease, the probability of finding possible cancers increases, because there is less prostate volume, if there is any PCa present.
That is why it appears that higher grade cancers seem to be found more frequently with those on Avodart, because the decrease in prostate size make the biopsy sampling less area to find a hot spot.
That you had a targeted biopsy was prudent, but it does not eliminate the possibility that there could be a PCa elsewhere in the prostate that was not observed on the MRI.
The one 4+3 is concerning, and it might be beneficial to request a genetic test on the biopsy sample, such as decipher, prolaris, or oncotype, to help you determine the risk you are dealing with. Also, having a free and total PSA if you haven't done so. You might also consider a second read on the positive prostate biopsies through Epstein at John Hopkins to confirm the gleason grade.
If you are taking Avodart you need to establish a new PSA baseline. Once that has been established, then your PSA monitoring would be based on that NEW baseline.
Thanks for your helpful comments. My prostate size is 51 cc. I'm 69 yo.
I'm attaching my PSA history, which shows a slow PSA increase for a couple of years, probably due to BPH increasing prostate volume. Then, on 6/23 the PSA takes off and doubles in about 8 months from 5 to 10, indicating a growing tumor. I started Dutasteride on 12/1/23, and my PSA has dropped to 3.3 after 3 months. I expect the PSA will continue to drop for the next 1-3 months to about 1-2. I'll get it measured again in 1 month.
I looked for papers about PSA kinetics, but didn't find any support that PCa cells produce PSA at a greater rate than normal prostate tissue cells.
I did find a paper that reported the cellular "proliferation rate" in terms of % of cells that turnover every day. They reported a rate of 0.2 %/day turnover for normal prostate cells, and a rate of 1.5-2.9 %/day turnover for prostate cancer cells. That's a big difference (factor of 10). But, they didn't say anything about PSA expression rates, unfortunately.
So, there may be two different effects going on. One relates to the question: Does a single PCa cell produce the same, or different amount of PSA in a day, compared to a single normal prostate cell? I'm sure that's been measured, but I didn't find it yet in my short search. So, we don't know the answer to that question.
The second effect is based on the observation that tumors contain a large number of tightly-packed (dense) cancer cells. That's why it feels hard in the DRE, and why it's dark on a T2 MRI image. (less water in the tumor). This means that the rate that a significant tumor expresses PSA is much greater than the surrounding normal tissue, due to the large number of cancer cells. As the tumor grows, the PSA levels increases exponentially until treated. That explains the rapid acceleration of my own PSA numbers over 8 months. Part of the early PSA increase is mostly due to a growing prostate, but the steep acceleration is definitely caused by a growing tumor (1.3 cm wide on MRI).
PCa cells respond only to DHT, and not testosterone. So, anything that reduces DHT will slow down the PCa growth rate. This can be done by lowering testosterone (ADT), or by reducing the conversion of testosterone to DHT by using an aromatase inhibitor like Dutasteride (or both).
Dutasteride reduces the DHT level by 95% (Clark, 2004). This is why my PSA dropped by 70% after I started Dutasteride (with no ADT). I believe the drop is caused by two factors: a shrinking prostate,and a shrinking tumor. We'll never know the proportion of these two effects, but I could imagine it's 20% due to a shrinking Prostate and 80% due to a shrinking tumor. Or, it could be a 50/50 mix. I will get another MRI in 3-5 months, and that will show how much the prostate and tumor has shrunk on only Dustasteride. (I have to have low back fusion surgery before I start ADT, because of the risk of osteoporosis causing the bone graft fusion to fail).
You explained well the detection bias problem that caused the black label warning for Dutasteride. I think more men would use Dutasteride if there was no black label warning. I have two papers that debunk the early report of high-grade cancer with Dutasteride. If you send me your email in a private chat, I'll email you the two papers.
You mentioned two papers refuting the claim that Avodart, which results in reduction in the size of the prostate, does not make the prostate vulnerable to high grade PCa. That isn't the impression I meant to convey. What I meant was that because the prostate size is reduced with Avodart, it makes the smaller prostate volume more likely to find a PCa, whether it is low or high grade, if there is one present. I didn't mean to imply that it causes a higher grade PCa.
When they found PCa in me it was a low volume, low grade 3+3 in 2013, and I went on Active Surveillance. My PSA was slowly going up, not as dramatic as what happen in your situation. At that time I requested an Avodart Rx, and have been on it since 2013.
Increases in PSA can be due to more than PCa or BPH. It can also be caused by an infection, inflammation, etc.
In 2022 my PSA slowly started to increase with my new baseline under Avodart, had an MRI, and a transperineal directed prostate in the suspicious area in the transition zone, along with an additional core sampling in other prostate quadrants. The transition zone identified a 3+4 gleason grade which was identified on the MRI, and a small volume 3+4 in the peripheral zone, not identified with the MRI.
At that time I decided on Treatment at UCLA using viewray real-time MRI guided SBRT with SpaceOar.
In other words, I don't think it is a good idea to assume Avodart prevents or reduces a PCa.
As I mentioned before you might want to consider Decipher or another genetic test on the biopsy sample, especially the 4+3, to try and determine the actual risk.
I got very excited when I discovered two things a couple of months ago:
(1) DHT is the fuel that drives PCa growth, not testosterone itself, and
(2) Dutasteride 0.5 mg reduces DHT levels by approximately 95%, down to a median value of about 24 pg/mL.
These two factors, plus the dramatic drop in my PSA after starting Dutasteride, makes me think the tumor is shrinking. I guess we'll find out (along with a shrinking prostate) at the next MRI.
I just reviewed my 10 + papers about Dutasteride and found that there were varying degrees of the reduction in PCa risk, depending on the study:
ARIA (2004) N=4325 51% reduction in PCa risk;
REDUCE (2010) N=8231 23% reduction in PCa risk; and
CombAT (2011) N=4844 40% reduction in PCa risk.
The average of these three studies is 38% reduction in risk. That's impressive for a mono therapy. Plus, there are very few side effects of Dutasteride, and it's cheap.
Clearly, there are good statistics that Dutasteride monotherapy reduces prostate cancer. I'm not expecting a cure from Dutasteride alone, and plan on doing ADT (likely Estrogen patches). But, I'm happy that the PSA is falling quickly, for whatever the reason might be.
Your experience with Avodart appears to have been not very helpful, however. I'm sorry to hear that.
I'm posting a plot that shows a 50% reduction in DHT levels for increasing the daily Dutasteride dose from 0.5 mg to 2.5 mg, and a 70% reduction in DHT for a 5 mg/day dose. You may want to consider increasing your dose to 2.5 or 5.0 mg. Clark (2014) also reported that there were no significant changes in adverse side effects when increasing the Dutasteride dose to 2.5-5 mg/day.
I'm also excited about the possibility of combining Dutasteride with ADT. See my recent post on "Should Dustasteride dose be increased?"
I think Dr. Kishan has ordered the Decipher test, but I need to check with him.
My MO ordered the Artera.ai test a few weeks ago, and I hope to get that back soon. It will tell me if I'm one of the 66% percent of men who won't benefit from doing ADT.
I did do PROMISE gene testing and I have no gene mutations among the 30 or so genes that were tested, including BRCA 1/2.
Thanks for the stimulating discussions!
Let's keep in touch. I plan on doing SBRT with Barrigel spacer in 3-4 months. I have to have a low back fusion surgery in the next 1-2 months, and I don't want to start ADT and become osteoporotic due to low testosterone (which will cause the fusion bone graft to dissolve...that happened to me once before).
If you send me your PSA history, I'll make a nice plot for you!
If you are consulting with Dr. Kishan, that is the genetic test he goes with.
As for whether Avodart worked for me or not, I was on active surveillance since 2013 while on Avodart, so I wouldn't necessarily say it work. 9+ years on Active Surveillance isn't a bad thing. In fact, all the doctors I consulted with indicated that Active Surveillance was still an option. It was me that decided that it was time to treat when the Gleason grade upgraded happened.
Also, both Stuffy Myers, and Mark Scholz recommend the use of Avodart. I have been using Dr. Scholz for consultation since I first was Dx with PCa.
I think the most important thing any of us should do is get as much information to make an informed decision.
Sorry about your back situation. I will connect with you and send you my email. If you are seeing Dr. Kashan he will work with you.
I do plot of my PSAs through Excel. Before treatment my PSA was running 2.7 on Avodart. Right now the PSAs are currently .4 to .5 ng/ml. Dr. Kishan has told me it can take up to 5 years for NADIR to be reached.
Do you think there's any chance that the cancer will adapt to the lack of DHT at some point? Might it adapt the way it does to immunotherapy after several years?
Yes, PCa cells are sneaky bastards. After prolonged testosterone depravation, they mutate to generate their own DHT, create more androgen receptors (ARs), and other tricks to stay alive and proliferate. That's the basis of castration-resistant PCa (CRPC).
Fortunately, the 2nd generation anti-androgens like enzalutamide, apalutamide, and darolutamide are so successful...they bind to the androgen receptors and prevent DHT from binding to them. It's very clever!
The recent BAT protocol (periodic injections of high-dose testosterone every couple of months to reach super high T levels) + ADT is so successful. It "resets" the cancer cells back to their earlier condition where they are now sensitive again to Lupron ADT.
I've seen some papers that Dustasteride is effective at reducing G8-10 cancers. The reduction in PCa risk ranges from 23% to 51% (n=4500-8500 men) for all Gleason scores.
Selective pressure is why only the beneficial mutations survive.
If you deprive the cancer from DHT it will start growing again very rapidly if a mutation happen which can synthesize DHT.
Your point that the DHT will be blocked with darolutamide is also not totally correct because the drug will not pass the blood brain barrier therefore making your brain vulnerable to cancer spread.
But assume that you are successful with enzalutamide to stop binding the DHT to the cancer receptors and as a result you are depriving the cancer from food to grow than the cancer mutates to a neuroendocrine variant which could happen in 15 % of cases. I am not saying that enzalutamide is not beneficial but not always and enzalutamide is only more effective than Bicalutamide if the number of your Mets are low. If the number of your Mets are high than there is no difference in the effectiveness of enzalutamide and Bicalutamide according to the ENZAMET study. Therefore you have multiple limitations of the enzalutamide therapy.
"Inhibition of SRD5A to block the terminal step of the frontdoor pathway (conversion of T to DHT) has proven ineffective against CRPC."
I think that statement is based on one Phase-II trial by S. Shah, that, indeed, it did not show a big benefit for using Dutasteride in CRPC men (he is my Urologist, by the way...).
The plot I posted today refutes this conclusion. I'm reposting it here. Dutasteride appears to have significant benefits to men who have progressed past PSA Failure (presumably that are CRPC), in terms of increasing PSA doubling time by 2X, and increasing time to disease progression also by 2X. It's not a "cure", per se, but is palliative.
Inhibition of dihydrotestosterone synthesis in prostate cancer by combined frontdoor and backdoor pathway blockade
Michael V. Fiandalo,1 John J. Stocking,1 Elena A. Pop,1 John H. Wilton,1,2 Krystin M. Mantione,2 Yun Li,1 Kristopher M. Attwood,3 Gissou Azabdaftari,4 Yue Wu,1 David S. Watt,5 Elizabeth M. Wilson,6 and James L. Mohler1
"Androgen metabolism inhibitors, such as the SRD5A inhibitor, dutasteride, or the CYP17A1 inhibitor, abiraterone [7, 17], have been disappointing clinically. Dutasteride inhibited SRD5A activity [18], depressed T uptake and lowered DHT levels in vitro [19], but dutasteride proved ineffective against CRPC in a Phase II clinical trial [20]. CYP17A1 metabolized steroids, such as pregnenolone or progesterone to adrenal androgens, such as DHEA, that provided intermediates for the androgen pathways that generated T and DHT [21]. Abiraterone decreased intratumoral DHT levels [22], but abiraterone extended survival by only approximately 4 months [23]. CaP resistance to abiraterone presumably resulted from enzyme redundancy, progesterone accumulation that led to increased CYP17A1 expression and/or the generation of AR splice variants [24–27]. The need to produce an androgen metabolism inhibitor that performs better than abiraterone has become more important since abiraterone will become used earlier in the disease as a result of the demonstration of improved survival when used with standard ADT for newly diagnosed metastatic CaP [28, 29]."
The phase ii clinical trial which provides details that avodart is not effective (it was a small trial only 28 people). They concluded that further investigation is needed.
Phase II Study of Dutasteride for Recurrent Prostate Cancer During Androgen Deprivation Therapy
We determined the response rate to and safety of a dual 5α-reductase inhibitor, dutasteride, in men with castration recurrent prostate cancer.
Materials and Methods:
A total of 28 men with asymptomatic castration recurrent prostate cancer were treated with 3.5 mg dutasteride daily (luteinizing hormone-releasing hormone treatment continued), and evaluated monthly for response and toxicity. Eligibility included appropriate duration antiandrogen withdrawal, baseline prostate specific antigen 2.0 ng/ml or greater and a new lesion on bone scan, increase in measurable disease using Response Evaluation Criteria in Solid Tumors criteria, or 2 or more consecutive prostate specific antigen measurements increased over baseline. Outcomes were progression, stable disease, partial response (prostate specific antigen less than 50% of enrollment for 4 or more weeks) or complete response.
Results:
There were 25 evaluable men with a mean age of 70 years (range 57 to 88), a mean prostate specific antigen of 61.9 ng/ml (range 5.0 to 488.9) and mean Gleason score 8 (range 6 to 10), 15 of whom had bone metastases. Eight men had 10 grade 3 or higher adverse events using National Cancer Institute Common Terminology Criteria, all of which were judged to be unrelated to treatment. Of the 25 men 14 had disease progression by 2 months, 9 had stable (2.5, 3, 3, 4, 4, 5, 5, 8.5, 9 months) disease, 2 had a partial response and none had a complete response. Overall median time to progression was 1.87 months (range 1 to 10, 95% CI 1.15–3.91).
Conclusions:
Dutasteride rarely produces biochemical responses in men with castration recurrent prostate cancer. However, further study is warranted given its favorable safety profile.
Thank you. Excellent summary of Shah's paper (2009).
It's important to compare similar cohorts. His cohort was men with Advanced PCa, who were also doing ADT.
The normal range of DHT in men is 10-90 ng/dl. T normally ranges from 300-1000 ng/dl. So, DHT is roughly about 10% of T.
Men doing ADT would also be expected have a very low DHT level (for example If T drops from 400 to 40 ng/dl on ADT, then that's a 90% reduction). Therefore, DHT would have also been reduced by the same amount (a 90% reduction) from average of 50 down to 5 ng/dL.
For reference, men not on ADT, Clark (2004) reports that taking Dutasteride reduces DHT by 90-95% from normal levels (men withoutPCa).
So, adding Dutasteride to a man already doing ADT could further reduce DHT from 5 ng/dl down to 0.5 ng/dl, a very small absolute change of -4.5 ng/dl (when considering that the normal DHT level is about 50 ng/dl.
So, there was not much that adding Dutasteride could do to further reduce DHT below an already very-low, ADT level. And, that's what this study found...not much of an affect of Dutasteride on this group of men.
I'll see Dr. Shah in about 1-2 months, and we will discuss the recent literature about Dutasteride.
My own personal experience is with Dutasteride monotherapy (i.e. no ADT). I experienced a 70% drop in PSA after 3 months. I will retest PSA and DHT in 1 week, and then have a new MRI in 1 month. I expect the MRI to show that the initial 1.3 cm long tumor has now shrunk due to Dutasteride monotherapy.
The article by Fiandalo still refers primarily to Shah's (2009) paper. Fiandalo doesn't reference the ARTS trial by Schroder in 2012 that shows a significant benefit in delaying progression times of PCa by 2X using Dutasteride.
Do you have a link for the above mentioned information? I am interested in a inclusion criteria etc. Do you have also a link to the clinical trial which resulted with the above charts?
I would be interested in the overall survival data which can't be available for phase ii clinical trials plus the size of the study should be bigger.
The plot I posted today refutes this conclusion. I'm reposting it here. Dutasteride appears to have significant benefits to men who have progressed past PSA Failure (presumably that are CRPC), in terms of increasing PSA doubling time by 2X, and increasing time to disease progression also by 2X. It's not a "cure", per se, but is palliative.
Thank you for this posting, it's informative. What minimal side effects do you have being on this? Are you on any dietary changes such as a vegan diet?
FWIW- a good friend has for a couple decades taken Finesteride, his PSA was as high as 14 one time, then now that he is 80 his Dr. says just live his life. He has always been physically active, though not sure about the diet issue in his case.
He has good genetics, his parents lived long. He had it creep up years ago- in the 1990's I believe. Didnt do surgery, radiation, or anything but controlled it he told me using Finesteride it dropped down to something normal range for his age so I assume under 6.
I personally don't think that I could handle a drop in libido. The stress I have already is already enough change. The more I read this forum and the Mayo one, all the invasive procedures and treatments for this all of them are risky, and can really suck as far as quality of life. I just can't believe how awful this disease is and the side effects of treatment are- I had no idea until I started reading a few months ago.
I don't know about that treatment, first I heard of it- isn't estrogen going to reduce my libido ? I am now exercising and just started vegan diet (though it appears even vegan's get this disease), a non smoker, non drinker, lost 40lbs now good bmi, testosterone over 800 same time as my PSA test of 17. Maybe I might get lucky?
For me, the big question is: If the cancer could essentially be cured through using dutasteride and some other kind of treatment such as immunotherapy, radiation, or even surgery, is the root cause also extinguished? (I know the answer to that unfortunately.). So, how do we address the root cause???
I also have taken multiple genetic tests including Promise, All of Me, and others, and all show no genetic predisposition.
I'm also now a vegan for 7 years and do intense exercise, lead an overall low-stress life, etc
You're asking the fundamental questions of why a healthy prostate cancer cell turn cancerous. One factor is age...the older you get the more damage to DNA occurs, which ccumulates over time due to environmental exposure to toxins, pesticides, Diet, and exposure to natural radioactivity (including cosmic radiation and naturally-occurring radioisotopes in tobacco). I wish I had a better answer.
Another factor is baseline testosterone level. Low baseline testosterone levels when first diagnosed with PCa is associated with worse PCa outcomes. See attached plot. That could be a root cause (one of many).
Also, as you age, your SHBG levels increase, which means there is a decrease in Free PSA and Free testosterone available to do good stuff. Lower levels of % Free PSA / Total PSA is strongly associated with increased prostate cancer risk.
Doesn't sound like you smoke, which is good.
prostate cancer odds ratio multiplier vs Testosterone level (pre diagnosis).
Those are all good points. Thanks for addressing them.
No smoking for me ever! I've never been much of a drinker, but I've pretty much cut all alcohol out now. I've also increased my strength training routine so testosterone is probably increasing a bit while DHT is decreasing due to Finasteride. I will be discussing dutasteride with my urologist once I secure a new one.
Thank you for your comments. I'm not worried about the black label warning.
Many papers have debunked this unfortunate conclusion. As Mascouche explains below, two different "biases" are active and should be considered. Here are my personal remarks about the black label warning:
"There is a black label warning on Dutasteride (0.5 mg/day), because one study reported a small increase in the risk of having high-grade prostate cancer (i.e., large tumors).
I have two papers (there are many more) that debunk this report. They call for a removal of the warning label.
There are two different biases that caused the higher incidence of high-grade tumors.
One is a “detection bias”, that relates to the fact that Dutasteride shrinks the prostate’s volume by 25-50%. So, the probability of a biopsy needle increases as the size of the prostate decreases, assuming the number of tumors remain the same. One of the papers (Cohen, 2007) did a calculation of how much the probability of hitting a large tumor (high-grade tumor) increases when the prostate shrinks, and the calculation predicted the same magnitude of increase in the incidence of high-grade tumors in men on Dutasteride.
The other bias is a “diagnosis bias”. In a large study of Veterans at VA hospitals, they also found an increased risk of higher-grade PCa for men on Dutasteride. The explanation for the increased rate of larger tumor detection is related to the fact that the PSA drops by about 50% (or more) after a few months of being on Dutasteride. For some men, the PSA dropped below the threshold for getting a biopsy (e.g., PSA = 4). So, those men decided to not get a biopsy. But, some of those men eventually got PCa later on (as their PSA continued to rise even on Dutasteride.) The fact that these men weren’t screened (because of their low PSA values), meant that they eventually ended up with higher-grade (larger) tumors, as compared to men who got early screening. The paper by Sarkar (2019) explains this “diagnosis bias”.
Both types of biases explain why the black label warning was originally applied. But, the effect has since been debunked because of both the detection bias and the diagnosis bias.
Recent studies with large numbers of men support that Dutasteride reduces prostate cancer rates across all risk groups. These are:
I sent the following question to Microsoft's AI, Co-Pilot. Keep in mind that AI is sometime right but also sometimes so very wrong. Can't tell which it is for this one.
My question was to the AI was: What are your thoughts on prostate cancer cells only responding to DHT and not to testosterone?
Copilot's answer was:
***
Prostate cancer cells exhibit a fascinating preference when it comes to hormone response. Let’s delve into the intricacies:
Androgens and Prostate Cancer:
* Androgens, including testosterone and dihydrotestosterone (DHT), play a pivotal role in the development and maintenance of male characteristics.
* The prostate, a gland in the male reproductive system, relies on androgens for normal growth and function.
* Both normal and cancerous prostate cells express the androgen receptor, a protein that binds to androgens.
* When activated, the androgen receptor stimulates specific genes, promoting prostate cell growth1.
DHT vs. Testosterone:
* DHT exhibits a greater binding affinity for the androgen receptor than testosterone.
* Prostate cancer cells, in particular, have a penchant for DHT.
* Interestingly, some prostate cancer cells even acquire the ability to produce testosterone themselves. (See note1 at the end)
Hormone Therapy:
Hormone therapy (also known as androgen deprivation therapy) aims to disrupt androgen action.
By reducing androgen levels or blocking their effects, hormone therapy inhibits the growth of prostate cancers that are sensitive to androgens.
However, over time, some tumors become castration resistant, continuing to grow despite low androgen levels. (See note1 at the end)
DHT and Castration Resistance:
The progression toward castration resistance often involves the synthesis of DHT from 5α-dione, bypassing testosterone.
DHT remains the principal androgen bound to the androgen receptor in prostate cancer cell nuclei. (See note2 at the end)
In summary, prostate cancer cells exhibit a nuanced preference for DHT, emphasizing the intricate dance between hormones and cancer progression.
I've looked into the mention of Seasid about "This medicine may increase your risk of developing high-grade prostate cancer."
There is an article at ncbi.nlm.nih.gov/pmc/articl... but here is the conclusion: "This study confirms that finasteride significantly reduced the risk of prostate cancer; however, the malignant degree of prostate cancer was increased. Studies with larger sample sizes are needed to better clarify the correlation between finasteride use and prostate cancer."
Here is another at cancer.gov/news-events/canc... but here are two paragraphs from it: "What about the increased risk of high-grade cancer finding? Does the January 2019 study on prostate cancer-specific survival end the debate about that finding?
You are referring to the fact that, despite nearly 20 years of follow-up, we did not see an increase in prostate cancer mortality among men who took finasteride.
Due to the relatively small number of men who died from prostate cancer on both study arms, these findings probably won’t end the debate. But I feel they go a long way toward alleviating concerns regarding the potential of this drug to increase the risk of lethal prostate cancer.
So how do you explain the increased risk of high-grade disease reported in 2003?
There are two mechanisms by which we believe finasteride enhances the detection of high-grade cancer on prostate biopsy.
First, finasteride is known to decrease the size of the prostate gland by about 25%. When you biopsy a smaller gland, you are more likely to sample an area of cancer—or high-grade cancer—with your biopsy needle, compared to doing the same biopsy in a larger gland.
Second, as we showed in another analysis of the PCPT, finasteride improves the sensitivity of the PSA test for the detection of overall and high-grade prostate cancer. Because the decision to perform prostate biopsies during the study was based on PSA levels, this may have contributed to increased detection of prostate cancer, in general, and high-grade prostate cancer, in particular, among men receiving finasteride.
Due to the effects of this drug on gland size and PSA performance, it seems quite likely that the PCPT not only overestimated the harm of finasteride in terms of the observed increase in high-grade cancer, but may have underestimated the benefit of finasteride in terms of the amount of reduction in prostate cancer risk.
There are two mechanisms by which we believe finasteride enhances the detection of high-grade cancer on prostate biopsy.
First, finasteride is known to decrease the size of the prostate gland by about 25%. When you biopsy a smaller gland, you are more likely to sample an area of cancer—or high-grade cancer—with your biopsy needle, compared to doing the same biopsy in a larger gland.
Second, as we showed in another analysis of the PCPT, finasteride improves the sensitivity of the PSA test for the detection of overall and high-grade prostate cancer. Because the decision to perform prostate biopsies during the study was based on PSA levels, this may have contributed to increased detection of prostate cancer, in general, and high-grade prostate cancer, in particular, among men receiving finasteride.
Due to the effects of this drug on gland size and PSA performance, it seems quite likely that the PCPT not only overestimated the harm of finasteride in terms of the observed increase in high-grade cancer, but may have underestimated the benefit of finasteride in terms of the amount of reduction in prostate cancer risk."
Ok, I see. We don't really know for how much avodart extends survival and that would be very important.
Just a reminder that Abiraterone adds to survival only four months. That was enough for the FDA to approve Abiraterone.
After abiraterone failure enzalutamide would also fail shortly. The reason is cancer mutations as a result of abiraterone use.
I would be very reluctant to use avodart without more trials. If the use of Avodart results in cancer mutation and subsequent enzalutamide failure than it maybe not be worth the risk.
The results reported by Schroder (2012) show, for example ,doubling times increasing from 9 months to 18 months, a factor of 2X, by using Dutasteride for men who had RP or RT and are now experiencing PSA Failure.
From Schroder (2012):
"Dutasteride significantly delayed the time to PSA doubling compared with placebo after 24 mo of treatment ( p < 0.001). The relative risk (RR) reduction was 66.1% (95% confidence interval [CI], 50.35–76.90) for the overall study period. The Kaplan-Meier curves for time to PSA doubling began to diverge from approximately month 6, and the divergence between the two treatment groups continued to increase through to month 24 (Fig. 2). The incidence of PSA doubling over the 2-yr treatment period (based on ITT subjects with at least one post baseline PSA evaluation) was 57% (82 of 144 subjects) in the placebo group and 28% (41 of 146 subjects) in the dutasteride group ( p < 0.001)."
Also, from Schroder (2012):
"Dutasteride significantly delayed disease progression compared with placebo ( p < 0.001); the overall RR reduction in favour of dutasteride was 59% (95% CI, 32.53–75.09)."
Every man has to decide for himself what to do. Preferably, his decision is based on the best available data and not on untested theories, in general.
Recent studies with large numbers of men support that Dutasteride reduces prostate cancer rates across all risk groups. These are:
ARIA (2004) N=4325 51% reduction in PCa;
REDUCE (2010) N=8231 23% reduction in PCa;
CombAT (2011) N=4844 40% reduction in PCa.
The average reduction in PCa is 38%. That's a significant improvement!
None of these very large studies have shown any increase in PCa rates due to Avodart. If "Avodart results in cancer mutation", the data doesn't support this statement.
These studies are good enough for me.
Plus, my PSA has dropped 70% on Dustasteride monotherapy. That's consistent with the recent literature, especially Schroder (2012) and Obinata (2020).
Of course, there are some people who are non-responders (about 15-30% of men). The only way to determine if you are is do a trial of 3-4 months of Dutasteride and see if you have a strong PSA response (50% drop).
My oncologist keep saying that survival is most important. If abiraterone adds only 4 months than I am just wondering how much would Avodart add?
They should really conduct a proper trial before I would consider it to myself. I just know that that medication has a black box warning that it can result in high grade cancer.
Prostate cancer patients can benefit from 5-alpha-reductase inhibitor treatment: a meta-analysis
Tuo Deng # 1, Xueming Lin # 2, Xiaolu Duan 1, Zihao He 1, Zhijian Zhao 1, Guohua Zeng 1
Affiliations expand
PMID: 32547884
PMCID: PMC7271889
DOI: 10.7717/peerj.9282
Abstract
Background: The efficacy and safety of 5α-reductase inhibitors (5ARIs) in treating prostate cancer (PCa) have not been fully determined. We performed a meta-analysis to evaluate the effectiveness and safety of 5ARIs for PCa patients.
Methods: A comprehensive literature search of online databases was conducted to obtain comparative studies exploring the effectiveness and safety of 5ARIs in treating PCa up to October 2019. Summarized odds ratio s (OR s) or hazard ratio s (HR s) were calculated to compare the outcomes between 5ARI and control groups. Our meta-analysis was registered in PROSPERO under number CRD42018109809.
Results: A total of 2,277 patients from 10 studies were included. No significant difference was found in prostate-specific antigen progression between two groups (OR = 0.82, 95% CI [0.52-1.29], P = 0.40). However, 5ARI treatment significantly reduced the total progression of PCa (OR = 0.61, 95% CI [0.48-0.77], P < 0.0001), especially for patients with local (OR = 0.56, 95% CI [0.44-0.73], P < 0.00001) and low-Gleason score (≤7) PCa (OR = 0.63, 95% CI [0.48-0.84], P = 0.002). Additionally, 5ARIs also significantly prolonged the progression-free survival time (HR = 0.57, 95% CI [0.34-0.96], P = 0.04) for PCa patients. No significant difference was found in the occurrence of PCa recurrence, metastasis, biopsy reclassification, and side-effects between two groups.
Conclusions: Our study suggests that 5ARI treatment can benefit patients with local and low Gleason score (≤7) PCa, especially in delaying the disease progression. More studies with larger sample size and comprehensive study design are still needed to verify our outcomes.
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27 months post 39 sessions of EBRT and completion of 3 years of ADT my PSA remains at <=0.08
DHEA and Pregnenolone
