[Updated May 24, 2008]
Introduction
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.
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 sufficient 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 whereas anti-apoptotic proteins protect cancer cells so apoptotic proteins are good and anti-apoptotic are bad.)
Naive Model 1
In 1996
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
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 which in turn promotes cancer:
T -> (5AR) -> DHT -> AR -> PCa growth
Individuals with a certain genetic defect in 5AR exhibit pseudohermaphroditism and produce high levels of testosterone with low levels of DHT and have never been known to exhibit prostate cancer. "The expression of 5α-reductase-2 gene in prostate cells is regulated by various factors. A high dietary fat intake, a risk factor of prostate cancer, induces prostate 5α-reductase-2 gene expression and subsequently stimulates prostate growth, which is blocked by genistein, a phytoestrogen. Inhibition of 5α-reductase activity by medication is used in the treatment of BPH and male-pattern baldness, while its use in prostate cancer prevention is still controversial although it can decrease the incidence of prostate cancer. "
[PMID: 18483578]. Also see
this figure from the same paper which illustrates the use of our Model 2 to describe a hypothesized model of fat and genistein effects.
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. 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:
- Amplification pathway: prostate, hair, skin
T -> (5AR) -> DHT -> AR -> PCa growth
- Direct pathway: muscle
T -> AR -> PCa death
- Diversification pathway: brain, bone
T -> (Aro) -> E2 -> ER -> PCa growth
- 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.
- Estrogen receptors:
There are two estrogen receptors in this model:
- ER-alpha: accelerates prostate cancer
- ER-beta: puts the brakes on prostate cancer
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 counteracts the ER-alpha and its no longer effective. This gives it an inverse dose response curve.
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 consuming natural 5AR inhibitors such as saw palmetto and its key ingredient beta sitosterol or with white button mushrooms. See Ed Friedman's comments.
Example: Histone Deacetylase Inhibitors. Referred to as simply HDAC or HDI, there is some evidence that these inhibit the detrimental ER-beta without also inhibiting the beneficial ER-alpha 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].
- 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 produces the apoptotic protein AS3 which acts against the cancer. 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. Like the animal model, the amount of bcl-2 found in the remaining cancer increased during the course of hormonal therapy." PCRInsights 6(1). 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. One 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.
- 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 are other proteins similar to AS3 in function
- 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 R
D refers to the rate of prostate cancer cell death and R
G 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 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.
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].
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.
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].
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 AS3 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.
![[this diagram from Endotext]](http://www.endotext.org/male/male2/figures2/figure2.jpg){kind=link}