Prostate cancer topics, links and more. Now at 200+ posts!

News: Health Day, Medical News Today, ScienceDaily, Urol Times, Urotoday, Zero Cancer Papers: Pubmed (all), Pubmed (Free only), Amedeo
Journals: Eur Urol, J Urol, JCO, The Prostate Others Pubmed Central Journals (Free): Adv Urol, BMC Urol, J Endourol, Kor J Urol, Rev Urol, Ther Adv Urol, Urol Ann
Reviews: Cochrane Summaries, PC Infolink Newsletters: PCRI, US Too General Medical Reviews: f1000, Health News Review

Monday, February 4, 2008

Testosterone Metabolism and Prostate Cancer

[Updated June 12, 2013]


In this post we discuss theories of testosterone metabolism as it relates to prostate cancer. The research discussed here involves, in part, theories which, while based on scientific studies, still require additional investigation in order to establish their validity in a medical context. We will primarily rely on the four pathway model found in Endotext, an online endocrinology textbook, and further modelling efforts based on the highly accessed 2007 [PMID: 17678531] [Full text] and 2005 [PMID: 15777479] [Full Text] papers by Friedman in the journal: Theoretical Biology and Medical Modelling.
[Note that since this page was written Ed Friedman has published a book entitled "The New Testosterone Treatment: How You and Your Doctor Can Fight Breast Cancer, Prostate Cancer, and Alzheimer's". This book was just published so I have not seen it nor is the information below based on it. June 2013]
We start by discussing two naive single pathway models that likely correspond to what many believe to be the case but are too limited to give sufficiently complete understanding of the biochemical dynamics. To overcome this limitation, we then expand the single pathway model to a four pathway model. This is followed by a discussion of the androgen and estrogen receptors that form key components of the four pathway model. To this we discuss a further layer involving certain apoptotic and anti-apoptotic proteins. (Apoptotic proteins cause cancer cells to be killed, which is desirable, whereas anti-apoptotic proteins protect cancer cells which is undesirable.)

Naive Model 1

In 1966 Charles Huggins won the Nobel Prize in Medicine (with Peyton Rous) for his discovery of hormonal treatments for prostate cancer. The naive model of testosterone simply says testosterone leads to cancer growth:

T -> PCa growth

One recent result that would tend to reinforce the idea that testosterone fuels prostate cancer is the finding that in response to drugs that suppress testosterone and other androgens (a common treatment for advanced cancer which tends to work for a period of time but then typically becomes ineffective after a while), metastatic prostate cancers develop genetic pathways enabling them to generate their own testosterone. See [PMID: 18519708] [full text] or [News Release]. This suggests that such testosterone is advantageous to them. In fact, Cougar Biotechnology is in Phase III clinical trials: NCT00485303 [Trial participant blog] of a drug, abiraterone, whose mechanism of action includes preventing prostate cancers from manufacturing their own androgens inhibiting androgen production in the testis, adrenals and prostate by blocking 17-alpha-hydroxylase and an enzyme required for androgen synthesis C17,20-lyase (also known as CYP17 or P450c17). See [Medical News Today] [BBC News and audio interview] [Times News and video] [PMID: 18645193] [Abstract] [ASCO presentation] and [Urotoday ASCO summary] [PCF Video], [Abiraterone Clinical Trials].

An example of using this simple model is Gat's hypothesis [prostatecancerinfolink article] [PMID: 19737278] that an age-related malfunction can allow a very much higher than normal amount of testosterone to reach the prostate from the testes. By performing microsurgery to block this transmission he was apparently was able to reverse prostate cancer in 5 out of 6 patients. (Note that the models discussed below could lead to other explanations.) A brief article on Gat's hypothesis appeared in the Feb 2010 US Too Newsletter.

Problems with Model - Lower T implies Higher Gleason Score. Although the idea that testosterone fuels prostate cancer, is appealing in its simplicity unfortunately there is evidence that seems inconsistent with it. In particular, [PMID: 18692874] found that men with lower levels of testosterone had higher grade, i.e. more aggressive, tumors. If testosterone fuels prostate cancer one would have thought that those with the lowest testosterone would have the least aggressive tumors, not the most. This suggests that there must be more to the model than just testosterone.

Problems with Model - TRT. Also, although reducing testosterone is a major approach taken in prostate cancer therapy experiences with Testosterone Replacement Therapy (TRT) in prostate cancer patients have, contrary to the above models, not consistently shown an adverse effect.

In a July 2008 review [PMID: 18638000] the authors conclude that "In the few available case series describing testosterone replacement after treatment for PCa, no case of clinical or biochemical progression was observed. ... Although further studies are necessary before definitive conclusions can be drawn, the available evidence suggests that TRT can be cautiously considered in selected hypogonadal men treated with curative intent for PCa and without evidence of active disease." A 2008 UrologyTimes article cites four studies: [PMID: 15310998], [PMID: 15643240], [PMID: 17509298], [PMID: 17183557] in which Testosterone replacement therapy was administered to prostate cancer patients beneficially. On the other hand, in the same article Dr. Lamm pointed out: In a "meta-analysis of nine studies, 11 of 987 patients given TRT developed prostate cancer versus zero of 129 control group patients [PMID: 14749457]. While not statistically significant, these figures raise the possibility that TRT fuels prostate cancer development" [reference modified to point to pubmed]

Dr. Morgensterm interprets this as "levels of androgens in the prostate do not reflect levels in the blood". He further says, referring to [PMID: 17169647] which he authored: "This is a new and exciting area that has turned on its head our idea about the relationship between testosterone and prostate cancer," Dr. Morgentaler said. "In fact, the latest data show the opposite of what we used to believe: It's not that high testosterone is a problem with prostate cancer. Actually, low testosterone appears to be a problem."

Summarizing the situation, Judy Foreman writes in the January 5, 2009 Boston Globe that: "In 2006, Morgentaler cowrote a study on 345 men with low testosterone. The study - published in the journal Urology and not industry funded - showed prostate cancer risk was higher in men with the lowest testosterone, a finding supported by a handful of other small-scale studies using human subjects. That was contrary to findings suggested by the Physicians' Health Study in 1996, a discrepancy doctors can not fully explain." On the other hand, another view expressed in the same article was: "To say that testosterone replacement therapy is safe because we have no evidence it's harmful is making an assertion on faith, not facts," said Dr. Ian Thompson, chairman of the department of urology at the University of Texas Health Science Center at San Antonio, echoing the view of other doctors who disagree with Morgentaler." Morgentaler has written a book "Testosterone for Life".
Problems with Model - Calcium. Although removal of testosterone (T) kills most cancer cells, consistent with the model, Friedman points out that this destruction of the cancer cells occurs through calcium ion influx, i.e. calcium ions entering, the cells. If calcium ions are prevented from entering the cancer cells then 70% of the cancer cells survive even in the presence of low T. Thus it seems clear that cancer cells can very well exist without T which again seems contrary to the model. See [PMID: 2235727]. (Recently it was discovered that high blood calcium levels increase the risk of fatal prostate cancer; however, this refers to calcium in the prostate cancer cells and not the blood. [PMID: 18768497] [WebMD]. Also see [Urotoday] where hypotheses related to PTH and calcium are discussed.)

Naive Model 2

A more refined, but still too naive, a model is that testosterone is converted to DHT by 5AR and the DHT that is produced then acts on the androgen receptors.

T -> (5AR) -> DHT -> AR -> PCa growth

Supporting the critical role of 5AR and DHT in the process is that individuals with a certain genetic defect in 5AR exhibit pseudohermaphroditism. They produce high levels of testosterone with low levels of DHT and have never been known to get prostate cancer. This would tend to support the role of DHT as a critical step in the model.

5AR is involved in a number of different prostate cancer and non-prostate cancer examples:

  • Fat and Genistein. Even though models one and model two may be incomplete they may still be adequate for explaining certain phenomena. For example, [PMID: 18483578] uses this model, as seen in this figure to hypothesize the effects of fat and genistein on prostate cancer. "A high dietary fat intake, a risk factor of prostate cancer, induces prostate 5a-reductase-2 [i.e. 5AR] gene expression and subsequently stimulates prostate growth." On the other side 5AR and the associated growth can be inhibited by genistein, a phytoestrogen. As the two opposing forces are thought to both act on 5AR this model seems sufficient to describe these dynamics if the hypotheses of the paper are correct.
  • BPH. Inhibition of 5a-reductase [i.e. 5AR] activity by medication is used in the treatment of BPH.
  • Male-pattern baldness. Inhibition of 5a-reductase [i.e. 5AR] activity by medication is used in the treatment of male pattern baldness.
  • Diagnostics. Regions of higher blood flow within the prostate are thought to be higher risk areas of prostate cancer. Thus if we can locate regions of higher blood flow using imaging we could focus biopsy sampling on those regions to increase the likelihood of detecting prostate cancer. Contrast agents are drugs which make it easier to image this blood flow. The imaging itself, is done via ordinary grey scale ultrasound or color doppler ultrasound or power doppler ultrasound. Color is thought to make it easier to detect the blood flow and power doppler is a variation that is thought to be less dependent on the angle of the reflected sound waves. (For comparison of ultrasound types see this table from this 2006 review by Halpern.) A promising new method to enhance this further, which has been investigated [PMID: 16183033] [full text] and is currently the subject of further clinical trials at Thomas Jefferson University, makes use of the fact that 5AR inhibitors appear to reduce blood flow within healthy prostate tissue but do not reduce it in cancerous tissue. This would mean that by administering 5AR agents such as dutasteride two weeks prior to biopsy imaged blood flow is more likely to indicate prostate cancer.
  • Prostate Cancer Prevention. The use of 5AR inhibitors "in prostate cancer prevention is still controversial although it can decrease the incidence of prostate cancer." [PMID: 18483578]. In fact in the PCPT trial 18.4% of the men on finasteride vs. 24.4% of the controls developed prostate cancer -- a nearly 25% drop. (There was a greater number of advanced prostate cancer cases but that was thought to be due to the fact that as mentioned above 5AR inhibitors make it easier to detect cancer so we have to correct for the fact that a greater percentage would have been detected in the Finasteride group. See [Urosource] and [New York Times, June 15, 2008].) Finasteride is sold by Merck as Proscar.

Four Pathway Model

The previous model is still insufficient as it does not capture the fact that testosterone is known to exhibit some anti-cancer effects as well as promoting cancer.

Problems with Model - DHT correlates with survival A result that appears to be inconsistent with the above model is the observation, albeit in a small sample study, that the 15 year survival of prostate cancer patients who had higher DHT at diagnosis tended to survive longer than ones with lower DHT at diagnosis. If DHT were truly the key critical step then one would have expected the reverse. See [PMID: 18462534] [Full Text]

This suggests that a better model is required to truly understand what is going on. See [link]. We add additional pathways to the above model. See [this diagram from Endotext] for a better drawn version. Below, in addition to the pathway illustrated in the Endotext diagram we have added PCa, i.e. prostate cancer, growth or death at the end of each pathway to emphasize the typical relationship of each pathway with prostate cancer -- PCa growth is bad and PCa death is good:
  1. Amplification pathway: prostate, hair, skin

    T -> (5AR) -> DHT -> AR -> PCa growth
  2. Direct pathway: muscle

    T -> AR -> PCa death
  3. Diversification pathway: brain, bone

    T -> (Aro) -> E2 -> ER -> PCa growth
  4. Inactivation pathway: liver

    T -> excretion
Naive model 2 is just the first of four pathways in the Four Pathway model. As before, the first pathway, now labelled the amplification pathway, says that in the presence of 5AR testosterone (T) is converted to DHT which interacts with androgen receptors (AR) to encourage prostate cancer (PCa) growth.

In the second or direct pathway, testosterone (T) acts directly on the androgen receptors and has an opposite effect from the first pathway. That is in the direct pathway testosterone (T) acts against the prostate cancer (PCa). This is the opposite of what one might expect if one only looked at the first pathway.

The third or diversification pathway converts testosterone (T) to Estradiol (E2) via Aromatase (Aro). This acts on the estrogen receptors (ER) to promote cancer (PCa) growth. Friedman's model suggests that it this pathway that triggers prostate cancer.

The fourth or inactivation pathway is a route by which testosterone (T) is eventually excreted.

Hormone Receptors

Since even the four pathway model does not explain all observations seen in practice, Friedman suggests taking it to an additional level of detail where we focus on the hormone/receptor interactions. Rather than any hormone being good or bad Friedman suggests that we model the system in such a way that each hormone can exert positive and negative effects depending on which receptor is involved. In Friedman's words "testosterone, estrogen and progesterone can be either helpful, harmful, or not do much at all. It all depends on the amount of each hormone receptor within the prostate cancer cell. Each hormone has receptors that acts in contradictory manner (in effect the cells drive with one foot on the gas pedal and one foot on the brake pedal). Since in vivo you are dealing with a heterogenous population, even if 99% of the cancer cells die in the presence of any one hormone, the 1% left will thrive in that environment. Also, for different individuals, one hormone treatment might initially be extremely helpful and for another be extremely hurtful."

  1. Estrogen receptors:

    There are two estrogen receptors in this model:
    • ER-alpha: accelerates prostate cancer
    • ER-beta: puts the brakes on prostate cancer.
      It is believed that ER-alpha and ER-beta have a relationship to TMPRSS2-ERG gene fusions. These gene fusions are associated with more aggressive cancers and future diagnostics may use their presence as a marker to distinguish between indolent and aggressive prostate cancer. Also see [PMID: 18505969]

      Example: Toremifene. Toremifene is in a class of drug known as a selective estrogen receptor modulator (SERM). Low doses of toremifene act again ER-alpha and to a much lesser extent against ER-beta. Since ER-alpha accelerates the cancer the effect of toremifene is anti-cancer; however, at higher doses toremifene acts against not only ER-alpha but also against ER-beta so at these higher doses the ER-beta no longer counteracts the ER-alpha and so is no longer effective. This gives it an inverse dose response curve: i.e. toremifene is effective at lower dosages where it only knocks out ER-alpha but at higher dosages it is less effective or ineffective since it starts blocking the beneficial ER-beta as well.
      Example: phytoestrogens. Phytoestrogens have an anti-cancer effect via a pathway outside the scope of this model; however, they also bind to ER-beta which could have the effect of disabling ER-beta's moderating influence on prostate cancer and encouraging the formation of bcl-2, a protein which protects cancer cells. Particularly problematic might be if the patient simultaneously increased bcl-2 from multiple sources such as by consuming high amounts of phytoestrogens such as soy and at the same time generated even more bcl-2 by taking 5AR drugs or natural 5AR inhibitors such as saw palmetto and its key ingredient beta sitosterol or with white button mushrooms. See Ed Friedman's comments and more comments. "Green tea catechin (-)-epigallocatechin gallate (EGCG) is a natural AR5 inhibitor. Flavonoids that were potent inhibitors of the type 1 5alpha-reductase include myricetin, quercitin, baicalein, and fisetin. Biochanin A, daidzein, genistein, and kaempferol were much better inhibitors of the type 2 than the type 1 isozyme. Several other natural and synthetic polyphenolic compounds were more effective inhibitors of the type 1 than the type 2 isozyme, including alizarin, anthrarobin, gossypol, nordihydroguaiaretic acid, caffeic acid phenethyl ester, and octyl and dodecyl gallates." (quotes from [PMID: 11931850])

      Example: Histone Deacetylase Inhibitors. Referred to as simply HDAC or HDI, there is some evidence that these inhibit the detrimental ER-alpha without also inhibiting the beneficial ER-beta and therefore may form a new class of anti-cancer drug in the future. See [PMID: 16158045] [full text]
      References: The use of the terms "accelerate" and "brake" as a mnemonic to remember alpha and beta and the discussion of toremifene comes from page 60 of a March 2006 presentation of Gerald L. Andriole [pdf] [flash] who in turn references Price, AUA 2005. Also see [link] and [link]. Also Sabnis et al (2007) [PMID: 17942301] have created a mouse model which has predicted the outcome of some clinical trials of breast cancer involving aromatase inhibitors and estrogen receptors in the amplification pathway. A review of SERMs focusing mostly on breast cancer is available [PMID: 17117297] [here]. Some discussion of toremifene and prostate cancer in the context of osteoporosis is available [PMID: 17062721] [Full Text]. A clinical trial on prostate cancer prevention with toremefine is discussed: [here].
  2. Androgen Receptors. There are androgen receptors on the cell membrane and within the cell:
    • membrane androgen receptors (mAR) modulate (acts against) PCa by upregulating calcium which in turn kills prostate cancer cells. See [PMID: 15585562] [Full Text]
    • intra-cellular androgen receptors (iAR) invigorates PCa by counteracting the effects mAR. At the same time iAR also has certain anti-cancer effects. Unfortunately counteracting the mAR is the stronger of the two effects so the net effect of these two opposing forces is to promote the prostate cancer (which is bad).

    Example. T and DHT. DHT binds more strongly to iAR than T does to mAR.
    We can summarize this in the following:

    DHT:iAR >> T:iAR

    DHT:mAR = T:mAR

    where we use : to mean the two sides bind to each other and we use >> to mean the left side's effect outweighs the right side's effect.

    This means that the:
    • effect of DHT binding to iAR outweighs the effect T of binding to iAR and
    • DHT binds to mAR equally well as T binds to mAR
The above explains a number of phenomenon:
  • DHT is pro-cancer
  • T is anti-cancer but only in the absence of DHT
  • if a subject has impaired iAR so that the DHT:iAR interaction is ineffective then increasing T could have an anti-cancer effect
In addition to T, AR5, DHT, mAR, iAR, aromatase, ER-alpha, ER-beta there are several additional components to the model:

Anti-apoptotic Proteins (Promoting Cancer)

The following proteins promote cancer:
  • bcl-2. A small protein which promotes prostate cancer by protecting cancer cells from cell death. bcl-2 is often found in hormone resistant cancer cells. "Bcl-2 is undetectable in about 70% of patients with hormone responsive cancers. In contrast, hormone resistant tumors showed high levels of the protein."
    PCRInsights 6(1) One study found that 65% of patients with androgen independent prostate cancer exhibited high levels of bcl-2. [PMID: 8996359]. "Like the animal model, the amount of bcl-2 found in the remaining cancer increased during the course of hormonal therapy." PCRInsights 6(1).
    A May 2009 study [PMID: 19414838] found "a significant statistical association between patients' eventual death from prostate cancer and abnormal expression (using protein staining) of "bcl-2", which regulates cell death, or of the "p53" tumor suppressor gene. Similarly, high microvessel density (the number of small blood vessels in the tumor) from biopsy specimens taken at diagnosis was also associated with an increased risk of death over 11 to 16 years." [summary]. ER-alpha upregulates bcl-2 (bad) while ER-beta downregulates bcl-2 (good). Progesterone recpetor A (PRA) upregulates bcl-2 (bad) while prosterone receptor B (PRB) downregulates bcl-2 (good). (P) administered with RU-486 downregulate bcl-2 (good). mAR upregulates bcl-2 while iAR downregulates it. Note that there are many anti-apoptotic proteins similar to bcl-2 and bcl-2 may simply be a prototype that refers to them all. In fact, in [link] bax and bcl-xl were more closely related to Gleason score than bcl-2 and in [PMID: 18331646] investigators found that zinc increased bcl-2 which would appear to be bad but it increased pro-apoptotic bax even more, which is good, and the ratio of bax/bcl-2 (higher is better) may be more important than either constituent alone. Several drugs may inhibit bcl-2 formation: (1) In a 1997 paper entitled Bc12 Is the Guardian of Microtubule Integrity investigators hypothesize that the action of the drug taxol is related to reducing bcl-2 and associate it with an increase in bax. (2) Another agent that appears to have the potential to inhibit bcl-2 which, if effective might render the cancer defenseless against attack by further anti-cancer agents, is DCA. See our earlier post on DCA. (3) A third bcl-2 antagonist that is currently under investigation is WL-276 [PMID: 18519699] [full text].
  • Calreticulin appears to be a primary androgen-response gene protecting the cancer cells from being destroyed by calcium influx. One reason that T suppression can destroy cancer cells is that the lack of T and DHT increases calcium
    influx while simultaneously downregulating the calreticulin that would have otherwise have protected those cancer cells from the calcium.

Apoptotic Proteins (Anti-Cancer)

The following have anti-cancer effects:
  • AS3 is a protein that shuts off cell proliferation (good). Calcitriol, the active form of Vitamin D upregulates AS3. iAR upregulates AS3 (good) while mAR downregulates AS3 (bad).
  • apoptotic proteins act against cancer
  • calcitriol is the active form of Vitamin D. It inhibits certain anti-apoptotic proteins which would otherwise protect cancer cells from cell death.
  • other apoptotic protiens.

The Friedman E-D Model

Putting together all of the above, Friedman summarized the effect of hormones on the hormone receptors in this [table of the 2005 model] based on his earlier paper and then revised and extended the model in this [table of 2007 model]. In this latter table RD refers to the rate of prostate cancer cell death and RG refers to the rate of prostate cancer cell growth. The up and down arrows indicate that the effect is to increase or decrease the relevant rate. Of course, increasing prostate cancer cell death and decreasing prostate cancer cell growth are good while decreasing prostate cancer cell death and increasing cancer cell growth are bad.

The idea is that the relative rate of growth and death of cancer cells is the key balance:
Cancer is a heterogeneous mix of cells. Some cells will slowly die off, where their rate of growth is only slightly less than their rate of death. Some cells will slowly increase in number, where their rate of growth is only slightly greater than their rate of death. However, those cells that thrive under the conditions of androgen deprivation are the ones that typically are the cause of death ... There are various reasons why such cells are able to thrive - high levels of the anti-apoptotic protein Bcl-2 is the reason for over 65% of the known androgen independent cells. Other mutations, such as in the pro-apoptotic protein p53 are also bad news.[Friedman]

For each of the hormones (testosterone, progesterone, and estradiol) there are two receptors acting in opposition to each other. In reality, for men with normal genetic makeup, all of the hormones initially increase the rate of cell death. If their levels are high enough, e.g. a typical teenage level, then PCa can not proliferate. As men age, and the hormone levels drop, then PCa can start up. Once it starts up, Darwinian evolution occurs, and each mutation that protects it from the hormones has a selective growth advantage. By the time a man becomes terminal, it is likely that the PCa will increase its growth rate in response to each of the three main hormones. ... in theory it is possible to have PCa cells die solely by using hormones, but in practice in will never happen unless you can start increasing hormone levels at the point that there is only a few cancer cells and no mutations yet.

... the initiating step in causing PCa is high local levels of estradiol (same for breast cancer). Continual high levels of estradiol immortalize those cells by producing oncogenes such as Myb which cause the cells to divide and producing telomerase which allows the cells to divide without shortening their telomeres. However, even though this initiates PCa, the hormone levels (especially T) must be low enough in order for PCa to proliferate. [Friedman]
The BC and PC in the table refer to breast cancer and prostate cancer as the table covers both. We recommend that the reader examine the 2007 E-D model table link carefully since it together with the Endotext diagram link conveniently summarize what we have discussed so far.

In addition to the information in the 2007 E-D model table Friedman has pointed out the importance of Dambaki (2005) et al [PMID: 16293185] [Full Text] who discovered that the mAR increase with disease progression. In particular, since T interacts with mAR to increase bcl-2 (bad) while interacting with iAR to decrease bcl-2 (good), at early stages when there is less mAR the net effect of T is to decrease bcl-2 and so T is anti-cancer but as the ratio of mAR to iAR increases over time the balance tips and the net effect of T becomes pro-cancer.

Example: Effect of DHT. As an example of using the full model together with the Dambaki et al observation of increasing mAR as disease progresses we consider whether DHT has a favorable or unfavorable effect.

In advanced PCa, DHT (and T) is bad because of the increase in mAR that occurs. The DHT downregulates the apoptotic proteins upregulated by mAR, and bcl-2 increases because of the extra mAR that is present. In very early PCa, DHT still downregulates the apoptotic proteins, but now ends up in a decrease in bcl-2 because with fewer mAR the effect of DHT binding to iAR is more effective that the effect of DHT binding to mAR.

Example: Effect of T in Healthy Men. A second example of using the full model is consideration of the effect of testosterone (T) in men without prostate cancer (PCa). As this is somewhat tricky to explain we quote Friedman directly:
Basically, there are two results that have been repeated at least twice each that seem to contradict each other. First, for men with a normal range of T, the higher the free T, the greater the chance of getting PCa. Next, for men with a low range of T, the lower the T, the greater the chance of getting PCa.

Let's look at the first case - that for normal range of T. The higher level of free T means that there is more E2 if Aromatase is turned on. This higher level means that more normal prostate cells will start dividing when they shouldn't and increases the chance of a mutation that will turn this growth cancerous. Although the rate of developing PCa is higher per year the greater the level of free T, the amount of bcl-2 produced also decreases, so that the PCa that results is less aggressive. As the level of T increases, eventually you reach a level (around teenage level) in which bcl-2 is so low that the PCa dies more quickly than it divides.

Next, looking at men with low levels of T, the rate of developing PCa each year will in fact be lower the lower the amount of T present. However, the amount of bcl-2 produced will be higher, so the PCa will be more aggressive the lower the level of bcl-2 present. The researchers are not checking for the rate of PCa developing each year - they typically would look at a bunch of 50 year olds and see how many of them have PCa. Because the lower the T the more aggressive the PCa and the lower the T the earlier in life the sooner PCa has a chance to develop, the result is that lower levels of T will result in a greater chance of PCa having grown to the size that it is capable of being detected for men at the same age.

What is interesting is that all of the above is just an examination of the PCa rate that occurs naturally. For men who don't have any PCa cells in them who take T supplementation, then bringing T to teenage levels with enough Arimidex to keep E2 within the normal range should make it almost impossible to ever get PCa.

Example: . Soy and 5AR Inhibitors. Soy may have drug interactions with 5AR2 inhibitors as mentioned by Friedman in this [here] (which can also be found [here]).

Protocols to Investigate

Friedman discusses several potential protocols. Note that these protocols are of an experimental nature. Future research will be needed to determine the effectiveness and safety of these approaches.
High Testosterone Low DHT (HTLD)
Lowering DHT would allow Testosterone to exhibit its anticancer effect. Testosterone would have to be high enough and DHT low enough for this to occur. Administration of testosterone together with an AR5 inhibitor to depress DHT would be required to effect this protocol. One significant potential problem is that (1) interaction of high T with the mAR receptors and (2) lowering of DHT both increase bcl-2 so some other strategy is required to concurrently lower bcl-2. Friedman discusses the possibility of increasing progesterone in conjunction with RU-486 and also decreasing phytoestrogens to get this effect. He also discusses the possibility of increasing calcitriol, the active form of Vitamin D. (The calcitriol component is not necessarily related to bcl-2.) Friedman summarized the effect of these action in this [HTLD table].

Dambaki (2005) et al [Full Text] discovered that mAR increase with disease progression. Thus it would be expected that the undesirable effect of T combining with mAR to produce bcl-2 is magnified in later stage patients (as there are more mAR available and therefore more bcl-2 being produced) which may restrict the useful range of the HTLD protocol to early stage patients.

Dr. Leibowitz has been using HTLD and his clinical observations seem consistent with those predicted by the models discussed here. See the following discussions on his web site: [soy], [testosterone replacement therapy], [testosterone replacement therapy case reports].

Research by Eggener et al [PMID: 16372330] is also supportive of this approach. In that study, Androgen Deprivation Therapy followed by HTLD was more effective than continuous ADT. Also see [Friedman comment] and also this [Friedman comment].

One scenario under which this protocol might be harmful is if mAR have mutated so as not to moderate PCa despite the high T. Then the hoped for beneficial effect would be absent while bcl-2 levels were increased giving a net unfavorable effect.
Low Testosterone High DHT (LTHD)
One problem with the HTLD approach is that it is pro bcl-2. Thus consider the opposite of that protocol. That is consider low testosterone and high DHT. The aim of this protocol would be to lower bcl-2. That is, since T increases bcl-2 and DHT decreases it we attempt to minimize T and maximize DHT. As with the HTLD approach we would add progestone with RU-486 and calcitriol components. Friedman summarized the effect of these actions in this [LTHD table]. The LTHD protocol, if viable, would be a prevention protocol rather than a treatment protocol. Such a protocol might sequentially follow HTLD and itself be sequentially followed by just high T. All these protocols would include calcitriol as a safeguard.
All mAR No iAR (AMNI)
The existence of mAR and iAR suggest novel therapies. For example Casodex knocks out iAR but not mAR thus a combination of high T plus Casodex (or T plus Casodex plus Proscar) might be effective. See [Friedman comment].
Friedman summarized this protocol in this [AMNI table].
No mAR All iAR (NMAI)
This protocol blocks the mAR which also blocks the generation of bcl-2. Without the protection that bcl-2 affords the cancer cells, this would leave the prostate cancer exposed to destruction by nearly any agent at all while the upregulation of the iAR would generate apoptotic proteins to carry out such destruction. Other agents could also be used to destroy the cancer now that it is no longer protected by bcl-2. This is the protocol most favored by Friedman as a potential cure for prostate cancer but currently cannot be effected due to the lack of agents that selectively block mAR. NMAI is summarized in this [NMAI table].

Thanks to Ed Friedman who commented on an earlier draft of this post.


Anonymous said...


I have a few questions there seems no answer to. Please help.

Many patients will have prostate cancer recurrence after primary radiation therapy (RT). Some will choose watchful waiting (or be given a placebo in a clinical trial).

(1) How many of these patients would see their PSA go up (analogous to PSADT decreasing) at 2, 4, and 6 months after recurrence?

(2) How many patients would see there PSA go down (analogous to PSADT increasing) at 2, 4, and 6 months after recurrence?

(3) Also, what are the pros and cons of measuring PSA doubling time (PSADT) versus measuring PSA response (PSAR) in the first 6 months after recurrence?

I am looking for hard data and explanations why some placebo patient’s PSA variables improve, at certain time points.

Any assistance would be greatly appreciated!

Thank you very much,

Brian, MD, MBA

The Palpable Prostate said...

There are some pointers on this blog in:

Also look at the papers behind the relevant calculators on this page: