Advanced Prostate Cancer

Testosterone as "fuel"

I am not a fan of using the word "fuel" as a characterization of the relationship between prostate cancer and testosterone. It is too outdated, and misses too much of what now know. Testosterone is not consumed in the process, does not provide the energy for growth, and is not necessary at all for growth, as in the ARv7 variant.

The AR is a transcription factor. That is the new (for me) starting point for comprehension.

32 Replies
oldestnewest

I agree. From my experience, it seemed odd that I was prescribed ADT (Zoladex, Lupron, Firmagon, Casodex, etc) to "lower" my testosterone but the only thing the oncologists seems intent on monitoring was not testosterone, but the inexact biomarker of PSA. Also odd that "Low T" is now a so-called "unhealthy condition" for which men are being urged to seek treatment, yet we with PCa are being induced into an artificial Low T state. For me, I believe normal T levels are essential to the body's homeostasis and a good QoL. After three intermittent cycles of ADT, and 2 years out from completion of radiation, I'm experiencing consistently undetectable PSA and better QoL than I have since diagnosis in 2012.

2 likes
Reply

For the past 14 years and continuing on today, my PSA and T values are monitored parallel along other markers contained with several pages of lab work. Then again my guy is in academia and is a researcher, so I may be different. From the git-go, the relationship of PSA and T has been explained to me form those eyes.

BTW, when people who are "suffering from low T" take testosterone replacement therapy, there is a warning label.

Gourd Dancer

1 like
Reply

I'm confused. My T is <3.0 on ADT3. PSA is 0.3 ( good things come in threes)?

Is it safe for me to have T replacement therapy while on ADT3?

Bob

Reply

Testosterone may or may not be ok. My point is that calling anything "fuel" is not going to be a real helpful idea. Testosterone may be bad, but its not fuel.

"Fuel" is an inadequate model. We know more now than we can squeeze into the idea of "fuel". I have the same problem with "seed and soil". Outdated.

With the idea fuel come the associated idea of engine that is running. The running engine is cancer. The notion is that the less fuel, the slower the cancer engine goes. And zero fuel would stop the cancer engine. The ARv7 variant does not need testosterone, so does not need fuel. The engine model needs to be fixed for at least that. Then, there is not a direct (straight line) relationship between testosterone and the speed of the cancer engine, and its not clear at all what kind of line there is, if there is a line. So it has to be fixed for that. And PSA is used to check the engine speed, and the correlation between PSA and cancer speed is really not good at all. So what are we left with?

2 likes
Reply

I call Testastrone fuel of masculine life and energy.. Without it we quickly feminize and now I’m just preaching to the choir.

Reply

nobody can stop you.

1 like
Reply

You dont give the units of measure for your T. Usually people used to say "is less than 50", and now say "is less than 20". (As the "castrate" level.)

Reply

<3 NG/ML!!! Seriously castrate

Reply

I thought that they could not measure below 20. Live and learn.

Reply

YOur doctor, or somebody who can make an informed judgement, needs to say what he thinks and why in your case. It depends. What it depends on is another question.

Reply

Bob,

No, having T replacement while on ADT3 is contra-indicated. The purpose of the ADT is to make you castrate, adding T is the exact opposite. It would be like pumping water out of a swamped boat while also poring more water into the boat at the same time.

Joel

CancerABCs.org

2 likes
Reply

Bob asked:

> Is it safe for me to have T replacement therapy ("TRT") while on ADT3?

Your doctor (hopefully) knows more about this than I do, but I think the answer to to your question is No, it's not safe. T replacement and ADT3 work at cross purposes to each other. Using them together would cause each one to defeat the purpose of the other.

There is an alternative that is beginning to gain some favor which is not to use them together, but to alternate them. You use ADT for some period, then TRT for some period, then ADT again, then TRT again. This "Bipolar Androgen Therapy" ("BAT") is thought to first kill off cells that need T, then when most of the cells left are able to survive on very low T, overwhelm them with very high T, hopefully killing off a lot of the cells that are most resistant to ADT. Then when the cancer cell population gets to like T again, cut that off by stopping the TRT and re-instating ADT, and so on.

You can ask your oncologist about it. You'll probably get the best results if you can find an oncologist who has read up on this, knows who the best candidates for it are, has ideas about the length of time for each treatment for each type of patient, knows what the signs of failure are, and has some practical experience. However it's a new idea and it might be hard to find someone who has the requisite knowledge and experience. Looking for a BAT clinical trial might be the best approach.

BAT is still experimental. An even more experimental approach is to use straight TRT without any ADT. Some think it will work, but I think most experts would consider it to be pretty risky.

Best of luck.

Alan

2 likes
Reply

I am 3 months into a BAT trial, at Johns Hopkins, and the scan today looks like I will be cleared for another 3 months at the review session tomorrow.

It has some promise, and I am completely stoked for it, since it is cheap and easy, and may give you a cheap year of progression free survival. And, and, you would come out of that year most likely androgen sensitive again.

In my opinion, Nobel Prize territory. Of course, as they say, most trials fail.

So there is that.

Reply

I'm 4 years out from treatments of radiation and lupron for stage 3 advance of at 53 years old.

I checked into hormone replacement since it sounded like I could get back to my regular self again. Not 1 of 4 places I contacted said they would treat me after pc.

My oncologist checks PSA and T levels twice a year now. PSA is .10 and T is finally up to 358. My family doctor says since I'm that far out of treatment, I shouldn't have any side effects of lupron. Well, the low T is still causing my arthritis, aches, pains, and weight gain.

Now with this "opioid crisis" my family doctor won't help, and I'm no longer under the continued care of the oncologist.

I was happy I'm in remission or beat it, but really sad my quality of life still sucks...

1 like
Reply

Dale,

If your "arthritis, aches, pains" are in your small joints, for example in your fingers, that is indeed a side effect of hormone therapy. Contrary to what your doctor said, the problem CAN occur after treatment has ended, but it's still due to the treatment. I had that problem, starting some months after my hormone therapy was finished. I found a solution, or I should say several solutions. Here they are:

1. Hot and cold. Placing your hands alternately into hot and cold water can significantly relieve the pain and stiffness in your fingers.

2. Sleeping with clenched fists. I woke up every morning with stiff hands and "trigger" fingers, i.e., fingers that didn't want to open and close easily but would kind of pop into the open position when pushed to do so. If I slept with my hands straight, the problem was worse. If I slept with clenched fists, which took a while to learn to do, the problem was much less.

3. Exercise! That was the most important and best long term solution. I did massive amounts of hand exercise - squeezing rubber balls, alternately squeezing and relaxing my hands on the steering wheel when I drove my car, squeezing my hands shut and opening them again while sitting or standing around, squeezing hand exercisers - the steel spring with two handles kind. It was a small amount of work to get a very great amount of benefit. It made my hands stronger too. Ultimately, it completely resolved the problem.

As for weight gain, well, we all know the solution to that - eat less, exercise more. Lupron does cause weight gain, but the cure is the same as it is for weight gain caused by any other source. Exercise, diet, and a bit of extra sleep will also give you more pep.

Best of luck.

Alan

4 likes
Reply

Amen with the exercise!

2 likes
Reply

Freakin APC soap,opera my life is if I dwell on it. I’m your age.. andd so it goes...

Reply

I have been on Casodex for 4 years now, my PSA is undetectable and my testosterone is toward the high side of normal. It doesn't look like Casodex is a drug that lowers testosterone, for me anyway.

Reply

Casodex "blocks the androgen receptor"; it does not inhibit the production of testosterone.

en.wikipedia.org/wiki/Bical...

It is, in a sense, a fake testosterone; one that does not activate the Androgen Receptor because while it fits into the notch that testosterone fits into, it does not cause the same change to the shape of the AR that allows it to enter the nucleus, and so it disables the (that one) AR.

1 like
Reply

Thanks. I never quite understood how it works, I'm not sure actually understand now but I am glad it is working for me and I have little or no side effects from it.

Reply

I had prostate removed...cancer had found its way to my seminal vessels and I had one tiny positive margin. PSA kept rising so had radiation treatments and PSA still rose. Doc wanted to put me on the chemical castration crap but after reading the side affects I decided to have the nuts out. That happened a year ago and I'm in remission for that long now.....When I read things like this I wonder if I did the right thing? I chose a road to travel without drugs other than cannabis oil. So far so good but like I said I wonder?? I'm 57

2 likes
Reply

It’s all a crap shoot... everybody knows more than I do . I’m on the ADT until failure. At least that’s the plan presently. Brave to,stop . I’m not that brave.. If I stopped and it jumps back and slams me I’d feel like more of an idiot than I already feel with kidney failure tubes and or stints s for 11/2 yrs. # 4 That shit was brutal and I’m lucky that I made it. Best of luck in your decisions. We all need to follow our own path.. as crooked as it is...

Reply

Having the nuts out seems fine to me. It stops them from making testosterone, and its cheaper too. If you or your doctor decide that you need testosterone, he can give you shots of it, so you really should be ok as to your choice. You have not lost any options.

In either case, it seems to me, you run the risk of osteoporosis and muscle loss from a lack of testosterone (however you achieved it.)

1 like
Reply

Unavoidable loses. Osteoporosis and muscles fade.

Reply

I'm not an expert but I have done some reading in biochemistry and molecular biology. My understanding of the role of testosterone (hereafter referred to as "T") is as follows:

T is a "hormone", a chemical whose molecules are used for "signaling". Plants and animals both use hormones to send a signal from one place in the body to other places in order to coordinate activities throughout the organism. This is done by secreting hormones from one place in the body into the blood stream (in animals), where the "signal" can be picked up in many distant places. In advanced animals that have brains and nervous systems signaling can be done faster by nerve conduction but there are still many kinds of signals that work better by hormone signaling.

T is mostly produced in the testicles. The molecules distributed from there are received by cells with appropriate receptors ("androgen receptors") on their surfaces to import the T into the cells where various different types of chemical reactions may occur that require this signaling to begin. On the face, armpits, around the genitals, and for many men on the chest, back, arms and legs, T can signal that hair should be grown. There are also changes in muscles and bones - all things that distinguish men from boys. And one of the changes that is signaled is cell division inside the prostate. That can make the prostate grow bigger or cause it to replace cells that have died off. If some of the prostate cells are cancerous, it can signal them to divide too, and since cancer cells don't naturally die off at the rate that non-cancerous cells do, the cancer cells begin to proliferate. Cancer cells may also have mutations that break the mechanisms that control the rate of cell division, so cell division and multiplication may happen more frequently than in healthy cells. Cutting off the supply of T into the blood stream (Lupron, Zoladex, Eligard, Zytiga) or blocking its uptake in prostate cells (Casodex, Xtandi), turns off the signal for cell division and causes the cancer cells to become dormant or to die off because they need to be able to divide to remain viable. T is not so much "fueling" the cancer, but maybe we can say it "wakes it up" and tells it to grow.

At any rate, I think that's the theory. Someone may have a more accurate explanation, but I hope what I've said is reasonably correct.

Alan

3 likes
Reply

Possible slight adjustment. (I like the beginning a lot - hormones as signals, and inevitably being part of a feedback loop.)

T is a small molecule, and should be able to get into cells without much trouble due to osmosis. I say this is part because I have never seen a reference to a 'channel' that pumps T into the cell. This means that the T level in the blood is about equal to the T level in the cell, and possibly to the T level in the nucleus.

However the T is a signal, rather than a catalyst or a component (or a fuel), and the receiver of the signal is called the AR (androgen receptor). The AR is a transcription factor, meaning it goes into the nucleus to express genes. When the T binds to the androgen receptor at the "ligand binding domain", the AR changes shape (I tentatively think of it as kicking up the kick stand), and allows the AR to enter the nucleus. ARv7, variant 7, does not have the ligand binding domain, and enters the nucleus at will.

Once the AR is in the nucleus, it pairs up with another AR, to form a dimer (a pair), and the DNA binding domain binds onto a spot on the DNA, and then the standard part of any hormone receptor goes to work, creating messenger RNA that exits the nucleus.

Some of this may be incorrect, but that is my understanding at this point.

There are two normal forms of the AR, called AR-alpha and AR-beta. No idea if there is any clinical significance to that, making three possible dimers.

Expressing genes is different from cell division, and I am not clear on the relationship between creating protein (expressing genes) and cell division. One guesses that it is related somehow, but it is not at all clear.

1 like
Reply

Martingugino wrote:

"T is a small molecule, and should be able to get into cells without much trouble due to osmosis. I say this is part because I have never seen a reference to a 'channel' that pumps T into the cell. This means that the T level in the blood is about equal to the T level in the cell, and possibly to the T level in the nucleus."

I just looked that up and found - you're right. The cell membrane is hydrophobic (consisting of electrically non-polar molecules) and blocks the entry of of water and other electrically polar molecules, but testosterone can pass easily through the membrane.

Thanks for the info.

You wrote: "Expressing genes is different from cell division, and I am not clear on the relationship between creating protein (expressing genes) and cell division."

My understanding is that cell division uses a considerable number of proteins. Some are involved in unraveling the chromosomes, in splitting apart the DNA double helix, in assisting in DNA replication, in drawing the replicated DNA into two different halves of the cell, in splitting the cell in two, and so on. Most proteins don't stick around forever, they get degraded in the cell and their component parts (amino acid molecules) get recycled to build other proteins. So when cell replication begins lots of DNA -> protein translation occurs.

It appears that, as you explained above, some of the proteins in this process are only produced when the androgen receptors (themselves protein molecules) are put into an active state by receiving the testosterone signal.

As with so much else, there's a pretty good article about androgen receptors in the Wikipedia.

Alan

Reply

No one is more accurate Thank you sir..

Reply

Well I was told that androgens are also formed in the adrenal cortex which is on top of the kidneys. This where adrenaline is released when you are in fear. So removing the testes does not stop all the other androgens. Lupron does stop all androgens including in the adrenal cortex. The cancer cells in the prostate need to have an androgen present in order to multiply and form tumors. So when cells metastasize into the body they can not form tumors. Adding testosterone injections would allow tumors to grow in the body, because the cancer cells that metastasize also have an area on each cell called "Androgen Receptor" or AR. The less testosterone in the prostate cancer's body, the lower the PSA, and longer the survival.

2 likes
Reply

This part is not correct: "Lupron does stop all androgens including in the adrenal cortex. " Maybe you meant Lupron does NOT stop all androgens.

Lupron stops leutinizing hormone (as well as FSH) and LH signals the testes to produce T. LH and FSH do not affect the adrenals. I think Casodex/bicalutimide can stop androgens from the adrenals.

Kind of bizarre. They give casodex during initial Lupron flare, but that seems like it would be pretty ineffective in counteracting high levels of T. (!!)

------------

This statement seems probably true, but what evidence do you have? (I want to learn).

"The cancer cells in the prostate need to have an androgen present in order to multiply and form tumors."

What is the role of androgen in prostate cell multiplication? The mechanism.

Reply

Hi! Great questions. Well Wikipedia says under "Adrenal gland" - (Androgens)

"Cells in zona reticularis of the adrenal glands produce male sex hormones, or androgens, the most important of which is DHEA. In general, these hormones do not have an overall effect in the male body, and are converted to more potent androgens such as testosterone and DHT or to estrogens (female sex hormones) in the gonads, acting in this way as a metabolic intermediate."

So, Mayo Clinic states - DHEA is a hormone that is used to make both androgens and estrogens. DHT is dihydrotestostereone and is a more powerful form of testosterone and forms testosterone. LH and FSH are used in female reproduction. Lupron stimulates LH and FSH (in women) and is used to release eggs in women.

My oncologist told me that Lupron does stop androgens in the adrenal medulla. Also, I was told that the prostate cancer cell has an AR (adrenergic receptor) area on the side of each cell and when an androgen interacts with a prostate cancer cell it enters the nucleus of the cell and the double helix of the DNA is allowed to form, allowing the cell to subdivide and make more cancer cells or tumors.

At the first dose of Lupron there is the release of stored testosterone into the blood stream for about 2 weeks. Casodex helps this from becoming a problem, however, Casodex does not continue to work as well as Lupron to keep androgen levels low. This is different in different patients. I have been on Lupron for 5 and 3/4 years and my PSA (the enzyme that tells how may prostate cancer cells are subdividing) is 0.000! But each patient has other diseases, different Gleason scores, different locations and involvement of cancer areas. I am 72 and I have diabetes, heart disease, and liver disease.

I am aware there are supplements available to build lean muscles like "Testo Muscle Fuel". These supplements are most effective in those men who have a low level of testosterone to begin with. Using the word "fuel" is an old term used 30 years ago and is not accurate. I notice that companies using the word "Fuel" are trying to sell you something. Your metabolic rate is a good measure. Testosterone supplements are not indicated for someone with prostate cancer in my opinion. I was a retail pharmacist for 35 years and I am now retired. I hope you continue to stay well for a long, long time!

Reply

You say "My oncologist told me that Lupron does stop androgens in the adrenal medulla. "

Lupron is drug that is received by the pituitary.

en.wikipedia.org/wiki/Leupr...

It does not (directly) act on the the adrenals, or even on the testes.

The pituitary secretes hormones that control the testes: LH and FSH. These do not affect the adrenals. I believe that your doctor is mistaken, although the adrenal gland may be affected by *elevated* LH in post-meapausal women. ncbi.nlm.nih.gov/pubmed/167...

-------------------------------

The AR (androgen receptor) is a transcription factor that, like all transcription factors, is triggered by a hormone, and causes the expression of genes. Presumably it has a role in cell division, but the mechanism is less than clear, and the definition of transcription factor does not include this feature.

---------------------------

Regarding "flare" of testosterone after first exposure to Lupron.

Lupron is an "agonist" (a stimulator) rather than an "antagonist".

en.wikipedia.org/wiki/Gonad...

After a while however the pituitary shuts down apparently due to over-stimulation. This ends the secretion of LH and FSH. The end of LH secretion by the pituitary ends testosterone secretion by the testes. I dont know the effect of the end of FSH secretion for men.

Casodex suppresses androgen production from the adrenals. How does this help? The adrenals do not produce that much, and I have not seen anything that says that Casodex reduces the testosterone produced in the testes as a result of the flare, which is (much) greater than any reduction in androgens from the adrenals.

==========

Nice to have a pharmacist here.

Reply

You may also like...