This plot compares prostate cancer specific mortality probability versus time for two different levels of testosterone: Low and Normal. The low testosterone has a median value of 162 ng/dL [120-236] and the average normal T = 680 ng/dL. The cohort is 58 men with unfavorable intermediate risk who underwent RT and 6-months of ADT.
The important takeaway is that having a low testosterone (T < 280 ng/dL) after completing ADT is associated with extremely poor survival outcomes.
One thing men in this situation can do is supplement their Post-ADT testosterone to get it back to normal levels as quickly as possible.
While I like the implications of this study for my personal situation.
One could also conclude that those with very aggressive cancers GL 9 - 10 would have quicker regrowth of cancer and hit failure earlier before Testosterone has had a chance to reach a higher number. Especially for a 76 year old who may not recover to pre DX "T" levels for as long as they had been on ADT (30 months in my case).
My concern is all they have measured is the aggressiveness of the individuals cancers.
Highest Gleason score
8–10 (n, %)** 6 (54.5% ***** 12 (25.5% 0.04
7 (n, %) ** * 5 (45.5%) ****20 (42.6%)
≤6 (n, %) *** 0 (0%) ***** 15 (31.9%)
Median survival time (IQR, years) 4.06 (3.28, 8.45) 7.55 (3.96, 15.05) 0.046
Your long ADT predicts a very long T-recovery time, close to 60 months (see plot).
Have you considered doing testosterone supplementation to raise your T back to normal levels? Doing that appears to be very protective, based on this study.
I wouldn't do T supplementation because it incures "laziness" to the body. Since there is going to be exogenous T supply why bother with endogenous production. The same is very clear with kidney's disfunction. As soon as the patient starts dialysis any residual kidney function ceases.
April 2015 diagnosed with Immediate Bilateral Orchiectomy
May 2015 HEMI- CRYOABLAION of GL10 right half followed with IRE in left half plus immuno-injection by Dr. Onik of Opdivo+Yervoy+Keytruda in situ right half
January 2016 as/Dr. Onik begin bi-weekly Cypionate Injections brings T>1,600ng/dL down to 500+/- before next injection
Followed PSA with my own BAT approach as PSA rose and dropped, when stopped injections having T<2.5ng/dL
April 2018 minor GL6/7 recurrence left side treat IRE.
After treatment back on *T*
2024 - PSA .19 to 3.0 to 6.0 in 3 months, PYLARIFY PSMA PET/CT finds spots in Left side ONLY
STOPPED *T* and in 2 weeks PSA <3.0 with *T* =39ng/dL, HAD biopsy with 3 - GL3 +3 spots so watching PSA as I remain OFF *T*
NOTE --- T will be tested soon and should be <2.5ng/dL but feeling better now than when on *T* and it was up to 1,600ng/dL
I wish I knew. Ive been looking for an explanation, but can't find any.
Castrate-Resistant PCa have a ton of changes/alterations/mutations that make them castrate resistant. The testosterone effect on mortality is just one aspect of a very complex system.
I'm trying to understand this. So, this is the PCa mortality rate where time = 0 represents the date of measured PSA failure, correct? So , to look at the whole picture from date of RT treatment, there is zero mortality for the x months from treatment to PSA failure, correct? To make it more meaningful, how many recovered to normal T at date of PSA failure?
I'm having a difficult time accepting that men need only boost their T post treatment and pre-recurrence, and that will lead to incredibly better survival times??????? Or am I reading these results incorrectly?
It's a fascinating result, and seems to be consistent with the successful BAT treatment protocol.
I agree with you th it would be very interesting to know what the T-level was at date of PSA failure. Probably it ranges a lot, depending on age, original baseline T level, duration of ADT, and possibly fitness level. Lots of factors could influence this.
What's the harm of raising T after becoming castrate-resistant? I'd like to see data that says higher T after PSA failure causes reduced mortality.
All of the data I've seen indicates that higher T is associated with improved outcomes after becoming castrate-resistant.
Here’s one interpretation: patients who had successful RT and ADT treatment were able to discontinue ADT, explaining why their T stayed normal.
Those whose RT/ADT treatments were less successful needed to stay on ADT, explaining their low T levels. There was a higher mortality rate in this group.
You may be right...that's a interesting working hypothesis. Perhaps these results will cause more researchers to study this unusual effect. PCa behavior is complex, for sure.
For the first two years, the plot shows the mortality rate was identical (and equal to zero) for the two groups (Low or Normal T). Most men would have recovered their baseline T over this time period. The plot shows that Normal T-levels after recovery from ADT are associated with better outcomes, compared to Low-T after recovery from ADT. But, they didn't explain why this happens.
We know that Artera.ai tests predict that 66% of men will not respond to the beneficial effects of doing ADT. That may be a factor here.
You are correct about correlations. I'm trying to use the word "association" instead of "causation" or "correlation".
I am a bit confused, Thought goal of us not curable was very low T as this feeds the cancer. Does this study infer supplementing T would help men on forever ADT?
This is the basic idea of the BAT therapy for treating castrate-resistant men. Periodic high doses of testosterone causes the cells to "reset" and become castrate-sensitive again. At least, that's the theory of Dr. Denmeade at Johns Hopkins University.
I think the answer to your question depends on if the patient is castrate-sensitive or castrate-resistant (which happens later in the progression of the disease). For the first group, castrate-sensitive, men respond very well to ADT, which lowers the testosterone down to castrate levels (T< 50 mg/dL). So, in this regime, lower T is protective and improves outcomes (for example, PSA recurrence).
In the second group, castrate-resistant (CRPC), the data shows that (1) doing ADT is ineffective in this regime, and that (2) higher T is associated with better outcomes. Something is very different about PCa cells that have become castrate-resistant. More study is needed to explain "why" this happens.
As to your question, if you are on "forever ADT", the assumption is that you are still castrate-sensitive. In this first regime, lower T is much better than higher T. So, supplementing T would not make sense while you're on ADT.
I agree it's confusing, and that many doctors aren't aware of these recent results.
Adding-back estrogen patches or creams/gels would help to reduce the bad side effects of forever ADT, and would help to keep the T-level below castration levels (50 mg/dL), as an extra benefit.
Thank you, that was a big help!!!!!! I am informed I am castrate resistant. I guess I meant I will forever be on treatment. Don't have many side effects currently. In an odd way this seems Zytiga failed after 2 years and Xtandi in 10 months, Doc seeking "trial" Have appointment next Thursday
The "old" science is still good for castrate-sensitive men. In this regime, lower T gives improved survival outcomes. This is the well-established basis of doing ADT (Lupron and/or Estrogen). That's what Huggins discovered in 1941.
But, in the subsequent castrate-resistant regime (after PSA failure), the opposite becomes true. Here, lower T is associated with worse survival outcomes, not better. Morgentaller talks about this in many of his papers, and the data from Atkins (2018) supports this (see my recent postings).
I began with perpetual ADT with immediately having a bilateral Orchiectomy so there's never a vacation from ADT but was prescribed Cypionate bi-weekly injections after treatment and can vary my *T* > 1,600ng/dL after injection to *T*<2.5ng/dL when holding off and unlike most I am remaining HORMONE SENSITIVE by experimenting with my own BAT Protocol.
Thanks for the additional context. I believe (based on my extensive research and the opinion of my three urologists) that T supplementation post prostate cancer surgery (Tulsa Pro, 2019) was and remains very appropriate, for me. I also believe that the “T stokes the PC fire” thesis is often wrong, at least again, for me. However, you and many others in this Forum are far better educated than am I, on this subject—I would simply encourage those who are reading this and other posts to, in Reagan’s term, “Trust but verify…..”. Thanks again….
Studies like this should inspire additional research into the topic. There's lots of data out there for someone to study. It would be an easy study to conduct.
@janebob99, thanks for the interesting data. Along the lines of your graphs, I just finished reading a book by Freidman, The New Testosterone Treatment. The theories in this book are drawn from meta analysis. He concludes that it's the presence of excess aromatase (which converts testosterone into cancer-causing estradiol) that is the culprit. Testosterone is capable of killing prostate cancer and needs to be boosted, but block its conversion to estradiol via aromatase inhibitors. He presents several theories, but introduces his model for as the Hormone Receptor Model as the root cause of prostate cancer. If you have not, I highly recommend you read it with your analytical skills.
I would beg to differ on his assertion about "cancer-causing estradiol", though. That may be true in women, but not in men, I believe.
Huggins won the Nobel prize in 1966 for his discovery that estrogen effectively chemically castrated men. Estrogen therapy was the Standard of Care from the 1960's to the 1980's. It worked, and it worked well (except for causing blood clots)
I believe that the effect of testosterone on PCa flips between castrate-sensitive men and castrate-resistant men. For the former, very low testosterone (castration) is associated with greatly improved survival outcomes. For the latter, in castrate-resistant men, the opposite statement appears to be true. Here, higher levels of testosterone appears to be protective. (as the top plot shows).
I believe that the 10-year outcomes from the phase-III PATCH study will contradict his "cancer-causing estradiol" theory.
From what I've read, many patients that are on TRT being prescribed testosterone have also been prescribed an aromatase inhibitor such as Arimidex or Anastrozole with a goal of suppressing estradiol levels into what are considered more normal ranges between 10 and 40 pg/ml.
Under ADT, we stop our Testosterone, shutting down estradiol at the same time. So how do we know for sure if the regression in cancer while under ADT is due to the lowering of testosterone or if it was due to the lowering of estradiol as a side-effect of lowering the testosterone?
If Testosterone was the sole culprit for prostate cancer, it would seem to make sense if that condition hit young men with higher Testosterone. But it typically hits older men, at a time where Testosterone is low enough to cause an imbalance of ratios between itself and estradiol.
You might like this link that ties higher Testosterone to higher health. It's title is "Higher testosterone and testosterone/estradiol ratio in men are associated with better epigenetic estimators of mortality risk" at ncbi.nlm.nih.gov/pmc/articl....
Maybe lowering only estradiol might not carry as many side-effects as lowering testosterone itself?
The good news for those not on ADT is that there are also natural aromatase inhibitors that can lower estradiol. If you eat more cauliflower, broccoli, cabbage, and Brussels sprouts, you will have higher levels of calcium D glutamate and diindolylmethane, which will naturally counter estrogen dominance.
Turmeric, Pomegranates, Green tea are other foods that naturally reduce estrogen levels.
And you can also try to avoid environmental sources of estradiol. Store food in ceramics or glass and avoid using plastics as much as possible. If you ever use plastic, avoid heating them in the microwave, even if they are made to resist the heat. Choose a soap and shampoo with natural ingredients. Don't drink bottled water that use plastic.
I have heard of one individual that theorizes that high estrogen causes PCa. But, if that was true, the Phase-I, -II, and -III PATCH trials comparing Lupron ADT to high-dose estrogen would have been stopped early on due to poor outcomes. But, these studies of transdermal estrogen patch therapy have been going on for over 20 years (since 2004),with very favorable results.
In fact, estrogen has been used for over 84 years, since 1940, to chemically castrate men and reduce PCa, after being discovered by Huggins and Hodges in 1940. Attached is a 1-page summary of the past 84 years.
Estrogen works by supressing the LH and FSH hormones that stimulate testosterone production from the testes. In that respect, it is identical to Lupron ADT (but without the bad side effects of Lupron).
It could a just a matter of ratio such as the following theory which I am pulling out of nowhere and should be not be considered as accurate. If it is accurate, it is pure luck.
* If T levels are much higher than Estradiol, such as when you are younger, then the body's environment is not conducive to prostate cancer appearing.
* If T levels are not much higher than Estradiol, such as when you age and are generating too much Estradiol because of the plastic and other contributor, then the body's environment becomes conducive to prostate cancer appearing.
* If T levels are much lower than Estradiol, such as when you use Estrogen as ADT, then you testies become non-functional and T becomes suppressed.
Again, I want to say that while the above looks logical to me but this is not based on some research I came across (unless it is my subconscious bubbling forgotten memories to the surface of my mind).
The ratio of T/E2 remains essentially constant at a given age. If I double T, then I double E2. See attached steriodgenosis figure.
As you age, the T/E2 ratio may change if the amount of aromatase enzyme changes accordingly. I haven't looked up how T/E2 changes with age, but I'm sure it's been published.
We also know that SHBG proteins increase as you age, which directly affects the ratio of Free T to Total T (and, likewise for Free E2 to Total E2 ratio, and Free PSA to Total PSA ratio).
Rising SHBG may also affect the level of aromatase enzyme (but I'm just speculating here). Perhaps more SHBG reduces the amount of aromatase available??
The amount of fat in a body also affects how much estrogen is stored. So, the T/E2 ratio likely depends on BMI (for a given age).
When on high-dose estrogen therapy, the level of T is reduced to very low levels, and E2 rises to the level of a pre-menopausal woman. So, you are correct that "T is suppressed" when on high-dose estrogen therapy. That's the principle behind the 15-year PATCH study.
We also know that the risk of getting PCa increases dramatically as you age (over 60 y.o).
It's all very interesting. We are chemical factories (as my RN wife says).
Yes we are indeed. Even more so for women as their factories have to deal with a higher level of monthly hormonal fluctuations than w do. Because of ADT, we here have had a little taste of what women go through their whole adult life and I have to admit that they have it much harder than we do.
I just asked about "Do you have a chart of the ratio of Testosteron and E2 across age?". Here is the answer it gave:
The testosterone to estradiol (T:E2) ratio is an important parameter related to male sexual function. Let’s explore this ratio and its variations across different age groups:
***
Normal T:E2 Ratio:
* The normal testosterone to estradiol ratio can vary depending on factors such as age, sex, and overall health.
* In men, a typical ratio is often considered to be around 20:1 to 30:1 (testosterone to estradiol) 1.
Testosterone Levels by Age:
* Testosterone levels can change with age. Here are approximate reference ranges for total testosterone in men based on age:
The balance between testosterone and estradiol is crucial for male health.
Low testosterone and elevated estrogen have been associated with increased incidence of erectile dysfunction.
Researchers have studied the T:E2 ratio in relation to chronic heart disease (CHD) and found that it plays a role in modulating the effect of androgens on CHD in males 3.
Low T:E2 ratios in patients with atherosclerotic disease were associated with increased systemic inflammation and an elevated risk of future major adverse cardiac events (MACE) 3.
****
Then I asked it a follow-up question since it did not how the estradiol levels in its answer. The follow-up was: "I want to see the estradiol levels in men by age" The answer was:
***
Certainly! Let’s explore the estradiol (E2) levels in men across different age groups:
1- Prepubescent Males:
Estradiol levels are typically undetectable to 13 pg/mL 12.
During this stage, estradiol plays a minor role in male development.
2- Pubescent Males:
Estradiol levels increase during puberty.
The typical range for pubescent males is undetectable to 40 pg/mL 12.
Estradiol contributes to sexual maturation and bone health.
3- Adult Males:
In adulthood, estradiol levels remain relatively stable.
The average range for adult males is 10 to 40 pg/mL 12.
Estradiol continues to play a role in maintaining sexual function and overall health.
4- Clinical Significance:
While testosterone naturally decreases with age, estradiol tends to increase slightly.
Abnormally high estradiol levels can be a risk factor for conditions such as diabetes and certain forms of cancer 1.
Symptoms of elevated estradiol include infertility, gynecomastia (excessive breast tissue development), and erectile dysfunction 1.
I also asked the AI: "How can I increase my T:E2 ratio naturally?"
Teached me nothing new but in case it is useful to someone, here is the answer:
***
Certainly! Increasing your testosterone to estradiol (T:E2) ratio naturally involves several lifestyle adjustments. Here are evidence-based ways to optimize this ratio:
Exercise and Lift Weights:
* Regular exercise, especially weightlifting, can boost testosterone levels. High-intensity interval training (HIIT) is also effective 1.
* Aim for a combination of cardiovascular exercise and resistance training.
Nutritious Diet:
* Protein: Adequate protein intake helps maintain healthy testosterone levels and supports fat loss.
* Healthy Fats: Include healthy fats (like avocados, nuts, and olive oil) to support hormone balance.
* Balanced Diet: Opt for whole foods with a balance of protein, fat, and carbs 1.
Vitamin D:
* Ensure sufficient vitamin D levels. Sun exposure and dietary sources (like fatty fish and fortified foods) can help 1.
Minimize Stress:
* Chronic stress can negatively impact hormone levels. Practice stress-reducing techniques such as meditation, yoga, or deep breathing 1.
Avoid Estrogen-Like Chemicals:
* Limit exposure to endocrine-disrupting chemicals found in plastics, pesticides, and certain cosmetics 1.
Quality Sleep:
* Prioritize sleep. Poor sleep can affect testosterone levels 1.
Consider Supplements:
* Some supplements, such as zinc, magnesium, and ashwagandha, may support healthy testosterone levels 2.
Remember that individual responses vary, and it’s essential to consult a healthcare professional for personalized advice. Lifestyle changes, along with professional guidance, can help optimize your T:E2 ratio naturally.
I'm just learning about this stuff. It's very complex.
But, I am curious why you are still doing ADT if you're castrate-resistant. Why have all the bad side effects of low testosterone if it's not doing anything for you??
Is your PSA rising?
Does a MRI show a growing tumor?
Do you have METS elsewhere. PSMA-PET scan result?
You might be a good candidate for BAT therapy, or, at least, moderate Testosterone supplementation. Especially since you are castrate-resistant.
If you were still castrate-sensitive, then doing ADT would make sense.
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After bicalutimide and a high testosterone level is pre treatment T just guess work?
Low Testosterone After ADT
Post radiation and low(er) testosterone
Very low testosterone after ADT not rebounding after 8 months post treatment
