G’day comrades. I am here reporting and trying to analyse my experience up to now of Bipolar Androgen Therapy (BAT). I have concluded that it has reversed the resistance that had built up to ADT (gnhr agonist zolodex) +bicalutamide (Casodex). Its about 6 months since I rechallenged the beast with bicalutamide after PSA started rising at the end of the BAT. There was a rapid drop of about 80% in PSA, maintained at the 0.5-0.6 level. The response has been markedly better than the original response to bicalutamide. When resistance will cut in I do not know. That will be the subject of another report. I consider the process a management tool to extend the usefulness of antiandrogens but trials underway are exploring it also as pretreatment for PARP inhibitors. For those considering this treatment I urge you to do your research and risk analysis and try to do it under good medical supervision with prescribed T. Done carefully it is not an especially difficult procedure. I am not recommending you do it but if you do do it, have as much knowledge as possible (or find a trial).
BAT is a treatment that raises T levels to supraphysiological levels quickly from a castrate ADT base. T then declines rapidly back to close to the underlying castrate level due to the continuing ghhr (ant/agonist). It is a sharp jolt to a cancer adapted to a low T environment. There is only one way to achieve it: intramuscular injection of T (about 400mg T cypionate or enanthate, but variable responses, some may need more). You just cannot achieve that level with patches and oils. Supraphysiological means about twice or more of the max of natural blood T values, say over 50nmol/l or about 1500ng/dl. That’s a fair whack of T over a few days, then a decline to near castrate levels in a month. Then repeat. Do not do a PSA test in the first month but then do them monthly after that. If after the third month the 2 PSA readings are trending up and above the starting baseline then that is a signal to stop and rechallenge with whatever you were using previously. You may still get a reaction. Then when that fails move on to the next standard of care. If the trend is down or below baseline, keep going until PSA starts to rise (3 rising readings) then rechallenge. In my case that was 8 months of the monthly T injections then starting again with the bicalutamide that had failed previously. All the while continuing the Zolodex (Lupron equivalent). The above is basically the Johns Hopkins protocol but there are others used by individual doctors such as a 3 months on, 3 months off cycle instead of the monthly cycle continuing until failure that I used.
A word on testosterone measurements: at the very least get one 36-48 hours after the first injection to judge how your body reacts and maybe modify the dose. Look at both T and calculated freeT which should be about 3 times the normal max (say about 1500pmol/L in proper currency).
There are issues I want to share and maybe get a different perspective from youse-all. The first is about timing and sequencing. The reliable reports on BAT are from trials associated with Johns Hopkins. One name appearing in most is Sam Denmeade and a quick search of him will give a lot of good info. So far, most trials have involved patients who had failed ADT 1 (Zolodex, Lupron) and the second order antiandrogens like Enzalutamide and Abiraterone. So they were in the context of evident resistance against Abi and Enza shown by rising PSA (and I think shortening doubling times).
My experience was firstly of failure of zolodox. Castrate resistance is not a good psychological experience at the best of times and I resolved to take control of my treatment. I proposed at this early stage to try BAT. My wise urologist’s parting words were “at least try bicalutamide first”, advice backed up by my oncologist so I waited until bicalutamide failed and moved as soon as I could after that. It seemed an ideal time to strike (so to speak). Most trials so far have been off the back of Abi or Enza failure and have documented a pattern that does not seem to be repeated when BAT is done after Bicalutamide failure. The Johns Hopkins trials showed that the best responders seemed to be those at a late stage with high PSA and the rechallenge with Abi or Enza typically did not result in a better performance than the original antiandrogen. PSA did not go as low and response did not last as long. This is interesting because in my case PSA at the start was still low (about 4) and rechallenge with bicalutamide gave a far superior response to my initial response. There seems to be something different about bicalutamide in its response BAT that may be useful as a management tool.
Another of our number, Bigdon about 4 months ago posted his report on a version of BAT that also started with low PSA and bicalutamide failure and the rechallenge was still working after 20 months. His conclusion was:
“Here us what I am taking from this, 1. PSA is still going down after 20 months and was doubling every 1.5 months prior to starting BAT. 2. I am still chemo and other treatments naive after almost 14 years. 3. When PSA decides to rise again I will try BAT before moving to second line treatments.”
So that is the first set of issues: timing and sequencing, when in the disease and treatment progression to do it. My guess (that is all it is) is as early as possible after hormone resistance to antiandrogen sets in, not at first castrate resistance to primary ADT (Zolodex, Lupron etc). Let the antiandrogen do its work first. The effect we are looking for is reversal of hormone resistance.
The 2nd set of issues is clearing the body of all remaining antiandrogens before starting BAT. I found no mention of this in the research I read but it seems logical that if you are trying to suddenly expose the cancer to extremely high T levels you do not want androgen blockers stopping the cancer’s access to it. Bicalutamide has a half life in the body of about 6 days, so it will take about a month after stopping it for it to clear and then start BAT. The issue has not arisen in trials because the nature of the trial process (a few months waiting) meant the antiandrogen was well and truly out of their system by the time BAT started. This is important because ALL antiandrogens have a biological half life, some in hours, some a month or so. I know some readers supplement with finasteride (Proscar) and dutasteride (Avodart), 2 old antiandrogens that inhibit 5-alphareductase (5AR) and prevent the formation of dihydrotestosterone (DHT), a very powerful androgen that our cancers love. Fin has a low half life and will clear the body in a couple of days. Dutasteride however has a half life close to a month and takes about 6 months to clear, so if you are taking it you need to wait that long after stopping before you start BAT. I don’t think that is viable. I did try Fin in my rechallenge phase but concluded it had minimal impact and in addition, all 5ARs tend to mask PSA over time and so make the PSA readings you are relying on, not so reliable. In addition to all that, they have not been shown to be actually effective against PCa despite the appealing theory, so I decided against using them. However I think the conclusion remains that if you are contemplating BAT, clear the antiandrogens from your body first.
I am sorry this is a long winded post (if I had more time I would write a shorter one). It has been useful writing my thoughts down. I hope I have been reasonably clear. It is very comforting to know you mob are out there to pick up on any faulty reasoning or misremembered facts and to add more pieces to the puzzle.
This was a report by one of our number who did it and seems to have achieved a reversal of resistance to bicalutamide too: healthunlocked.com/advanced...
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Thanks for the report. I have one suggestion to add.
Testosterone can be administered subcutaneously. This is much simpler and more convenient for the patient than intramuscular injections. You can be trained to do it yourself in a few minutes.
The traditional limit for subcutaneous injections is 1 ml, and testosterone cypionate is available in 200 mg/ml vials. Most men will need about 400 mg to raise T levels from castrate to above 1500 ng/dL. I needed 600 mg, probably because of my size. So I split the dose into 3 separate injection sites. There are many available sites for sub-Q, the abdomen and thighs are convenient.
This worked very well and was both less painful and far more convenient that traveling 40+ miles each way to the oncology clinic for a quick jab by a nurse.
Testosterone cypionate is carried in an oil and is quite thick. You have to draw it up with a larger gauge needle, then swap to a short, fine gauge needle for the injections.
The article below is entitled
Serum Testosterone Concentrations Remain Stable Between Injections in Patients Receiving Subcutaneous Testosterone
For BAT we're not trying to maintain a constant level, but the article demonstrates the sub-Q injections are safe, effective, and produce the same rapid rise in T levels. Splitting the dose into 2 or 3 sites of 1 mL each seemed to speed up the rate of rise of serum T. In my experience the rise, dose response, and half life of the serum T levels were more consistent using sub-Q injections than with IM injections.
I did try sub Q using 28g insulin needles but the T is so viscous that it was impossible to hold the needle steady long enough (resulting in a bit of sub Q scar tissue that cleared up after a few weeks). I didn't try splitting the dose and that may be a way to do it. I normally use 24g needles for intramuscular and that needle size may work with subQ too.
28 is pretty fine and the T cypionate is quite viscous. I was using 25 or 26 gauge, 3/4" needles for the sub Q injections, and a 22 or 23 gauge to draw the T out of the vial.
We use BAT a little differently, in that you seem to view it as a way to reverse drug resistance after it occurs, while I use it to avoid such drugs - or rather, to delay having to use them.
I hadn't thought of quitting Avodart, but perhaps it makes sense to allow T to convert to DHT while doing BAT. Makes me nervous though. In my early PCa years I used T patches continuously & was not concerned about DHT. In normal prostatic epithelial cells (or PCa cells never subjected to ADT), DHT induces an enzyme that rapidly clears it (i.e. DHT has a narrow window to stimulate growth). One of the DHT metabolites in that clearance is the natural ligand of the beta estrogen receptor [ERbeta], which inhibits growth. But, after some years on AndroDerm patches my PSA doubling time shortened & I figured that DHT was no longer my friend. I reluctantly switched to cycles of 3 months castrate, followed by 3 months of AndroDerm. But recently, I have gone to the monthly BAT cycle.
You are correct about the long half-life of Avodart. It takes a long time for blood levels to plateau at the prescribed dose, & a very long time for the blood to be cleared of it.
I'm glad that you are having such success with BAT. Your experience should interest many here.
Thanks Patrick. There is great variability in responses to exogenous T but I don't see how to get to unambiguously supra T using current gels and patches. Certainly high T is achieveable. If there was a patch able to do it, that would be useful, very quick delivery. There was talk of developing one but I have not heard anything since. High T (with biscuits?) might be enough but the Johns Hopkins people went for supra T on the basis of suddenly exposing the cancer to levels not achieveable normally. Maybe its overkill, maybe not. Probably depends on individual response.
When I was using AndroDerm patches, my T was often above 1,000 ng/dL, but not by much. And I wasn't aiming for supra-T. I started out with 5 mg (the company also had a 2.5 mg patch). After a while, the product was changed to 4mg & 2mg. The 4mg still got me to ~1,000 ng/dL.
The only reason that I switched to T cypionate is that my insurance company was about to ask for proof that I needed the patches - they are expensive. T cypionate in the U.S. would cost me under $100 for a 6 month supply. No need for insurance. But, in fact, insurance has covered it without a problem.
I don't understand what T at the 2,000 ng/dL can achieve. Morgentaler's saturation model predicts that androgen receptor saturation occurs well below the hypogonadal level of 350 ng/dL (more like 250 ng/dL). How does the extra T help? "Dr Bob" Leibowitz in LA seems to have been the first to use high levels. Perhaps Sam Denmeade was influenced by him?
It's interesting that not all men respond in the same way to the Denmeade dose. There is quite a wide range of achieved T levels. I once tested myself 8 days after injecting, & I was still well above 1,000 ng/dL. I wonder how long it takes me to become castrate? There are only 28-31 days in the BAT cycle.
I thought BAT woud be injecting T during ADT. You are not on ADT so how does it work? Would be interesting (I think for a lot of people here) to know what you did till now, since you did a non standard treatment, and also to know what you would do differently, if, now.
Did you ever have a PSMA Pet Ct? Your treatment was after prostatectomy failed, but you know it failed just from PSA?
I know everyone is different, but single stories are very interesting and maybe not less than all very valuable research you feed this site!
There is no requirement for ADT to be continuous. The T injection overrides ADT for at least a week. With Lupron, one cannot easily stop & start, so it is a convenience that it be continuous.
With a daily oral ADT drug, such as DES, one can skip the first week of the month.
Surgery was deemed unsuccessful when my first PSA was 0.3.
I had to have a scan prior to salvage radiation. No bone mets at that time.
Some men regularly travel across the country to get the most sophisticated imaging, but I haven't done any of that, since I lacked a plan of what to do with the results. My spinal lesion at L5 was discovered by accident, since it was not causing pain. Had it been found a few years earlier, I might not have been able to find someone to radiate it - unless I faked pain.
For most of my adult male life I only had 4 feelings: Hungry, thirsty, sleepy, and horny. It wasn’t till I went on Lupron that I realized there were so many, many, many more feelings. Sometimes I would get them all in the same day. I could handle the physical aspect of the cancer: joint pain, fatigue, mental fog and weakness. However the emotional aspect was like a multiplier to everything that happened to me. It was the unstable emotional ground that made it hard once I stated losing my testosterone.
So how was it to go to those high levels of testosterone and back to nothing again? Was it as bad as the first time? I’ve read that most men feel great again (more energy, muscle mass, even having sex again). I didn't read too much about the down side. I’m in an emotional limbo. I don’t go to the mountain tops no more but I also don’t go into the dark deep valleys. My family went for a rough ride with me. Is it worth it?
My experience was similar to yours, in that being castrated took away far more than just sex drive. It took away my desire to live, to eat, my ability to think, my curiosity, my personality. I talked and thought about the "new me" versus the old me, and I didn't like new me at all.
BAT was an enormous improvement in my quality of life compared to castration. It wasn't nearly as bad as ADT. For me, ADT started getting really, really intolerable after 3 months or so. With the monthly cycles of BAT I never got that bad again.
That said, the monthly cycle was intense and quite unnatural. It was like a woman's monthly cycle on steroids - literally! My mind and mood would improve in just a couple of days after the injection. Hot flashes took a week or ten days to resolve. I've been weight training since I started ADT, and with the supranormal levels of T my muscle mass improved quite rapidly. My %body fat went from fairly normal to nearly that of a trained athlete. I could see why body builders juice, although I didn't find the experience appealing at all.
The rapid crash back to castrate levels was quite a ride, like that big, big drop on today's monster roller coasters. You know you are going to be all right, but it is a bit frightening nonetheless.
I never stopped having sex, go figure, but I sure as hell thought about it a lot more when T levels were very high.
For the past few months I've been on a vacation from both ADT and BAT. My T levels recovered to about 70% of my normal in a few weeks. I've been amazed at the difference. Like they say, you don't know what you've got 'till its gone. I feel better now that I have for 20 months. I feel like my old self again.
It's been a sobering, humbling experience to learn how much of what I thought was me was in fact due to this simple steroid.
I don't know if I will go back to ADT. I'll be talking it over with my MO in a few weeks. But quality of life is important to me, and life on ADT was not worth living.
I'd consider BAT again if conditions warrant it, but I wouldn't look forward to it. It's not that it's so bad, it is infinitely preferable to castration, but it is very artificial and unnatural.
Forskolin is used as a fat loss supplement. It does increase free testosterone. How much I don't know but I would be doubtful that any supplement can get to supra T levels and do it quickly. It takes a direct injection of 400mg+ of T cypionate to get there quickly.
I am still trying to understand the underlying dynamics of how the biphasic action of T affects Pca when T is in the Supra hi level. What are the actual mechanics?
My case is different as my body seems to react to Xtandi by generating Supra levels of T , I suppose by blocking the AR and transcription action. But why such hi levels and how does this mono T state form have such a beneficial effect of creating what seems a hi sensitivity to action of Xtandi?
This not a case of shocking Pca by the BAT cycling.
There's a lot going on, and they are still figuring it out. The men who had the best response to BAT may share a common genetic feature. We don't know for sure, yet.
One way it works is that ADT kills AR-dependent PCa cells, but that leaves behind those cells that can get by on very little T. ADT eventually fails because those cells grow to replace the ones killed by ADT. Tumors are limited by blood supply, kill off one variant and you leave the equivalent of a freshly tilled garden - with a few weeds left. In short order those weeds grow into the newly available spaces and take over. That's when you start to get castration-resistant disease.
These cells tend to overexpress Anrogen Receptors (AR) - like 100 times as many as a typical AR-dependent PCa cell. When they are challenged with supraphysioilogical levels of T, they take in a huge amount.
The short answer is that the huge influx of T poisons those cells. The more detailed answer is that when the cells divide, as cancer cells do so often, they have to exclude androgens (T and others) from the nucleus during DNA replication. The cells that overexpress androgen receptors have so much T they can't exclude T well enough. The presence of T during DNA replication messes with a process called DNA licensing, which enforces only one copy of the DNA. When the DNA licensing breaks down, there are multiple copies, and the cells end up with double strand breaks - incomplete pieces of DNA. That's fatal, and they die.
It's more complicated than that, and there may be other mechanisms at work.
As to how it resensitizes the cancer to ADT drugs, its the weeding analogy again. The BAT kills off the cells overexpressing AR during the high T phase, then the low T phase kills cells that need T. You're weeding the garden twice a month, destroying different kinds of weeds as the T cycles from super high to near castrate levels.
There are quite a number of possible routes by which BAT may work, shown in vitro and vivo and they may vary from patient to patient. One way is suppression of the androgen receptor variants, another is the double strand DNA breaks. Hence the interest in combining BAT with PARP and checkpoint inhibitors which prevent repair. In the early BAT trials there was a super responder whose PSA went straight to zero for about 2 years. His DNA had a BRCA2 mutation but not much else to explain the response. In early trials of PARP inhibitors there were 2 super responders. It turned out they had both done BAT some time before. There's something going on but we don't quite know what it is. Here is a link to a good review article on possible mechanisms etc:
mdpi.com/2072-6694/9/12/166
Truth is, we know bugger-all. I followed the Johns Hopkins protocol because it works in many cases and has shown no great adverse effects. Many get a good reaction just from the BAT, others from the rechallenge. Failure generally leaves you no worse off than if you had done nothing. As Demeade says, it either works or it doesn't and you find out in the first 3 months.
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