The paradox of testosterone and ADT

Yes. And my curious mind is searching for studies that show hormone resistance prior to ADT. If one has a very low (relatively) PSA of 0.33 (17 yrs post RARP) with a normal testosterone of 750 ish prior to ADT, is there a chance this particular cancer is already not tracking with testosterone? Might it be a mutation or have already become a neuroendocrine tumor by natural progression over those 17 yrs? Especially, given PNI from the surgical pathology? I find I just have more questions when the answers don’t quite fit.

We are in this window just before starting triple therapy most likely, so looking for some certainty prior to going down the slide, I guess.

I would need to modify this strategy our of fear of the consequences.

I don't remember seeing a post indicating what your T was prior to your enrollment in PCa Creative Writing 401 at U of T. What was it? This whole topic of tumor development in a low T enviroment is interesting.
Bill

This hypothesis posits that when a prostate tumor arises in a naturally low-testosterone environment, it may already be adapted to grow with minimal reliance on androgen stimulation. In such cases, administering androgen deprivation therapy (ADT)—the standard treatment aimed at starving the tumor of testosterone—could paradoxically backfire. Instead of suppressing the tumor, ADT may trigger an adaptive response, encouraging the cancer to further exploit alternative growth pathways it has already begun to utilize. This could potentially accelerate tumor aggressiveness, progression, and resistance, particularly by promoting neuroendocrine or castration-resistant phenotypes earlier in the disease course. Thus, in these patients, ADT might be not only ineffective but counterproductive. And my testosterone was below the minimum.

Interesting hypothesis. I posted earlier about low (ish) PSA of 0.33 seventeen yrs post RARP and no further tx. At PSA0.33, PET showed 3 nodules + ‘micronodules’ on lungs but no where else. High burdrn? Testosterone 745 pre ADT. I keep wondering if this ca has already transitioned to neutoendocrine and thus not dependant on T, or wouldnt PSA be higher? Hate to start ADT when the cancer isnt dependant on the T. I have asked why not further test the biopsy for androgen receptivity to be sure, but sounds like no further testing is being done. What are anyone’s thoughts on my thinking - am I way off or missing something? It seems like this cancer has had 17+ years to mutate already.

Seventeen years is a long time - anything can happen. But it’s not like your husband was on ADT all those years so why the castrate resistance?
True, it can happen all on its own but I’d be interested to see if the PSA drops - if and when- your husband is placed on ADT. If it does, he’s probably not castrate resistant.

@hanscasteels you have seen the radical thinking study out of Duke September 2024? It begs the question you are asking about tumors that may not take the testosterone track or how adding testosterone may confuse the tumor into submission in some cases. A paradox like fox in the chicken coop of ADT. https://medschool.duke.edu/news/study-solves-testosterones-paradoxical-effects-prostate-cancer

@heavyphil Thanks for the input and we are curious too. The eventual failure of ADT when the tumors become castrate resistant, along with side effects of ADT, urge us to question everything prior to swallowing the pills. What if the tumor seeds living in lung tissue all this time have mutated and are not reliant on testosterone? My hubs T has risen pretty significantly since the RARP (from 495 - 800) - is that coincidence, protective intention by the body? Why not test for androgen receptivity prior to ADT? I ask these questions here so those docs trying to care for my hub don’t show me the door!

Thank you so very much. It’s what I always had intuitively expected, but the local dogma treatment moron didn’t want anything to do with the hypothesis, probably because he didn’t know. When I brought it up again, just yesterday, he said that “it’s not necessary because there’s no evidence of that “. Of course there’s no evidence for “that” as he never attempted to establish that evidence. So his ignorance served as a basis for his decision. I need to go to a professional, not some moron who is determined to remain relevant by not being informed. Thank you again to send this link.

Prostate cancer patients — and their families — are being asked to make life-altering decisions based on protocols that often lag behind science, overlook nuance, and pretend complexity can be reduced to a flowchart. That’s why we need to get educated, not just informed. There’s a difference.

When a doctor says “ADT is the standard,” what they often mean is, “This is what we’ve always done.” But the biology of prostate cancer isn’t standard. It’s layered, unpredictable, and frequently resistant to the assumptions baked into many treatment pathways.

Why are we still treating every tumor like it responds the same way to hormone suppression, even when we know tumors can adapt — even thrive — in low-testosterone environments? Why are we not testing for androgen receptor activity before flipping the hormonal kill switch? Why do patients have to go digging through PubMed to understand what their care team hasn’t mentioned?

Because passivity can be dangerous.

Patients — especially those navigating advanced or recurrent disease — are not just recipients of care. They are collaborators in it. Or at least, they should be. The rise in testosterone post-RARP, the possibility of androgen-independent tumor clones, the very real psychological and cardiovascular toll of ADT — these are not abstract concerns. They are lived realities. They deserve more than a shrug and a standard-issue prescription.

So yes, we ask questions. We read the studies. We wonder whether the seeds hiding in lung tissue have mutated past testosterone dependency. We question the timing, the thresholds, the assumptions — not because we’re difficult, but because we’re awake.

If the professionals are truly committed to caring, they should welcome an informed patient. And if they don’t? Then it’s all the more reason we have to speak up. Before the side effects. Before the resistance. Before we’re told “this is just how it’s done.”

Because our lives — and our clarity — are on the line.

https://www.mdpi.com/2402756