Two prostate cancer models...food for thought

An old thread but an interesting read. Check dates before you reply. Much of this is five years old. -- PeterDisAbelard

Introduction

During the 1940s Dr. Huggins proved the androgen dependence of prostate cancer. Since then, androgen deprivation has been the mainstream treatment for advanced metastatic prostate cancer. Initially, androgen deprivation was considered a magical cure because of the incredible reversal of symptoms. That enthusiasm was short-lived as in time most patient’s disease advanced and symptoms returned. Still, today androgen deprivation remains as the first-line therapy for advanced prostate cancer at diagnosis.

One significant difference today, during the PSA era, is that when advanced prostate cancer is detected at diagnosis, the stage of the disease is usually at a less advanced stage. This has a significant impact in how effective androgen suppression can be. Early application of androgen deprivation is possibly an important factor in the mortality reduction in PCa experienced in the US. It is medically recognized that the lower the tumor burden at diagnosis the better the response to androgen suppression. This fact is sometimes not recognized by medical practitioners who advocate for saving deprivation for a “rainy day” in detriment of some patients.

The cause of prostate cancer has never been fully defined. It is no doubt a complicated matrix because very rarely younger men develop clinical prostate cancer while older men frequently do. The implication here is that as testosterone levels in older men drop, as a consequence of age, the incidence of clinical prostate cancer tends to increase. This said, men with both high and low testosterone levels continue to be diagnosed with PCa.

In autopsy studies of men who die of accidents, indolent prostate cancer is commonly found as early as the fourth decade of life (30 to 40 years of age). This should not be ignored when considering models of prostate cancer. As clinical forms of prostate cancer arise as testosterone levels decrease, this could possibly be explained by the slow development of this cancer, environmental and lifestyle factors and last but not least on how the alteration of the hormonal milieu becomes a factor in this process.

Two Models of prostate cancer

The key hormone players in this equation are testosterone (T), dihydrotestosterone (DHT) and estradiol (E2). Both androgen and estrogen receptors are involved in this complex matrix. Ed Friedman, PhD (3,17) proposes that currently there are two models for prostate cancer that involve these hormones in the carcinogenic process. These models are totally opposed to each other.

Model I: Supports the notion that high levels of androgens cause prostate cancer. (1,14)

Model II: Supports the notion that high levels of androgen prevent prostate cancer and are effective in the treatment of the disease. (2)

At this point in time, of the two models, Model I seems to have more support as a model for prostate cancer. Major support for Model I is the initial work done by Huggins and more recent studies demonstrating both postponement of metastasis development and survival benefits. Few practitioners today are using testosterone supplementation to prevent PCa and fewer YET use it to treat prostate cancer. Still, Model II has supporters and logic behind it because under certain conditions androgens can inhibit cell proliferation and tumor growth. This is an interesting concept that practitioners such a Drs. Leibowitz and Tucker are using to treat prostate cancer in a cohort of men.
Implications of an altered T:E2 ratio

In general, as testosterone (T) levels decrease with age, estradiol levels remain constant. Estradiol (E2), the main female hormone is produced in males by an irreversible enzymatic process of aromatization. This implies that with reduced testosterone and same level of estradiol, the normal testosterone/estradiol (T:E2) ratio that exists in younger men is altered in favor of estradiol in older men.

As mentioned before, if latent (autopsy) forms of prostate cancer exist as early as the second, third and fourth decade of life, these cancers had their origin in men who at that age had not experienced a marked decrease in testosterone production. Is it possible that generation of oxidative species by androgen can cause this initial DNA damage that starts the carcinogenic process?(11,12) These cancers are by no means what clinical cancers are at a latter point. They are usually well differentiated and very small in volume. Still, they are present in relatively high numbers in younger men who were oblivious of their presence and experienced an accidental death.

What causes these cancers to progress to clinical stage cancers in some men and not in others? It is known that men with genetic defects affecting the production of DHT are not affected with prostate diseases such as hypertrophy or PCa. (4) It is also known that estrogen alone or in combination with androgens, can induce aberrant growth and/or malignancy of the prostate gland in animal models using human prostatic epithelium. Squamous metaplasia is an abnormal form of prostatic epithelial differentiation elicited by exogenous estrogen alone. (5)

Can a reduced ratio of testosterone to estradiol (T:E2) be the factor that promotes the progression of these latent prostate cancer cells found in younger men to more poorly differentiated cells? What is the range of such ratio to cause progression? Can testosterone supplementation avoid this causative effect? Can the control of estradiol at an older age have a similar effect as testosterone supplementation in controlling the ratio?

The Gat/Goren Hypothesis: Is testosterone the culprit?

The Gat/Goren hypothesis on the cause of most cases of prostate cancer is interesting and needs further consideration. It is well known that PCa is diagnosed in men with both low and high levels of testosterone.

The cause of PCa according to Gat/Goren is induced by an anatomic deformity. This deformity is induced by the destruction or malfunction of the one-way valves that drain the testicular venous system (internal spermatic veins). This deformity is known as varicocele and tends to be bilateral as they tend to be on on both the left and right spermatic veins.

The malfunction of these valves creates an abnormally high hydrostatic pressure causing a retrograde (back flow) of blood containing high levels of free and bound testosterone permeating the prostate gland. The “bathing” of this very high concentration of free testosterone can either deregulate the genes normally regulated by free testosterone or cause cellular damage by the creation of oxidative species that ultimately starts the carcinogenic process. Interesting hypothesis since the remedy for a varicoceles is known and therefore potentially important for men’s health.(14)

Testosterone supplementation for prostate cancer: Model II

Would testosterone supplementation or inhibiting its aromatization to estradiol “fix” this abnormal ratio while DHT is normal or elevated? These and other important questions come to mind.

It is important to think “out of the box” because many times solutions to problems come from the least expected places. Androgen deprivation in the treatment of advanced prostate cancer is well documented. Even after many decades of use the practice is still (rightfully so) not well accepted and medically recognized as non-curative. Androgen supplementation is poorly documented and less used in the treatment of prostate cancer.

Even those using testosterone supplementation are cautious about its use. The evidence in support of this form of treatment is tenuous at best and rejected by the majority of today’s medical practitioners. To the patient, failing current PCa treatments, its use is probably more appealing. Is there risk in this treatment?

If controlling testosterone to maintain a “normal” T:E2 ratio prevents the development of more aggressive forms of clinical prostate cancer and is a possibility to treat patients who have reach an androgen-independent stage, we need some supporting evidence that this simple maneuver (considering the complexity of the equation in which numerous hormone receptors are involved) is a potential avenue for many men.

It is important to understand how androgens affect prostate tissues. The main reason androgen suppression is not curative is because the gland is made up of cells that do not need androgen to survive. This compartment of prostate cells is in the minority in quantity, but not in importance. These androgen-independent cells of the prostate are the basal, pluripotent stems cells (mother of all cells) that make up and maintain the functioning of the gland.

How does prostate cancer, which for the most part is so androgen-dependent, get to the point where it does not need androgen to progress? If there are individuals that are androgen-independent at diagnosis, this must be a consequence of a natural adaptation process driven by a lack of androgen or by genetic changes (mutations) that cause the cancer cells to be unstable and to be able to proliferate and grow without their normal androgenic stimulus.

If for example, the ratio of androgen-dependent cell compartment to the androgen-independent cell compartment of the prostate gland is 80:20, there is a natural progression to androgen-independence by which this ratio is tilted to the independent side. Dr. Bruchovsky (6) contends that when the compartment of stem cells reaches a certain ratio to the number of tumor cells, resistance develops as an initial step to androgen-independence. In other words, the natural progression of prostate cancer to an endpoint seems to be androgen-independence, if given sufficient time.

With this in mind, science is searching for an answer to avoid androgen-independence. Intermittent hormone suppression is a first step in that direction which at the same time provides an improvement in QOL. Under improvements for QOL men with prostate cancer have used testosterone supplementation. The medical literature is very scarce of quality studies that shed a light on this issue. What is the level of risk for a PCa survivor to be treated with testosterone replacement therapy (TRT)? At what stages of the disease is this risk more pronounced? What is the hormonal receptor status at the time TRT is initiated?

Dr. Leibowitz is using TRT in prostate cancer patients to improve their QOL. The stage of disease in these patients covers all ranges. Other doctors are reporting TRT after primary PCa treatment in hypogonadal patients (7), but in general most urology practices are reluctant to institute this practice in known PCa patients. It is important to understand that many physicians are not knowledgeable enough to manage TRT effectively.

Dr. Leibowitz is cautious in its use of TRT when he said: “The only reason to use testosterone replacement therapy is for quality of life issues. Do not use TRT to try to decrease your PSA. If your PSA declines, it is an extra unexpected “bonus benefit.”

What are the characteristics of PCa patients that can potentially benefit from TRT?

As we look for studies that had used TRT to treat metastatic PCa in search for results and patient characteristics, the field narrows down to very few studies. The Fowler and Whitmore study (9) is extremely flawed. They treated all patients with the same amount of exogenous testosterone, but neither a baseline nor a post treatment testosterone level was taken. Very few patients responded and then only symptomatically, but wouldn’t it be interesting to pursue finding out why this minority responded? No effort was made to find why this happened.

Today’s hormone refractory patient is significantly better off that patients were a few years ago, but still they are left with reduced options. If TRT is another option for some of them it would by good to know (10,11). At this point, patients considering this form of treatment are left wondering if this approach is valid or not. It is frustrating to find that this potential avenue has been ignored. The existing studies dating back to the fifties and sixties do not provide information about who would and who would not benefit. One thing is clear, when hypogonadal men are treated with testosterone supplementation; there is no “explosive” generation of PSA to indicate that the treatment is carcinogenic. In general the use of TRT has generated controversy in spite of benefits.

Pending issues (hurdles to be resolved… at least in my mind)

a. Low incidence of prostate cancer in genetically 5-AR impaired patients. These men have after puberty normal amounts of testosterone but low amounts of DHT

b. Low incidence of PCa in Klinefelter syndrome patients.
These men resulting from additional X genetic material have low T as adults and rarely develop PCa. Here PCa should be rampant if low T is the cause of developing PCa. The prevalence is 1 to 2 males per 1000 population.(15)

c. Oxidative DNA damage induced by androgen(12,13)

d. Testosterone’s metabolic rate in PCa patients.
“Men with prostatic cancer have elevated clearance rates of testosterone and an increased conversion ratio of testosterone to its potent 5 alpha-reduced metabolites.”
In simpler words, there is a possibility that low T in PCa patients is caused by more aggressive forms of the disease that proliferate rapidly.(16)

f.. Growth factors. IGF, EGF, PDGF, FGF, ILs etc. Involvement in PCa progression

g. TRT in the treatment of PCa. What level of testosterone is the minimum level required to induce apoptosis of AI cells?

h)Further research on the Gat/Goren hypothesis (14)

REFERENCES

1: Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ.
Prospective study of sex hormone levels and risk of prostate cancer.
J Natl Cancer Inst. 1996 Aug 21;88(16):1118-26.
PMID: 8757191 [PubMed - indexed for MEDLINE]

2: Prehn RT.
On the prevention and therapy of prostate cancer by androgen administration.
Cancer Res. 1999 Sep 1;59(17):4161-4.
PMID: 10485446 [PubMed - indexed for MEDLINE]

3: Friedman AE
The Estradiol-Dihydrotestosterone model of prostate cancer. Theoretical Biology and Medical Modelling 2005, 2:10

4: Ross RK et al, Androgen Metabolism and prostate cancer: establishing a model of genetic susceptibility.
Cancer Res 1998, 58: 4497-4504

5: Cunha GR, Wang YZ, Hayward SW, Risbridger GP.
Estrogenic effects on prostatic differentiation and carcinogenesis.
Reprod Fertil Dev. 2001;13(4):285-96.

6: Akakura K, Bruchovsky N, Rennie PS, Coldman AJ, Goldenberg SL, Tenniswood M,Fox K.
Effects of intermittent androgen suppression on the stem cell composition and the expression of the TRPM-2 (clusterin) gene in the Shionogi carcinoma.
J Steroid Biochem Mol Biol. 1996 Dec;59(5-6):501-11.
PMID: 9010356 [PubMed - indexed for MEDLINE]

7: Agarwal PK, Oefelein MG.
Testosterone replacement therapy after primary treatment for prostate cancer.
J Urol. 2005 Feb;173(2):533-6.

8: Kaufman JM, Graydon RJ.
Androgen replacement after curative radical prostatectomy for prostate cancer in
hypogonadal men. J Urol. 2004 Sep;172(3):920-2.

9: Fowler JE Jr, Whitmore WF Jr.
The response of metastatic adenocarcinoma of the prostate to exogenous
testosterone. : J Urol. 1981 Sep;126(3):372-5.
PMID: 7277602 [PubMed - indexed for MEDLINE]


10. Scher H et al
Rapid hormone cycling for prostate cancer (PC) patients: The MENS cycle
ASCO 2003. Abstract 1669

11. M. J. Morris et al
Phase I trial of exogenous testosterone (T) for the treatment of castrate metastatic prostate cancer (PC).
Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 4560

12. MO Ripple, WF Henry, RP Rago and G Wilding
Prooxidant-antioxidant shift induced by androgen treatment of human prostate carcinoma cells Journal Of The National Cancer Institute, Vol 89, 40-48

13. Maureen O. Ripple, William F. Henry, Steven R. Schwarze, George Wilding, Richard Weindruch Effect of Antioxidants on Androgen-Induced AP-1 and NF- B DNA-Binding Activity in Prostate Carcinoma Cells Journal of the National Cancer Institute, Vol. 91, No. 14, 1227-1232, July 21, 1999

14. 1: Gat Y, Joshua S, Gornish MG. Prostate cancer: a newly discovered route fortestosterone to reach the prostate : Treatment by super-selective intraprostatic androgen deprivation. Andrologia. 2009 Oct;41(5):305-15. doi: 10.1111/j.1439-0272.2009.00972.x. PubMed PMID: 19737278.

15. Bojesen A, Juul S, Gravholt CH (Feb 2003). "Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study". Clin Endocrinol Metab 88 (2): 622–6.
PMID 12574191.

16. Meikle AW, Smith JA, Stringham JD.
Production, clearance, and metabolism of testosterone in men with prostatic
cancer. Prostate. 1987;10(1):25-31.

17. Edward Friedman, PhD
How you and your doctor can fight Breast Cancer, Prostate Cancer and Alzheimer’s
Prometheus Books, 2013

RalphV

Post Edited By Moderator (PeterDisAbelard.) : 8/20/2018 8:36:46 PM (GMT-6)

Break60,
You do not provide any diagnostic information. PSA, GS, number of positive cores and pathology results.

Testosterone supplementation is a complex issue involving numerous hormone receptors. For example, when on Androgel therapy were they checking your estradiol level?

It would informative to know your diagnostic parameters given the fact that you were on TRT for such a long period. Wish you a prompt recovery from surgery.

RalphV

Hi David,
You are correct. On the surface both models seem to be opposing each other but in reality there are finer points to be discussed. In the case of Model I testosterone converted to a metabolite (DHT) is the primary cause. Model II blames another metabolite of testosterone (in this case Estradiol) as the culprit. The common point is testosterone. I do believe that testosterone itself does not seem to be bad for us. I did TRT for months without ill effect.

The book by Dr. Friedman is a good read and explains the complex interaction of hormone receptors and their interaction with hormones in causing PCa (if one accepts his hypothesis). One can see value on ether model and understanding both models (and others he mentions in the book) makes us patients better informed when having to deal with proposed treatments if ever recurrent.

Thought the post would be interesting but unfortunately not many respond to technical posts. I always find the cause of things an all important issue if I am to understand what action to take down the line.

It was good to converse with you at the chat last night. Best regards,

RalphV

Wow, another zombie thread springs to life. Short answer to the question: because the accepted wisdom is that testosterone feeds PC, and it's so widely accepted that only a few contrarians are willing to touch it. Plus, TRT in PC patients is "not the standard of care", which makes those who go against it subject to malpractice suits.

Bob-

Listen to halbert. Dr Liebowitz's theories are way out there, have not been at all proven (not even by him), and his treatments may be dangerous. In fact, if you visit with him, he makes you sign a waiver acknowledging you know you will die if you undertake his "therapy."

If you want to try testosterone therapy look into BAT clinical trials at Johns Hopkins.

Not much. Simplistic causal explanations are usually wrong.

TA
Gotcha. You’d think someone would have tried to test his theory since it sounds eloquent and well thought out. He spent years writing the book ... all for nought? Are there any trials underway?
Bob

The BAT clinical trials are not easy to get into..They choose only those on whom the treatment is most likely to succeed..Cherry picking if you will...They want you to be hormone refractory but no detectable mets..Basicly, the BAT treatment involves giving you a large dose of testosterone once a month. The theory being the cancer cells which have been deprived of testosterone suddenly are overwhelmed with it. This shock results in their death. It takes just a few days for the "T" to metabolize out of your body and you are back to your normal ADT produced low "T" count. This roller coaster ride, in about 60% of the test subjects, results in a meaningful reduction of PSA numbers..

" A multi-centre randomised trial in the USA called TRANSFORMER is testing BAT versus enzalutamide in men with metastatic castrate-resistant prostate cancer whose disease had progressed after being treated with abiraterone. So far it has recruited 111 men with a target of 180. “If we find testosterone is superior then we would hope to move on to larger trials. Our problem is this is not a drug that is owned by a pharmaceutical company; it is generic testosterone. So moving forward is going to be difficult due to issues with finding funds to run a bigger trial,” concluded Prof Denmeade."

Another positive study..

/www.onclive.com/web-exclusives/bipolar-androgen-therapy-effective-after-enzalutamide-in-mcrpc

Since there have been no "adverse events" (deaths) directly attributable to BAT and it has been proven to be effective in a large percentage of the men that have obtained it, and it uses a generic, common, low cost approved drug with a low and tolerable side-effect profile, (Testosterone) you would think it would be more popular with MO's who were treating advanced PC patients who were running out of options...

Most of the men who might be interested in this have been diagnosed with "Terminal Cancer" Their cancer is going to cause the ultimate "adverse event" sooner or later...So they might be willing to take a chance on an unproven treatment regardless of the risks involved..Virtually ALL the approved treatments for advanced prostate cancer come with the possibility of an "adverse event", BAT is better than most in that regard. The most troublesome side-effect is heavy bone pain in some men with bone mets..This is not life threatening and can be managed with pain meds until the testosterone wears off which happens fairly quickly..But even with that, I think it still might be worth a try..

" There may be particular situations where BAT may be an effective therapy, but data are so far lacking:

What, if any, is its benefit in men who are metastatic but still hormone responsive (mHSPC)?
Does it have any benefit in men who have already had docetaxel chemotherapy?
Considering that metastases shrank in many men on BAT, should it be tried in symptomatic men as well?
What is its effect on AR-V7-positive or negative men?
Should it be used in combination with other therapies, such as PARP1 inhibitors, immunotherapies, and radiological therapies?
What is the optimal sequencing of therapies?
Is there any benefit to BAT used along with radiation therapy in high risk men ??

Instead of sitting around the conference table having another meeting, why not just allow advanced, terminal, cancer patients to try this and other therapies and see what happens first hand ?? If it works for them, great ! If it doesn't work nothing lost and maybe you will learn something from it..

"It is definitely not ready for prime time yet." Sure it Is !

When you consider the side-effect load, the dangerous reactions, delivered by VERY expensive chemotherapy drugs that provide minimal benefit but carry the FDA seal of approval, Bat looks pretty good...Even if it doesn't work very well, it usually "resets" the patients sensitivity to Zytiga allowing it to be effective again..Well worth undergoing a simple, safe, inexpensive treatment..(BAT)