I found this report and I thought it will be a good idea to share it with all of my friends here:
[[While it would have been unthinkable to give T to men with PCa not too many years ago, this is part of the cutting edge research currently in progress. An in vitro study showed that supraphysiological androgen levels induce cellular senescence in human prostate cancer cells [38]. The researchers used R1881, an androgen which cannot be converted to estrogen. This demonstrated that senescence was caused by androgen receptors and not estrogen receptors. Phase 1 trials were done in which T was administered to men with early-stage CRPC. In one study of 15 men, one patient showed symptomatic progression and three patients experienced drops in their PSA [39].
The study concluded that high dose exogenous T could be safely administered. Another similar study came to the same conclusion, with 7 out of 12 patients observing some drop in PSA, although many of the patients were treated with different doses of T and for different durations [40]. A different study analyzed the effect of T on men with low T and early-stage PCa that had no previous treatments performed. If T fueled PCa, then some of the patients should have experienced rapidly growing PCa, but none did. In fact, the 13 men who were treated for an average of 3.1 years had an average decrease in their PSA by over 33% [41].
These experiments demonstrated that the old beliefs about T were wrong, but they did not point the way to how T might be used as a treatment option. The most important thing to consider when using T therapeutically is that there must be a relative balance between the iAR and the membrane androgen receptor (mAR) in order for PCa to grow [42]. This is because mAR downregulates AS3, upregulates bcl-2 but upregulates proapoptotic proteins even more, with T and DHT binding equally well to mAR. Apoptosis occurs in the presence of mAR agonism with no iAR agonism [42]. On the other hand, iAR upregulates AS3 and downregulates bcl-2 as well as the proapoptotic proteins upregulated by mAR [14].
This means that if there is iAR agonism with no mAR agonism, then, in theory, the PCa should be unable to proliferate. In practice, when the LNCaP cell line was modified to have the ability to grow in very low levels of androgen, it resulted in the amplification of iAR by at least 10-fold. This new cell line, named LNCaP 104-R2, could not grow in the presence of T, but could grow in the presence of T plus finasteride [43]. Finasteride is a drug that inhibits 5-reductase (5AR) type 2, which is an enzyme that converts T to 5-dihydrotestosterone (DHT). In the prostate cell, T is almost always converted to DHT by 5AR type 2 and DHT binds to iAR approximately 5 times more strongly than T does [14]. Therefore, even though there is some agonism of T to mAR, with T and DHT having equal agonism to mAR [42], there is much more agonism to iAR because of its amplified number. This imbalance results in mitosis being prevented, presumably because sufficient AS3 is being upregulated. When finasteride is added to prevent the conversion of T to DHT, this reduces the agonism to iAR 5-fold. Although there is still more agonism than normal of iAR as compared to mAR, this is not enough to prevent mitosis.]]
Ed Friedman was one of the few key members of the group that Sammy Bates had founded, when I joined it 16 years ago. Sammy was outraged that castration was standard treatment for PCa. A very angry man. Got thrown out of every group he joined. At one point he threw out the many members who had never posted & we were down to 6 or so. The good old days. lol Sammy self-published a book that is probably still worth reading. -Patrick
I learned from a friend of his that Sammy's body was a mess at diagnosis in his 40's. The cancer had invaded the bowel. He didn't speak much about his problems, He had already passed 10 years when I met up with him. I see from emails that he hit 15 years in 2011, but he wasn't responding to anyone 4 years later. He almost made it to 20 years. He was so focussed on survival - & oddly, his anger may have kept him going.
This gives the mechanism by which the addition of finasteride while on Supra-physiologic T can sabotage the strategy and allow PC to progress. DS DNA breaks from high T may require DHT binding with intranuclear AR. Saw a diagram of that mechanism but now can’t remember where. 🤷♂️🥺
He also goes on to say:"There typically is a large increase in the amount of mAR when normal prostate epithelial cells become cancerous [46]. One treatment that took advantage of this used a form of testosterone replacement therapy (TRT) that used high dose T along with 5AR inhibitors, typically finasteride, dutasteride (which inhibits both type 1 and type 2 5AR), or both, to reduce the production of DHT. Because DHT binds to iAR five times more strongly than T does, removing DHT creates an imbalance in which agonism to mAR predominates. While this does not produce as great an imbalance as using T-BSA does, it still has some positive effects. Another possible benefit to this treatment is that the use of 5AR inhibitors helps to prevent the conversion of progesterone to 5-α pregnanes. 5-α pregnanes promote cell growth and metastasis in breast cancer [47] and are likely to do the same in prostate cancer. "
And there are some studies that show that DHT is more potent than T as a PCa therapeutic. It's one of my desire to have an RCT run to try to figure this out. There are lots of SPT/BAT experiments that I'd like to see. Is estrogen bad? How bad is it for therapy/prevention? How about SPE (supraphysiologic estrogen)? Some research shows that a very high dose of E can contain PCa. But the converse might also be true (EDT - estrogen deprivation therapy) - ar.iiarjournals.org/content....
Both theories seem plausible. I split the difference. I use finasteride on some BAT cycles. I don't on others. Someday I might get enough data to compare. I'm at month seven and the only thing I've concluded is that a high dose of SARMs does not appear to interfere with the low T phase of BAT. I am in the middle of a myokine inhibition / PPAR-δ agonism experiment.
What to do? I do have a big old supply of finasteride in the cupboard. Have not been taking it with my SPT cycles of mBAT, 10 weeks SPT 4 weeks off. About one year on this now. PSA has behaved at 0.11. Checking it tomorrow and adding Firmagon 80 to support the castrate month.The wild card now is a repeat PSMA PET last week reported 3 avid LNs, two in pelvis, one is new. And a “likely metastatic” one at celiac plexus. Reviewing with my RO. If true, I have progressed in the past year and officially M+. Yet otherwise my body runs so much better with T.
Exactly, what to do? I went on for months, then off, then on, then finally decided that until some kind of consensus could be reached (or I see some effects) I'll go on for one cycle and then off for the next.
Duta is more effective but has a really long half-life so I don't use it.
4 somewhat applicable RCTs: 1. ARTS - AVODART After Radical Therapy for Prostate Cancer Study - Study Results - ClinicalTrials.gov clinicaltrials.gov/ct2/show...
2. Feasibility of Hormones and Radiation for Intermediate or High-Risk Prostate Cancer - Study Results - ClinicalTrials.gov clinicaltrials.gov/ct2/show...
3. Prostate Cancer Study in Men Who Have Failed First-Line Androgen Deprivation Therapy - Study Results - ClinicalTrials.gov clinicaltrials.gov/ct2/show...
4. Assessment Of Dutasteride (AVODART) In Extending the Time to Progression of Low-Risk, Localized Prostate Cancer In Men - Study Results - ClinicalTrials.gov clinicaltrials.gov/ct2/show...
Dr. Liebowitz at Compassionate Oncology has been preaching this for over 20 years.
I want on the train. Cant afford it $
My dream is to experience T again somehow ,someday ?
I was on estrogen-ADT for 5 months. I'd look at the little girl in the mirror and cry. So I took the risk and jumped on the Friedman bandwagon. For 2 years my PSA stayed low (400 mg weekly cypionate shots). Rose to 0.17 so I started BAT. Modified for muscle. 7 months now. PSA is zero. My MO is impressed with my SPT and BAT results.
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Friedman - DHT, etc..
