Prostate cancer cells are said to be heavily influenced by T levels.
The literature says that even when one goes off of ADT, Testosterone will never return to normal or even near normal; usually it remains quite low versus normal if it rises.
So, if one's PSA has been low for a fair bit and one's T is low, what is the point of staying on ADT and continuing to expose oneself to the many potentially negative side effects of ADT and reduced QOL ???
Thanks for your input !
"The literature says that even when one goes off of ADT, Testosterone will never return to normal or even near normal; usually it remains quite low versus normal if it rises."
The best data we have tells a different story. There are two variables that determine what testosterone will recover to and how long it will take to recover:
1. T level at baseline (younger men usually have higher baseline T)
2. How long one was on ADT
"Overall, 87.4 % (167/191), 75.9 % (293/386), 54.8 % (181/330) and 43.2 % (80/185) of pts, recovered normal T on the 0-, 6-, 18- or 36-month schedule, respectively (p < 0.001). In patients recovering normal T, the median time to T recovery increased with ADT duration ranging from 0.31, 1.64, 3.06 to 5.0 years for the 0-, 6-, 18- or 36-month schedules, respectively (p < 0.001) and was significantly faster for those with a normal T at baseline (p < 0.001). On multivariable analysis, older age and longer ADT duration are associated with a lower T recovery."
thegreenjournal.com/article...
"So, if one's PSA has been low for a fair bit and one's T is low, what is the point of staying on ADT and continuing to expose oneself to the many potentially negative side effects of ADT and reduced QOL ???"
Low T is not at all the same thing as castration-level T (below 50, ideally below 20 ng/dl). Morgentaler showed that all androgen receptors are fully saturated at 150 ng/dl. So, low T does nothing but make you miserable, while castration-level T increases survival.
thanks for your usual quality help Tall_Allen ... appreciate you for how you give of yourself for all of us 
Thanks T-A!
Here is an interesting observation about the "saturation model". Saturation occurs, the model argues at around 200ng/dl (or 7nM) - correct me if I have got that figure wrong. So the argument goes that roughly above that level one should see no further cellular effect in PCa, but at much lower levels ie at castrate levels inhibition of PCa should occur. Which it does, but only for so long before ADT resistance occurs
Very detailed in vitro studies (and backed by animal studies) in Nature Comms (2018) "Androgen receptor monomers and dimers regulate opposing biological processes in prostate cancer cells", show that something interesting happens with higher doses of T.
At high doses (10nM and higher) the androgen receptor forms dimers or oligomers, these translocate to the nucleus where they inhibit cell proliferation and trigger return to a differentiated state. The mechanism of this effect seems to be that at high levels of T, heat shock proteins (chaperones) are released from binding sites on the androgen receptor allowing them to polymerise.
At very low doses of T this does not happen, the T receptor remains as a monomer within the cytoplasm and promotes cell proliferation.
In contrast PSA synthesis shows a straight dose response to T.
The work was carefully correlated with studies of the relevant metabolic pathways eg cMYC. I quote from their discussion:
The revised model of AR action we propose has significant implications with respect to strategies currently used to inhibit AR action in PCa. Notably, it suggests that the specific inhibition of the activity of monomeric AR is the optimal approach to block the pathobiological actions of androgen in PCa. The current approaches used to target AR signaling (competitive antagonists, PROTACs, CYP17 inhibitors, and GnRH agonists/antagonists) have the potential to effectively inhibit monomeric AR if they achieve absolute inhibition of the receptor. However, any monomeric AR remaining will be free to engage in the regulation of LD (low dose) biology. All existing AR-directed PCa therapies will disrupt the favorable activities of the dimeric receptor and would likely also increase the propensity for transdifferentiation of PCa cells to neuroendocrine prostate cancer.
The latter is exactly what we see in advanced hormone resistant PCa! The data bolsters the argument for treating with high dose T as a primary therapy! I have always wondered why PCa becomes more prevalent with advancing age just as T is falling and FSH is rising. Rather puts a question mark on the whole T hypothesis.
Take a look at the Nature paper, I would be interested in your thoughts.
Morgentaler found that saturation occurred at 120 ng/dl (4 nmol/L) in the healthy prostate. It is higher when the AR proliferates in PCa.
sciencedirect.com/science/a...
The Nature paper is just a lab study. In clinical trials, BAT prolongs Xtandi sensitivity (but not Zytiga sensitivity) in about ⅓ of men and accelerates or has no effect on progression in the rest. BAT trials have so far failed to extend survival.
It is well-known that hypogonadism is associated with increased PCa incidence.
Yes, as I said it is a lab study - so not sure why you are repeating this.
But in the lab one can, as the Nature paper does, examine mechanisms not accessible in the human and generate data and reveal mechanisms which challenge accepted models.
As far as I am aware the saturation model does not take account of what these data show namely that higher levels of T, although the receptor is fully saturated , trigger release of chaperones (HSPs) from the AR which allow dimerisation to occur leading the cell to change to a benign phenotype. This is an important observation which goes beyond the clinical BAT studies undertaken in late disease and has implications for treating early disease.
You say it is 'well known' that hypogonadism is associated with increased PCa incidence. However this 'well known' belief is now open to challenge. An international collaborative analysis of 20 prospective studies (12,000 controls, 6,900 cases) looked at this question and found low T was associated with lower risk of PCa. (Watts et al Low free testosterone and prostate cancer risk: A collaborative analysis of 20 prospective sudies.) They tested the hypothesis that the risk only appeared above a certain threshold of free-T, and that above that level there was no increase in risk with rising T levels (saturation model). That proved to be the case. BUT they did find a non-significant increase of high grade disease with low free-T. This may be a chance finding due to small numbers of these cases and multiple tests.
The same group, using the same population, and using combined genetic and observational data, showed that there is a dose relationship for aggressive and low level PCa disease with increasing levels of IGF-1, but no dose relation with increasing levels of T. (Watts et al Circulating insulin like growth factors and risks of overall, aggressive and early onset prostate cancer: a collaborative analysis of 20 prospective studies and Mendelian randomisation analysis. Int J Epidemiology 2023, 71-86
These are hellishly complicated studies involving Mendelian randomisation which I don't fully understand. But they do challenge the standard simple model - that T drives PCa.
The other wrinkle in all this is the clinical observation that in patients with prolonged androgen deprivation, in late hormone resistant disease, undifferentiated neuroendocrine prostate tumours may occur.
Anyway, can I ask if you have read the Nature Comms paper yourself? If not it is worth a look. The other two (I hope I have summarised them accurately) are also worth a read.
PS Another interesting review looked at whether testosterone replacement therapy in hypogonadal men was a PCa risk or caused disease progression and tentatively concluded it was not. However, there are no prospective controlled studies on this question. Michaud et al, Testosterone and prostate cancer: an evidence-based review of pathogenesis and cancer risk. Therapeutic adv. in Urology 2015, vol 7 378-387
PPS I am belatedly adding another thought. It is als an open question as to whether the sort of free-T doses used in these in vitro studies to achieve a suppressive effect might cause unacceptable side effects in humans eg liver toxicity.
I read it. In fact, I posted it above. I re-emphasized that it is only a lab study because many patients do not understand levels of evidence, and that changes in therapy should only be done based on high level clinical evidence. If there were clinical evidence then a lab study may provide a explanation. Contradictory clinical evidence supercedes any lab study.
This week, Nabid just presented his secondary analysis of his RCT. It showed that survival was almost twice as high in men who did recover testosterone after adjuvant ADT for high risk RT.
urotoday.com/conference-hig...
I was confused as my oncologist suggested after failed HIFU that turned out to be missed G9 but probably still localised (negative PSMA/CT and no SV evidence) that PORT + SV was best given my polio and wheelchair usage.
After 6 months of ADT my PSA was <0.01 after RT and my T was initially 17.5 ng/dl and then <14.5 (lab limit in U.K.) - I wasn’t happy with just 6 month of ADT as aware that 18 or if possible nearer 24 months for G9 was better SOC and having only had PORT +SVs. The logic THEY said (without having had a baseline T) that at my age 71 and my disabilities I probably would go 1-2 years before T recovery if not longer.
So I managed 2 months of bicalutimide with 19 months of goserelin - 17 were post end of RT. Tried to get oral antagonist but U.K. didn’t approve til few months ago.
Here’s the thing - at 3 months after the goserelin had worn off my T went f <14.5 (lab limit) to 23.1 and then at 6 months it was 81 whilst my PSA remained at the longstanding nadir of <0.01
Now this month - 9 months post ADT cover aged 74 (pretty low mobility so no exercise or all the stuff recommended but I just physically cannot do) my T is 461.5 but ( maybe nit surprisingly given to surge in T) my PSA is now 0.1. All this not what was predicted by my oncology team even though she wasn’t happy with my pushing on with the ADT over 12 months let alone the 6 months.
I feel slightly shaken by my T recovery (of course in other ways it has been better re QoL, as my other issues do limit what I can do so it’s nice to feel a bit more me - not that the ADT was as bad for me as many seem to report ).
The rise in PSA does however freak me a bit - but does the research suggest it positive re my rise in T curve?
As my prostate volume was only 28 at Dx pre HiFU and RT and I had NO urinary and have NO issues and no BPH - my argument is that there is likely very little healthy prostate tissue left so any PSA rise driven by T is more likely to be PCa especially as I had G9. The oncologist dismissed my concern and just stuck to the +2 above nadir as worthy of investigation or intervention. And also asking if I been taking replacement T !??? To which I replied - at this stage I would have been crazy and hadn’t.
So now reading all this T recovery trajectory and age and OSA which doesn’t of course mean BCR free survival - not sure if I glad or not that my T seem on an upward surge almost ! Good or bad as feeding the beast or … any help clearing my logic here ! ?
Yes, nadir+2 is BCR for RT. You still have lots of healthy prostate tissue putting out PSA. Enjoy the T recovery!
Doctorsceptic do you have a link to the discussion or study?
Hi. Which one are you referring to?
Doctorsceptic do you have a link to the discussion or study?
thanks so much Doctorsceptic ... supports my reasoning
Lupron itself has almost no side effects, it is the low testosterone and caused by that the low estradiol which cause the side effects.
How do you determine that Lupron has no side effects?
I wrote almost no side effects. At drugs.com I read regarding overdose of Lupron: "In early clinical trials with leuprolide acetate doses as high as 20 mg/day for up to two years caused no adverse effects differing from those observed with the 1 mg/day dose." This makes me believe the drug itself has low side effects.
T never returns to normal after ADT. So the goal is to keep it low or block it from getting to the cells.
I can only speak to my personal experience with the three different times I’ve been on ADT The side effects for me were interfering with my QOL. My Oncologist gave me me options to go on ADT vacations which I’m currently on a vacation now and have been for 14 months My PSA is slowly rising when it gets to .500 ( and this is not a typo) My Oncologist wants me to only have the Ultra Sensitive PSA test which is three decimals not two decimals so we can monitor the velocity more accurately. I will have another PSMA scan if anymore Mets are found then the plan is to use SBRT radiation on the Mets found and see if it slows my doubling velocity down which has been what it’s done each time. The plan is to get any Mets the scan finds SBRT and slow the doubling rate down until my PSA gets to a 3-5 dependent the doubling velocity then another PSMA scan and SBRT them and back on Lupron and Aberaterione/ Prendsione for 9-12 months then go on vacation and continue my monthly blood tests and wait for my PSA to come back. I know many people stay on ADT continuously but my Oncologist, my wife and I have chosen the vacation plan because when I’m on ADT the side effects are so severe that there is no QOL. Regarding the Testosterone ? Mine recovers back to normal within 4 months which for me is 400-600 every month. I’m not promoting vacations from ADT for everyone That’s a choice everyone has to make for themselves. The testosterone coming back is good and bad When it’s back to my normal I feel pretty good most days but on the months when it jumps from 400-600 my PSA goes up at a higher velocity which is not good but it’s worked for me for over ten years so I’m going to stay on my vacation ADT program till it stops working. Sorry for the long answer to your question but I wanted to answer you the best I could from my experience. I wish you all the best on this long journey
Thanks very much for this invaluable info. I will also consider trying this in the future. Right now I only just started the journey. I started Lupron 6 months shot in October last year and in January this year added Xtandi (Enzalutamide ) to that. Mets to bones and a couple of lymph nodes. Good luck and well done.
I'm pretty much where you are. My QOL was horrible on ADT , still is especially when Xtandi was added. It was during the plandemic that I missed my 6 month lupron injection due to my doctor's office being closed. ( Funny how covid could be spread everywhere but places like Lowe's and home Depot and big corporate stores).Anyway, I decided to see how long I could go. It took a year till I went past the 50 mark. But it did return. And so did my PSA ever so slowly. I may go on another vacation soon, I sure did feel good for a few months towards the end. I've been doing this for 14 years now. Good luck!
You have a comprehensive answer from talsllen.
I would add just this. ADT suppresses both T and estradiol (E2), the latter being synthesised from T. Some of the side effects of ADT - osteoporosis, cognitive effects, mood, metabolic syndrome are due to low E2 and reversed by transcutaneous E2. Sarcopenia is still a problem and E2 can cause some breast enlargement and weight gain.
It is worth considering the option of E2 patches as these are just as effective as ADT in depressing T (feedback loop) while avoiding some of the side effects plus QOL is reported to be better. Some of the data from the PATCH trial is published and full results expected second quarter this year.
I don’t have the references to hand but easy to Google.
Are E2 patches useable as QOL offsets during ADT?
Absolutely. Using E2 patches (or gels/creams) during Lupron ADT will:
1. Reduce or eliminate hot flashes;
2. Reduce or reverse osteoporosis and grow net bone;
3. Reduce blood glucose levels;
4. Reduce levels of bad cholesterol;
5. Increase levels of good cholesterol; and
6. Reduce fatigue, due to better quality of sleep from having reduced or eliminated hot flashes.
Downsides of using transdermal E2 are gynecomastia, mastalgia, and nipple sensitivity; as well as skin dermatitis due the the adhesive in the patches for a small percentage of men.
While E2 patches are not a Standard of Care for treating Prostate Cancer (i.e., high-dose E2 for replacing Lupron ADT), it's FDA approved for post-menopausal women for treating their hot flashes and osteoporosis due to very low estradiol levels after menopause.
Are E2 patches useable as QOL offsets during ADT?
Good question.
The data from PATCH trial is that E2 is a good substitute for ADT ie gives the required T reduction and same clinical outcome/PSA reduction, while compensating for at least some of the unpleasant side effects of simultaneous T and E2 reduction by ADT. Important to emphasise that monitoring of hormone levels initially to get dose right is important.
So we need to watch this space because although E2 is not yet standard of care it soon will be. I know that the Marsden is putting it on their formulary and that UCL is using it. If my consultant balks at E2 patches in April (when I am almost certainly due to restart ADT) I shall ask her to send me to UCL.
I would be encouraging your oncologist to read the data available as they ought to be interested and on the ball.
Best wishes
Great comments. I hope you are right that it will soon be SoC. I fear, however, that it may take a few years to be fully accepted. Prof. Wassersug and I are pushing hard to get it accepted as SoC, but it's slow going. Thank you for your support!
What is "UCL" ?
thanks for the valuable info Doctorsceptic
thanks Doctorsceptic
A fine point to Tall Allen's excellent reply.
The "saturation level" of Morgentaler's model is closer to 200-250 ng/dl, not 150 ng/dl (although it's not a sharp transition, but, rather, a smooth rollover who's precise "saturation point" is somewhat subjective).
I just finished a 6 month course of Orgovyx, but since I have hypogonadism I have started doing testosterone replacement therapy (TRT). I will monitor my PSA and T every 1 month for 4 months, and then switch to every 3 months if stable. I also had SBRT radiation therapy, and my PSA is < 0.02.
You might be interested to read my comments to Talallen.
No. Morgentaler said T saturation in healthy men was 120 — but lots of variance.
Bubbasurf6
Thanks for the informative post.
I am still on the first round of ADT. The MO says it will last for 2 years after the end of Radiation. So about a year from now "We" have to make a decision. No preconceived notion of what that path will be, however posts such as yours are information
PSA has been undetectable since Feb 2024, and T has been at 7.00 ng/dl since the same time.
Best wishes on your Journey ( I have started calling it my adventure)
My response is a bit simplistic. I am on both Lupron 6 month and Erleada. Side effects for me are mainly some muscle loss (Rambo won’t return my calls) and hot flashes which vary in intensity. Keeping active, eating well and telling bad jokes have helped. I realize that many people have worse symptoms but I am focused a bit on avoiding/delaying chemo which this SOC strategy seems to do. Some people do vacations which seems to have some QOL benefits as long as you are closely monitored. Good luck!
’The literature says that when one goes off ADT, testosterone will never return to normal or even near normal’.
There is a lot of ‘the literature’ out there that is wrong. This is why we are encouraged to learn how to interpret data and learn all we can.
I was stage T3C. Testosterone was 700 at diagnosis and returned fully after18 months on ADT. It is not rare. Many men have full return. Absolutely true that many have partial or none.
As has been said, likelihood of T recovery is strongly influenced by age, baseline T, and time on ADT.
I would add to this overall health/biological age. For if chronological age is a factor, then it follows.
This is pure speculation, but being as fit and strong as possible, preferably with no co morbidities, is an advantage in many areas not yet proven. T recovery after ADT is quite likely one of them.
What's the point of staying on ADT?
Is that the question?
I'll answer with a question!
Why did you or would you use the ADT in the first place?
It really is that simple...
Or are you looking for that Unicorn? Needle in the haystack?
Good Luck & Best Regards
to go on ADT is because it will reduce the PSA to nondetectable for four last 10 years The ultra sensitive PSA test is detectable at anything over 0.015. I don’t understand the unicorn question what do you do if you don’t do ADT.
ADT does nothing to PSA, you don't treat PSA. ADT shuts down Testosterone production. ASRi shuts down cell receptors for the rest of the Testosterone that's floating around as nothing lowers T to zero.
My question was to the OP, is he wanting to chase Unicorns? Or a needle in a haystack because there are no mysteries to this. The use of ADT and it's effects are known, charted and recorded across years and thousands upon thousands of patients.
Why DO you do if not ADT? Good question... There are alternate methods for PCa control. Question is, does the OP meet the patient profile that would benefit? Or even if not, would he then want to risk chasing the unknown for a chance at obtaining results not entirely expected?
Using SOC will get you to a certain place ... Again, the use of ADT has its benefits and also it's detriments. Most chose to use it, because the benefits outweigh the potential downsides. But not for all, some suffer very badly on ADT and are forced to change direction, use an alternate path.
I'm any event the OP wants to know about the return of Testosterone and the potential results of doing so. Bottom line is nobody can tell him what will happen. Nobody... He just has to decide what it is he wants to do!
ADT for 9 mos. Miserable experience. T was <50. Prior to treatment, 250s. After 1.5 yrs, T returned and is currently 350s. Go figure.
Good luck to you,
EdinBaltimore
I was diagnosed with metastatic PCa in 2009, and treated with surgery, radiation, ADT, and Provenge. (This is in my profile.) My testosterone and PSA have been undetectable since 2019, when I stopped all my cancer drugs. I had a clean PSMA PET scan in 2023. My new Johns Hopkins oncologist has recommended testosterone supplementation.
I am very excited and somewhat terrified, but I am going to try this. I'm hoping for better QOL, as well as not dying.
Being metastatic usually means no surgery. Can you tell more of your story and why had surgery,
Before surgery I had had a bone scan which did not show any metastases, but, after surgery, when my PSA went up, it turned out I had a single, distant, met.
Ah I see. Continued good luck
I've been on TRT for about 8 weeks now. I started weekly injections around mid-December.
We did a T/PSA test at about 2 weeks, and my T had gone up to around 440, PSA remained low (0.09). A second T/PSA test at 6 weeks showed T up to 541, and PSA up a bit to 0.23 - a number I was very familiar with - since that was the level when I initially recovered my T level naturally... but then my T cratered (170) which is when we started talking about TRT.
I really started feeling the effect of a reasonable T level after about 5 weeks of T shots. It took that long - but I feel much more active now, and at 8 weeks my leg and walking difficulties are slowly improving.
The paper referenced above, urotoday.com/conference-hig... has a conclusion that I appreciate:
"Dr. Nabid concluded that in high-risk prostate cancer patients treated with long-term ADT plus radiotherapy, testosterone recovery to normal levels is associated with a significant improvement in overall survival."
The bold "normal levels" is the point - the TRT goal should be to bring the patient's T levels to a level that would be considered normal. In my case, at my age, anything above 300 is considered "normal". 400-500 is wonderful (last test had it at 541.)
So for the patient doing TRT after concluding radiation and ADT - it appears this can be a case of having your cake and eating it to.. bringing T back up to normal levels appears to lengthen lifespan rather than reducing it. A win IMHO.
Story similar to yours, but with a shorter timeline. Surgery, radiation, triple therapy and undetectable PSA for >2 years. Solitary met successfully treated with SBRT. T never recovered after one year on Lupron. My JH oncologist has recently put me on TRT (through an endocrinologist). The change in my overall well being on T is night and day.
Thanks for letting me know! I'm reassured and excited by your story. I think the JH oncologists are more adventurous than most.
I don't know what the literature says, but my experience was different than that. After 3 years on Eligard, T level was around 20, no PSA. Went on a vacation. After 3 months T level was unchanged. At 6 months, T level was 770. At 9 months it was a little over 1000. I did not do anything to try to boost T levels, this is just what happened when I stopped ADT.
PSA increased over that time from < 0.04 to about 1.15. at that point I did scans. Did some spot radiation and re-started ADT. T leel is back to 19 ans the PSA is back to <0.04
Nous, here are some discussion Links that I made comments on regarding this subject...may not be spot on your question, but there is enough that treats your concerns. 30% of men suffer w their post ADT and for them TET does not return...otherwise its more complicated than you present. Take a look...TNX Rick
healthunlocked.com/advanced...
healthunlocked.com/advanced...
Your thoughts on getting off ADT while staying on AR inhibitor?PLEASE HELP ... REALLY NEED YOUR INPUT ... THANKS !
I am livid, confused , worried and scared as hell that my ORGOVYX -ADT symptoms are mine for life. 
YOUR ADVISE RE WHEN DO I GO ON CONTINUOUS ADT VERSUS INTERMETTENT ADT?
Need input on ADT, Brachytherapy, etc.
