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Testosterone inhibits the growth of PCa (in mice).

pjoshea13 profile image
12 Replies

New study below.

The BAT concept is that supraphisiological testosterone [T] is required for therapeutic effect. My own use of T has aimed to raise levels to ~1,000 ng/dL.

Men in the PCa years have lower T ("naturally"), but men with PCa seem to have less. To some extent, the cancer seems able to lower T. Men with the lowest T have a poorer prognosis.

From the few studies available 13 years ago, it seemed to me that T had a biphasic effect on proliferation - permissive at low levels & resistant at high-normal levels. My feeling was that the emergence of the pro-growth alpha estrogen receptor [ERalpha] in PCa cells was the impetus for growth, & that estrogen-dominance was to be avoided.

In the new mouse study:

"... results indicated that low T levels are optimal for PCa cell growth. Castrate T levels, as seen after orchiectomy, are not sufficient to support PCa cell growth. Higher levels of serum T inhibited PCa cell growth."

In terms of Morgentaler's Saturation theory, T saturation of androgen receptors occurs at 150–200 ng/dL. Reducing T below that level will slow proliferation. What is missing from the theory is that increasing T might also reduce proliferation.

"Traditional beliefs of androgen's stimulating effects on the growth of prostate cancer (PCa) have been challenged in recent years. Our previous in vitro study indicated that physiological normal levels of androgens inhibited the proliferation of PCa cells. In this in vivo study, the ability of testosterone (T) to inhibit PCa growth was assessed ..."

"Mice that had low serum T levels had the shortest tumor volume doubling time ... This doubling time was significantly shorter than that in the high dose 5 mg T arm ... and in the orchiectomy arm "

-Patrick

ncbi.nlm.nih.gov/pubmed/288...

BMC Cancer. 2017 Sep 7;17(1):635. doi: 10.1186/s12885-017-3569-x.

Testosterone inhibits the growth of prostate cancer xenografts in nude mice.

Song W1, Soni V1, Soni S1, Khera M2.

Author information

1

Scott Department of Urology, Baylor College of Medicine, Jones Building 506C, One Baylor Plaza, Houston, TX, 77030, USA.

2

Scott Department of Urology, Baylor College of Medicine, Jones Building 506C, One Baylor Plaza, Houston, TX, 77030, USA. mkhera@bcm.edu.

Abstract

BACKGROUND:

Traditional beliefs of androgen's stimulating effects on the growth of prostate cancer (PCa) have been challenged in recent years. Our previous in vitro study indicated that physiological normal levels of androgens inhibited the proliferation of PCa cells. In this in vivo study, the ability of testosterone (T) to inhibit PCa growth was assessed by testing the tumor incidence rate and tumor growth rate of PCa xenografts on nude mice.

METHODS:

Different serum testosterone levels were manipulated in male nude/nude athymic mice by orchiectomy or inserting different dosages of T pellets subcutaneously. PCa cells were injected subcutaneously to nude mice and tumor incidence rate and tumor growth rate of PCa xenografts were tested.

RESULTS:

The data demonstrated that low levels of serum T resulted in the highest PCa incidence rate (50%). This PCa incidence rate in mice with low T levels was significantly higher than that in mice treated with higher doses of T (24%, P < 0.01) and mice that underwent orchiectomy (8%, P < 0.001). Mice that had low serum T levels had the shortest tumor volume doubling time (112 h). This doubling time was significantly shorter than that in the high dose 5 mg T arm (158 h, P < 0.001) and in the orchiectomy arm (468 h, P < 0.001).

CONCLUSION:

These results indicated that low T levels are optimal for PCa cell growth. Castrate T levels, as seen after orchiectomy, are not sufficient to support PCa cell growth. Higher levels of serum T inhibited PCa cell growth.

KEYWORDS:

Androgen; Prostate cancer; Testosterone

PMID: 28877700 DOI: 10.1186/s12885-017-3569-x

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chascri profile image
chascri

I am baffled. I thought the whole point of hormone therapy was to keep T below 20.

curt504 profile image
curt504 in reply to chascri

As a Google BS (well short of a Google PHD) and now an avid reader of Pca literature, my assemblage of mechanisms believes its the Estrogen and DHT both of which convert from T (in men) is more the factor.

BUT! so many in isolation studies and not treating this as a holistic malfunction is frustrating. I get that its cheaper and ethically in line to study single mechanisms on mice. But what about the quuestion of does this apply to humans and if so are there variables (lifestyle etc etc).

What about ADT (forcing T, E, DHT down to very low numbers) demonstrably reducing the size of the prostrate gland, as chasri mentions? My guess is that T is thrown out with the baby and wash water in the quest to drive down E and DHT.

Also believing Standard of Care does not concern itself (much) with the ratio of quality of life vs profits for various delivery channels that its ok to prescribe compounds that have have proven evidence of what ever the FDA has stated is the "measure" which I'm guessing is prostrate size (reduction). Given the prostrate size does reduce from the standard protocols, to heck with T and other quality of life factors. So here we are!?!

What about my theory that hypothyrodism is common in the aging body, leptin and insulin resistance etc may also play in to PCa pre-disposition? So many factors that seem to be the ground work for so many malfunctions BPH, PCa just being a few.

Mean time the best single source of PCa/Ca reading is the Aug/Sept 2017 issue of the Townsend Letter. townsendletter.com, I have no connection, just a reader.

pjoshea13 profile image
pjoshea13 in reply to chascri

Absolutely!

Low - but not castrate - T is the worst place to be. Many men diagnosed with PCa have T values at the upper end of hypogonadal (not castrate), where T is growth-permissive.

-Patrick

in reply to pjoshea13

That was the case with me -- just under the hypogonadal threshold.

gusgold profile image
gusgold

Patrick,

Dr. Myers stated that when on IADT the best possible outcome was slow recovery of T, which in turn lengthens the off cycle. Over the last 9 years I have had 2 four month Lupron shots. At about 7 months out as the T started recovering, the PSA went up in tandem with the rising T, just as Myers stated.

Gus

pjoshea13 profile image
pjoshea13 in reply to gusgold

Gus,

PSA will usually rise as T recovers, but Myers has said that there is no added effect when T gets to & rises through the normal range. This is in line with Morgentaler's saturation model.

Dr. Freedland has said that T recovery takes so long, that the IADT off-period is largely a continuation of castration fore many men.

Years ago, when my urologist believed in such things, he showed me a study where, after two cycles of IADT, the T at recovery was much less than the initial high. The authors thought this a good thing. Most men starting ADT do not have youthful normal-high T anyway.

Dr. Myers may have thought that a slow recovery was good, because he was wary of a T recovery.

My feeling is that an extended period with estrogen dominance is not good. To get the benefit of the IADT off-period, T should be immediately raised above 350 ng/dL IMO. And estradiol should be kept at ~20 pg/mL IMO.

-Patrick

gusgold profile image
gusgold in reply to pjoshea13

Patrick,

During the off period when on IADT, if T is immediately raised above 350 ng/dl wouldn't the PSA also immediately rise in tandem with the T. With a slow T recovery could estrogen dominance be prevented by Arimidex. Your Uro is right about T recovery being less than the initial high with Lupron, because Lupron damages the leydig cells. This can be prevented by using Firmagon instead of Lupron. I just talked to an Onco involved in the BAT trials and he said a lot of the guys PCa got significantly worse after the T shots.

It is so complicated you don't know what the hell to do.

Gus

pjoshea13 profile image
pjoshea13 in reply to gusgold

Gus,

The hope (or hype) in IADT is that T will be normal in the off-period, in which case, PSA will have settled down to whatever the PSADT is going to be. If the PSADT is long & constant, all is well.

Morgentaler suggests that AR saturation occurs well below 350 ng/dL - perhaps by 250.

When T rises from near-zero to AR saturation, PSA will rise. The effect can be scary, but you can't calculate PSADT at that point.

The AR is often normal before ADT. Depending on time spent on ADT, various changes can occur. One of these is simply more copies of AR in the cell. Restoration of T will reverse that. Another change, however, involves amplification of transcription instructions, leading to more copies of AR-related genes. i.e. the AR has gained function. T restoration seems like a bad idea in such cases.

It strikes me that BAT should be safe when started with ADT.

T restoration after CRPC is hit or miss - some benefit, others do not.

-Patrick

gusgold profile image
gusgold in reply to pjoshea13

Patrick,

what is your opinion of the following protocol...the idea being to control PCa and not develop castrate resistance seen with Lupron.

When PSA reaches .5 start Xtandi and stay on it for 3 or 4 months (until PSA <.1)...stop Xtandi until PSA reaches .5 then restart.

Gus

pjoshea13 profile image
pjoshea13 in reply to gusgold

Gus,

My idea of ADT is to close all barn doors one can (at same time). Specifically with:

- Lupron, or similar

- Avodart

- Zytiga

- Casodex rather than Xtandi

- Simvastatin, or similar

After 3 months, to shock cells that are adapting to very low T, a month of T at ~1,000 ng/dL (remaining on Avodart & the statin). Repeat.

IMO; I'm not there yet.

-Patrick

gusgold profile image
gusgold in reply to pjoshea13

Patrick,

what protocol are you following now

Gus

pjoshea13 profile image
pjoshea13 in reply to gusgold

Gus,

Still 3 months castrate / 3 months T.

I use an old otc product (Prostasol).

But it can't last forever & I expect Lupron to be in my future.

-Patrick

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