Testosterone therapy to... LOWER testosterone production?

[noahware]

I know there is plenty of talk here about BAT and TRT and SPT (i.e., supra-physiological levels of testosterone) , but there is an aspect of getting high-T shots that sometimes gets mentioned without in-depth discussion. Namely, that high doses of exogenous T can serve to suppress the endogenous (testicular) production of T.

This is from an article on infertility caused by TRT:

"Testosterone inhibits both GnRH and gonadotropin secretion. Exogenous administration of synthetic testosterone results in negative feedback on the hypothalamic-pituitary axis, inhibiting GnRH, leading to inhibition of FSH and LH production. As a result, intratesticular testosterone levels (ITT) and overall testosterone production decrease. Exogenous testosterone therapies can suppress ITT production to such a degree that spermatogenesis can be dramatically compromised at ITT concentrations to less than 20 ng/mL."

So higher blood levels of T have the androgenic effects of our natural testosterone on sexual function and mood, but the effect on gonadotropins leads to the inhibition of sperm production and to potential action of high-T as a contraceptive. Can that be related to why TRT or SPT sometimes (!!) might (!!) seem (!!) to lead to the inhibition of PC progression? Can super-high-T be acting in some way as a form of ADT via negative feedback on the hypothalamic-pituitary axis? (That would be a different mechanism than the "shock" of SPT that comes after the ADT of a BAT protocol.)

Clearly you are not depriving the body of androgens by raising androgen levels with SPT, but you are screwing with the signaling mechanisms of the androgen axis. I believe you would also be raising estrogen levels. How might AR and ER signaling respond differently to SPT versus natural (testicular) testosterone? Aside from impacting the feedback loop, how do high serum levels of synthetic T differ from natural levels of gonadal and adrenal T?

I am wondering if any here have a deeper insight into these mechanisms, as much for the sake of understanding as for any practical implications in treating PC.

[Hidden]

Good topic. I can answer a couple of parts of that. Yes, high levels of T will definitely cause your body to decrease LH and cut your endogenous T production to zero or close to it. And your libido stays good or at least okay. Your estrogen does increase. Some of the T is converted to E. So with T high, E follows (via the aromatase enzyme). An aromatase inhibitor needs to be taken to keep E in check. Very effective. My T is 2100-3000+. I keep my E2 at 15-30.

Sperm production should go to zero. If someone wants kids they might want to factor this in or have their sperm frozen (I certainly don't want any more kids and I had an RP so double protected).

Russ

[humptedumpte in reply to Hidden]

This is a great topic. I have read that with APC one does not want elevated levels of FSH or Prolactin as both may adversely stimulate PCa cells. Has anyone else read of this?

If this is operative in cases of APC, one could postulate both may also serve as stimulation in earlier stages of PCa maybe enhancing or promoting increased growth of PCa cells.

[Hidden in reply to humptedumpte]

I've read research and case studies showing prolactin can be problematic.I've been keeping it below 3 by using 0.5 mg of cabergoline a week.

I haven't read that about FSH. I'll look into that. Thanks (hi T suppresses FSH in addition to LH)

[Hidden in reply to humptedumpte]

Lots of info. Pubmed, etc. Thanks again. gotoper.com/publications/aj....

practiceupdate.com/content/...

[Hidden in reply to humptedumpte]

Maybe the same thing for LH.

pubmed.ncbi.nlm.nih.gov/323...

T suppresses LH and FSH.

My situation:

High T

Zero FSH

Zero LH

Low E

Low DHT

Zero Prolactin (it was low but last year was undetectable)

[Tall_Allen]

That is the opposite of what anyone with advanced PC would want. Yes, it shuts down testicular T production but just replaces it with exogenous T. What is the point?

[noahware in reply to Tall_Allen]

It is not the opposite of what men whose cancers respond favorably to SPT want. The point of the exogenous T is that their cancers appear to respond favorably! If SPT always caused a progression of PC, then of course no men would want it. But that does not appear to be the case.

So with the question of which men might be helped rather than harmed, there are also the questions of how and why. It appears that no amount of increased serum T is sufficient to promote spermatogenesis, and that process requires testicular T. I am wondering about differences in cellular signaling that might occur with different T regimes in light of the fact that higher serum T can promote lower testicular T.

We already know that the circulating concentrations of hormones are poor measures of the intraprostatic hormonal milieu. I'm wondering what we know beyond that, so far as what happens when we artificially increase those serum concentrations.

[Tall_Allen in reply to noahware]

There is absolutely no evidence that sustained SPT ever caused a favorable response in men with metastatic PC. This is pure fiction.

[noahware in reply to Tall_Allen]

I am not promoting SPT as a treatment. I am wondering why, on occasion, it has appeared to serve as one for SOME men. (With "some" defined here as "being greater than none" and not defined as "a majority." No one ever claimed more men are helped rather than not helped.)

Not sure how you define "sustained" but there are certainly a few examples in the literature from the 40s and 50s of men, either with or without prior treatment, who had beneficial responses to exogenous T. According to Munger (1947), at least one metastatic man without prior treatment showed benefit from T for over ten months, before any progression. The question then is: why?

And you must admit: things that are NOT studied can NOT have evidence, by definition. Things that remain unstudied or unobserved are not necessarily "fiction." The questions I asked in the post are not a claim of evidence but are more a request for evidence, if any might exist.

[Tall_Allen in reply to noahware]

I assumed you knew that it had in fact been studied. I guess not. There have in fact been several small trials - none showed promise, so efforts were abandoned.

Liebowitz et al. did a chart review among 96 men who were given TRT for hypogonadal symptoms after treatment. When started on TRT, only 12% had metastases. 39% had had curative treatment. 61% had ADT only. After TRT, most had PSA progression, some had metastatic progression. It's hard to draw conclusions from this mixed population.

bjui-journals.onlinelibrary...

There was a small (12 man) safety trial at Memorial Sloan Kettering with short (<1 yr) f/u. Of the 12 men: • 7 had progressive disease on an FDG PET scan, Interestingly, 4 of them had a decrease in PSA, indicating progression to a virulent anaplastic form (e.g., neuroendocrine).

• 2 had stable disease on the FDG PET scan, but 1 had a sharp rise in PSA and the other had new lesions on a bone scan.

• 2 had mild improvement on FDG, 1 with a big increase in PSA

• 1 ended TRT when he had radiation for spinal compression.

• There was no regression of metastases in any of the men.

ncbi.nlm.nih.gov/pmc/articl...

Other small trials of TRT alone had mixed results.

acsjournals.onlinelibrary.w...

ncbi.nlm.nih.gov/pmc/articl...

So TRT alone doesn't seem to work. Both effects are necessary: (1) the TRT re-establishes hormone sensitivity, and then (2) the ADT kills off the hormone-sensitive cancer cells. For disease stabilization or regression, it seems to be necessary to alternate TRT with ADT - bipolar androgen therapy (BAT).

[kaptank in reply to Tall_Allen]

All this is about TRT which I agree does not have good form. However confusing TRT with the T levels required for proper BAT is something you know to be false. BAT requires supraphysiological levels of T. TRT does not do this.

[Tall_Allen in reply to kaptank]

And you have some data on what happens if T is even higher? You are in the realm of fantasy.

[kaptank in reply to Tall_Allen]

You do not know what BAT is. This is absolutely irresponsible. Our readers might conclude from what you say that simple testosterone replacement would suffice for what everyone else calls Bipolar Androgen Therapy. That I suggest is a very risky treatment proposition, it will not end well. You are misleading your readers.

[Tall_Allen in reply to kaptank]

I think you meant to reply to the OP, since I completely agree with you.

[kaptank in reply to Tall_Allen]

Maaayte. I am talking about you. You are the one who has consistently and knowingly confused supraphysiological T with the more physiological levels of testosterone replacement. This is very important since all we know about T and PCa is that if you are going to do exogenous T then you had better make sure it is ultra/supra high since all the evidence points to physiological levels of T (ie replacement T) being highly risky if you have active PCa. Some do TRT for QOL reasons but they should be aware that physiological T levels (whether continuous or cycled with castrate levels) are levels of T with which our cancer is comfortable. Supra physiological levels of T on the other hand do cause major damage to PCa cells for a time and also sensitize them to the lutamides. There are significant effects of supra T over those of physiological levels of T. Not to be confused.

[Tall_Allen in reply to kaptank]

I agree that supraphysiological levels of T are ideal to use as part of bipolar androgen therapy, although the UCDenver clinical trial uses transdermal. We shall see if results are any different. In the MSK study I cited above, while the T levels achieved were in the normal range, 8 of the 12 men achieved supraphysiologic levels of DHT, a much more powerful androgen. In fact, several of the ones with the highest levels also had progressive disease, new lesions on a bone scan, or elevated PSA.

The clinical evidence we have on supraphysiologic androgen levels are part of BAT trials at JH. There is no clinical evidence for your assertions of any benefit for supraT outside of a BAT trial. You are merely fantasizing.

[kaptank in reply to Tall_Allen]

On the contrary, I reckon that continuous supra T is something we do not know much about yet (in contrast to BAT where we do have a number of phase 2 trials.) Some of our number after much thought and consideration of risk are trying continuous supra T and their experiences will be important.

[noahware in reply to kaptank]

I think Bob Liebowitz (compassionate Oncology) is one of the few MOs who will try it, or least try it and actually talk about it. If T gets up over 2000 and men do not show progression, he will leave them on SPT, sometimes for years.

His preferred mode seems to be a single ADT/chemo course and then ongoing SPT. Of course that doesn't work for all men, and many have to return to ADT for a time. But it appears to work for some.

[kaptank in reply to noahware]

Yes, Liebowitz is interesting. What I would like to know is what selection criteria he has for inclusion in the program. Might give us some clues about which men it appears to work for.

[Tall_Allen in reply to kaptank]

Liebowitz hasn't published anything since 2009. Even then, his study was a mismosh. I think the results must have been very bad, or he would have published. He makes his patients sign a waiver saying "I know I will die if I do this"

[Tall_Allen in reply to kaptank]

Glad you finally admit "we do not know" instead of making outlandish claims. Individual responses tell one nothing. How can anyone know what would have happened. That's why we have RCTs.

[kaptank in reply to Tall_Allen]

From my very first post here I have always emphasised we don't know, especially when it comes to the complex interactions of T, DHT, E2 and PCa. We are classic cases of decision making under uncertainty. Individual cases do tell us things and we are quite capable of reasoning counter-factually to what would have happened. They are different to the things RCTs tell us. RCTs are background, wall paper on which we pin our individual case in order to make treatment decisions. RCTs are not immune from biases and assumptions. A prominent example is the 70+ year sway that the myth that "T is fuel for cancer" has had on treatment decisions and indeed the underlying rationale of many, many past RCTs. All this in the absence of evidence for the myth and an abundance of evidence against. RCTs are nothing but wallpaper. I am not saying wallpaper is bad. But it is fashionable.

[Tall_Allen in reply to kaptank]

The unknowns are why we do RCTs. It is ridiculous to imagine you know what would have happened - unless you stole that crystal ball from a gypsy. When you abandon "levels of evidence," you abandon science. You may as well just ask the gypsy with her crystal ball.

[Tall_Allen in reply to Tall_Allen]

T is certainly fuel for prostate cancer. Prostate cancer is among the cancers that have an androgen receptor (AR). When the androgen receptor is activated by T it starts a process that drives replication. As prostate cancer progresses, the AR is upgraded and becomes increasingly easy to activate with T. These are basics that have been known since 1947, and won Huggins & Hodges the Nobel prize. Perhaps you should review some basics.

[kaptank in reply to Tall_Allen]

T is fuel for cancer? A convenient picture. Think what it means. On this metaphor adding fuel to cancer must make it grow. Indefinitely. Add a handful of petrol to the barbeque and it flares up. Add 4 litres and you have a dangerous fire. Add say a container load and you have it on the evening news. That is not what happens. Full stop, hypothesis falsified. It does not fit the facts. Very high T limits PCa ( for a time just as very low T limits it). If that is fuel you are using a different dictionary to me.

As regards reviewing the basics, you have some reading to do. The gut-wrenching truth is we know fuck-all and we would be well served by engaging in adult, considered discussion

[Tall_Allen in reply to kaptank]

LOL.

[kaptank in reply to Tall_Allen]

Pleased to see a sense of humour.

[addicted2cycling in reply to noahware]

noahware wrote >>> " ...And you must admit: things that are NOT studied can NOT have evidence, by definition. Things that remain unstudied or unobserved are not necessarily "fiction." The questions I asked in the post are not a claim of evidence but are more a request for evidence, if any might exist."

Exactly, as in my living life having done but not medically being studied >>>

Gleason 10 diagnosis (done 6 years ago)

1st - castration (done 6 years ago last week)

2nd - cryoablation (done 6 years ago next month)

3rd - one time in situ Opdivo + Keytruda + Yervoy (done 6 years ago in December)

4th - bi-weekly Cypionate injections (ongoing since January 2016)

5th - watchful diet + exercise (ongoing for DECADES)

[LearnAll]

According to Saturation Theory, testosterone only stimulates growth of cancer cells up to a level of 300 ng/dl. Anything above this level does nothing to cancer cells.

[noahware in reply to LearnAll]

Well, perhaps "nothing" in terms of promoting direct progression. The question remains, could very high SPT ever have a direct cytotoxic effect on cancer cells, or otherwise influence AR or ER signaling in ways either beneficial or harmful (or both), and by what mechanism(s)?

[clayfin in reply to noahware]

We will never know - who is going to do research on a drug that costs $30 for 10ml?

[kaptank in reply to noahware]

SPT does have a pronounced cytotoxic effect on cancer cells. About as good as the chemo agents we had before docetaxel. The Johns Hopkins group in its early days before human trials checked this out in vitrio.

[Tall_Allen in reply to LearnAll]

Actually, anything above 250 ng/dl. But you completely misunderstand Morgentaler. He is NOT saying that ARs of metastatic PC are completely saturated at that level.

[Hidden in reply to Tall_Allen]

Are you saying that a T level of above 150 is more protective against reoccurrence than lower than 150?

I’m averaging around 80 with a high of 130 for one month out of 14 months? That’s testing monthly.

Your conversation was pretty hard to follow but that’s what I picked out of it.

[Tall_Allen in reply to Hidden]

No, not saying that at all. None of Morgentaler's work applies to men with advanced PC - that's what all of these wishful thinkers fail to comprehend. He said that for men who are not metastatic, that the androgen receptors within the prostate are fully saturated at T levels of about 250 ng/dl. Below that level, PSA drops as T levels go down. Above that level, there is no further increase in PSA. This is called "saturation theory." It just means that the cancer in the prostate gets no worse with rising T after T levels reach 250 ng/ml. It doesn't get better.

In fact, his theory is based on healthy prostates in rats and men. However, it seems to also hold true for men with low-risk localized PC. For men who have low-risk localized PC, and are on active surveillance and have naturally low testosterone levels, saturation theory says that they can have testosterone replacement therapy without fear that their localized PC will get worse:

ncbi.nlm.nih.gov/pmc/articl...

But for men with advanced PC, there are no data that show that the cancer won't get worse if T is added. There is no safe level of T.

However, TRT certainly can be considered after PCa has been cured.

[noahware in reply to Tall_Allen]

Yes, the paper you cite is about AS being studied to support the theory, yet it says this about saturation theory itself: "PCa is highly sensitive to changes in androgen levels at very low concentrations, but reaches a saturation point at relatively low concentrations, beyond which further increases in androgen concentrations have little or no effect."

Why wouldn't that sentence explicitly say "NON-metastatic PCa" if that is what Morgenthaler meant? He himself will prescribe TRT to men with advanced cancer, and presumably NOT because he thinks his model does not apply to these men.

Or perhaps Morgenthaler completely misunderstands Morgentaler.

[Tall_Allen in reply to noahware]

Because "active surveillance" for prostate cancer is only for favorable risk, localized prostate cancer, never for metastatic prostate cancer.

You are just making up that "He himself will prescribe TRT to men with advanced cancer..." He does no such thing. Where did you ever get such a preposterous idea? He only advocates TRT for men who have had curative therapy.

BTW, the correct spelling is Morgentaler (there is no "h").

[noahware in reply to Tall_Allen]

Are you suggesting there is no overlap between "men with advanced cancer" and "men who have had curative therapy"? I never said Morgentaler TREATED men for aPC WITH high-T AS the curative treatment mode... I said he prescribed it to men with aPC /mPC. It is a QoL issue. Yes, they already had other treatments... so what? If he believed your version of his theory he would NEVER treat a metastatic man.

You say he will NOT prescribe T to men with advanced cancer. Please tell me that the three men he treated here do NOT have aPC / mPC:

liebertpub.com/doi/full/10....

"Case records were reviewed for three men with advanced PCa treated with TTh for improved quality of life. Two had bone metastases and nephrostomies at baseline. The third had biochemical recurrence, and continued TTh after developing bone metastases."

Not only did he treat metastatic men, he concluded that the "results suggest a potential role for TTh in selected men with advanced or metastatic PCa." And that role is NOT just the standard BAT protocol.

[The extra "h" I included in spelling his name must stand for "hero"]

[Tall_Allen in reply to noahware]

He would never knowingly give TRT to men with advanced PC as a therapy. Total fantasy on your part. You seem fond of "strawman" arguments. What I wrote is "He only advocates TRT for men who have had curative therapy."

Did you actually read the case studies you posted? The citation you gave says "[The 3 men] accepted the risk of rapid PCa progression and death." You also misconstrue an exploratory case study with something he does routinely. I assure you does not.

[noahware in reply to Tall_Allen]

I did not misconstrue anything. You did. I never said he uses T "routinely" in metastatic patients. You made that up. I said he does do it, and clearly he DOES. He just published a paper about doing it. How do you suppose he could write about doing it, if he didn't do it? You should now tell us we NEVER put men on the moon, because it is factually true that we do not do so routinely.

I love the way you say "He would never knowingly give TRT to men with advanced PC as a therapy" in response to me emphatically saying it is not prescribed AS a PC therapy. What it is, is TESTOSTERONE THERAPY, period. It is prescribed... by him... TO metastatic men. Period. If you want to pretend I said he treats metastases with T, go ahead and have a party of one inside your head, or try to get Darryl to edit what I actually WROTE.

What I said is, he DOES prescribe T to men with metastatic cancer. I never said he did so to treat their PC. Again, you decided to make this up.

I wrote that he did this in the context of your claim that his saturation theory was explicitly not applicable to metastatic cancer by Morgentaler's own definition, when the link you provided gives no such indication that his definition requires that. There is no reason to suppose his willingness to give T to metastatic men means it is a "therapy for their PC" anymore than his willingness to give T to NONmetastatic men means it is in anyway "therapy for their PC' either. He officially gives TTh for QoL only, in all scenarios, advanced or not. Same for Liebowitz. If it ever actually helps with the PC, that is just a bonus.

Do you somehow suppose his willingness to give T to non-metastatic men far more frequently represents his belief that he is "treating PC" with that therapy? I don't. I think he does it because the risk is far lower for that group of men. Do you think he thinks it is impossible for ANY of these men to progress, merely because they are T? Of course not. What he thinks is, the TTh is not usually the cause of disease progression even IF IT IS the cause of a rising PSA. If you think he has explicitly claimed the same is not true of more advanced disease, then show when and where he claimed this. I would suggest he published the recent linked study exactly because he thinks it may be just as true for metastatic disease as for non-metastatic, even if riskier to try.

None of this has anything to do with any notion that TTh should somehow become "routine" in metastatic men, especially not as a supposed treatment FOR that PC. His reason for publishing would seem to be to show that TTh in such men does NOT always result in quick and certain progression, pain and death, as some have long supposed must be necessarily true.

You said he "does no such thing." Yes, he DOES do such a thing. Of COURSE it is not something he does routinely. He does it only when men request it and are persistent, and most men do NOT request something nearly all other doctors consider highly dangerous and ill-advised. By definition, such a thing CANNOT be routine.

Of COURSE men accepted the risk of rapid PCa progression and death. He would be sued out of business if he did not include that disclaimer, and no doubt he makes men sign something (like Liebowitz) to say he cannot be held responsible if T ends up killing them. Does he think it WILL kill them? Of course not. He is not in the business of trying to kill people... but he will let THEM decide to do the risk analysis and then proceed accordingly.

[Hidden in reply to Tall_Allen]

Thanks for the clarification.

[Hidden in reply to Tall_Allen]

Well it looks like I may get what I asked for which is more testosterone. This month after nearly 18 months since stopping zytiga and lupron my T hit an astounding 186. That’s up 60 points this month. 120s was the highest ever and only had 2 of those. The boys must have survived somehow.