INDCJournal: Hormones, Anti-Hormones and Cancer

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April 18, 2006

Hormones, Anti-Hormones and Cancer

Posted by Bill

*** Caution: This Post Might Just Be Long and Boring Enough to Cause Cancer ***

The WaPo features a bit of hype about a drug that may help prevent breast cancer:

A drug used to prevent bones from thinning also offers millions of older women a powerful way to protect themselves against breast cancer, a large government-sponsored study has found.
The study of nearly 20,000 postmenopausal women found that raloxifene reduces their chance of developing breast cancer as effectively as tamoxifen, the only drug previously shown to reduce the risk, but is less likely to cause serious side effects such as uterine cancer and blood clots.
...
Because an estimated 500,000 women use raloxifene to reduce the risk of osteoporosis, many will be more comfortable using it for breast cancer protection, several experts predicted.

"It's terrific," said Susan Love, a breast cancer expert at the University of California at Los Angeles. "This gives us another drug that we can use to prevent breast cancer that is less risky than the only other drug we had."

Preventing cancer sounds great. But how does the drug work?

Tamoxifen and a new class of drugs known as aromatase inhibitors can reduce the risk of breast cancer's recurrence, but tamoxifen is the only drug that had been shown to prevent tumors in the first place, cutting the chances by about half. It is not widely used for preventing primary tumors, though, mainly because it carries an increased risk of uterine cancer and blood clots.
Raloxifene works similarly to tamoxifen by blocking the effects of the hormone estrogen on breast tissue.

It's an effective hormone blocker with impact that may or may not be localized to breast tissue. To understand hormones and their link to cancer, you need to understand their role and relationship to DNA and RNA. Simplifying things immensely, our DNA is essentially a stored set of instructions that RNA refers to while synthesizing proteins. It's your metabolic blueprint. Hormones are a class of chemical messengers, acting as levers for processes related to growth and metabolism - helping to carry out the blueprint.

Repetitively simplistic review: DNA/RNA = coded/enacted instructions, hormones = messengers that govern aspects of metabolism.

Over time, natural aging and environmental influences (sunlight, chemicals, etc) accumulate damage to your set of instructions (DNA) that maintenance mechanisms fail to adequately repair. Some of these gene mutations that hit the right switches lead to cancer, which is basically defined as the neverending division and growth of abnormal cells (normal cells commit suicide at some point). Which is where the known influence of hormones on the course of cancer really comes in, since many of these chemical messengers have targeted anabolic (tissue-building) effects on certain parts of the body. The example that relates to this article is estrogen's stimulation of breast tissue growth. Some of the drugs mentioned work by blocking something called "aromatase," an enzyme involved in the production of estrogen, thus effectively blocking estrogen. The new drug blocks estrogen, though the article is unclear about the underlying mechanism. Whatever the method, blockage of estrogen slows down the targeted tissue-building in an area related to the cancer that this drug is intended to prevent (breast tissue). Slowed breast tissue growth = slowed breast cancer growth (and possibly development).

So does this drug "prevent cancer?"

I certainly can't say that it does or doesn't, but based on the stated general mechanism of the drug and related research into the dubious/disproven link between certain anabolic hormones and cancer causation, I'd be skeptical, saying "not really/maybe/sort of;" it may simply delay the full flower of mutations already in process by slowing the machinery, but may not (probably doesn't ) prevent the cancer itself. In my opinion, as a cancer preventative in apparently healthy subjects, blocking hormones is sort of like aiming to shoot an apple off of someone's head with birdshot.

Again, cancer is caused by gene mutations. Gene mutations are caused by chemicals, radiation, inflammation and the accumulated damage and impaired function of age. As far as I'm aware, natural hormones have not been causally linked to any gene mutations, though they serve as messengers that tell the body to build tissue in specific areas where these gene mutations tend to be present, which is why standard therapies for individuals that turn up with certain varieties of cancer prescribe drugs that block the hormones that cause ALL growth in the targeted tissue (i.e., aromatase inhibitors for breast cancer and 5-alpha-reductase inhibitors [which influences male sex hormones - finasteride] for prostate cancer).

Repetitively simplistic review: Offering the strong disclaimer that this is my subjective interpretation of accumulated research on the subject and not objective fact, by many indications, these hormone inhibiting drugs don't "prevent" the underlying cause of cancer; they influence the speed and course of tissue growth spurred by gene mutations that are already underway or malignantly developed.

So why should you care about how the drug works? If the end result is less people dying from cancer, why should the mechanism concern you? Because the human body is an endlessly complex set of interconnected levers and pulleys, and chronically yanking on some of those pulleys with a drug that blocks certain enzymes involved in the production of certain hormones is bound to have effects beyond the prevention of any cancer that you may or may not have brewing in your DNA. And considering the fact that reducing estrogen production in women thins skin, reduces beneficial cholesterol (HDL), can reduce sense of well-being and mood stability, among other things, I have a healthy skepticism towards a drug protocol centered around a long-term anti-estrogen therapy for tens of millions of women that may or may not prevent a cancer that occurs in about 40,000 women per year.

To wit, extended notes and bonus material:

No one knows what causes breast cancer, and no one can clearly say why we are seeing an increase in breast cancer cases. More women develop breast cancer than men — about 100 cases in females for every one in a man. Women’s bodies make more estrogen than men’s. Therefore, the conventional wisdom has been that estrogen causes breast cancer. (Stupid "conventional wisdom" -- ED)
Some would label this guilt by association; many direct links are missing. One of the biggest missing links is that women’s estrogen levels actually fall as they age, decreasing dramatically after menopause, but the incidence of breast cancer increases with age. The risk ratio that we all hear about — that one in eight women get breast cancer — is for women over 90 years of age. The rate for women in their fifties is more like 1 in 50. (Because cancer is caused by gene mutations that accumulate as we age, NOT hormones -- ED)

So obviously there is much more than estrogen going on in the development of breast cancer, and it is being over-simplistic to think of estrogen as a bad poison when it comes to breast health. Estrogen is a very beneficial hormone in general — it stimulates tissues to grow when we need it to, and it is also a helpful player in response to stress. Let's explore what we know about the causes of breast cancer, what we don’t know, and what this may mean for you.

The rest of this article is very good, and goes a long way towards explaining the details behind the "post-menopausal hormone replacement casuing cancer" hysteria that recently led to some unneccessarily sweeping conclusions about the dangers of HRT:

Another big problem is that all estrogen is lumped together as one entity — but estrogen made by human ovaries is different from a pregnant mare’s (the type used in Premarin), (Who supposed that it was a great idea to replace human estrogen with estrogen derived from the pee of a pregnant horse? This is the fundamental difference in the safety of HRT - BIOIDENTICAL hormone replacement [thus far, not unsafe] vs. 'synthetic God-knows-what' that has hormone-like effects [related to increased rates of cancer] --ED) as well as the estrogens from plants (phytoestrogens) or environmental estrogens from breakdown products of chemicals in pesticides or cosmetics (xenoestrogens). These xenoestrogens may play a critical role, as they boost effective estrogen levels above normal levels and interfere in unknown ways with estrogen metabolism.
The fundamental structure of estrogen, for those who remember basic biology, is a steroid ring which can have different carbon and hydrogen molecules attached. These little differences between our estrogen and synthetics or xenoestrogens can confuse the body and create havoc — like the DES story.

Intuitively (not definitively proven) environmental estrogens may be key players in both increased rates of relevant cancers and the increasingly early onset of puberty among young girls.

There were some women in the WHI study who tolerated Premarin, which is a much stronger estrogen than the body is used to, without problems — their bodies metabolized it, used it, and then excreted it without obvious difficulty. Other women didn’t like how the synthetic hormones made them feel and stopped using them. For others, something stimulated their breasts to make cancer cells. But what we don’t know is what caused that errant growth, how or why. Do certain women have a genetic error that doesn’t let them process synthetic estrogens or xenoestrogens?

I wouldn't term this a "genetic error," as the human body isn't designed to process synthetic substances not normally produced or found anywhere near the human body. In any event, general rule of thumb - chemicals and compounds not naturally occurring or traditionally tolerated in the body = bad. Naturally occuring or synthetic yet bioidentical substances = ok (probably).

We just don’t know — so the NIH decided it was safer to take all women off Prempro and Premarin because of the increased risk of breast cancer and other serious diseases. They are still investigating the difference between Premarin and bioidentical estrogens. We do not know if bioidentical hormones also increase the risk. There is no evidence that they do, and we believe because they are more natural that they are safer than synthetic hormones, but frankly more study is needed.

Again, genetic mutations cause cancer, and thus far, there has been no causal link between cancerous mutations and naturally occurring or bioidentical synthetic hormones. Is it possible that such a link exists? You bet, anything is possible.

Based on current knowledge, if I were a post-menopausal woman, my cancer prevention strategy would focus on not smoking, avoiding excessive sunlight, exercising and eating plenty of fruits and vegetables, rather than ingesting an aromatase inhibitor that blocks what's left of my body's natural estrogen production. If I were experiencing unpleasant changes related to menopause and hormonal decline, I wouldn't have particular fear of supplmenting with small amounts of bioidentical HRT.

Of course, this strategy changes when actually diagnosing cancer, at which point it's sensible to take the aromatase inhibitor to inhibit the growth of the cancer that already exists, so that it might be destroyed before it kills you. Disclaimer: take all of this with a huge grain of salt, as I'm not an expert. I'll try to add more reference links to buttress many of the post's assumptions as the day progresses. Second Disclaimer: all concepts simplified from their true extent. This is a triple function of communcation necessity, humanity's limited (though exponentially increasing) medical knowledge to date and my limited knowledge of that limited knowledge.

Posted by Bill at April 18, 2006 07:24 AM | TrackBack (7)

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Comments

By the same logic, then, anti-cholesterol drugs should also stop Breast Cancer, as Cholesterol is the initial molecule in the formation of steroid hormones, such as Estrogen.

One other note, as a signaling molecule, E binds to the nuclear steroid receptor, which then signals downstream altering the transcription of DNA segments containing a steroid-response element....

Posted by: Caltechgirl at April 18, 2006 01:57 PM

By the same logic, then, anti-cholesterol drugs should also stop Breast Cancer, as Cholesterol is the initial molecule in the formation of steroid hormones, such as Estrogen.

Well, you are technically logically consistent, though ...

A. lowering cholesterol a bit with statins, say, is MUCH farther down the assembly line to the manufacture of estrogen, and has a much more muted impact (even on lowering cholesterol itself), and thus would have much, much more limited, non-specific estrogen-inhibiting effects (I'm sure that you know this) compared to the targeted drugs we're talking about. So if the anti-cancer effect of the drug in my post is like shooting at an apple off someone's head with birdshot, an anti-cancer effect of a statin would be like giving a blind guy a handful of waterballoons and telling him to lob them at the apple from a football field away.

These analogies are all very precise and scientific, mind you.

B. It is still possible that hormones - in combination with the stressors mentioned - have some unique, multifactoral role in actually causing the DNA mutations that lead to cancer ... though no evidence for this exists. Obviously, I have my doubts.

Whenever "hormones" have been tied definitively to increased rates of cancer that indicates causation, they've been hormone-like pharmaceuticals or environmental chemicals, molecules not naturally occurring in the human body. Which would make sense, when we're talking about things that cause genetic mutations, and don't merely feed the byproducts of genetic mutations.

It's interesting, as the mechanism of this drug is the mechanism of a lot of drugs - targeting some point in the metabolic assembly line that has a larger relative role in the progression of disease, rather than even coming close to addressing the underlying cause of the disease itself.

We're still pretty crude with the interventions, when you think about what the future holds.

Posted by: Bill from INDC at April 18, 2006 02:09 PM

You're entirely correct, and that was my point. It's an extremely crude intervention, despite the fact that it works. Statins would be an even more crude intervention.

It's amazing that we get any of these things to work.

As for the difference between hormone and hormone-like molecules, I think you've hit on a key point. Many of these synthetic molecules are similar enough to play their appointed roles in the great chemical machine of our bodies, but the little differences (shape, binding affinity, microenvironment pH, etc.) are enough to "sludge up" the works, which leads to dysfunction. Which in some cases turns out to be cancer.

Posted by: Caltechgirl at April 18, 2006 03:30 PM

Bingo! Well put.

And how crazy is it that - from what I've read - at least one of the HRT therapies was modified in structure from bioidentical hormones to ... wait for it ... wait for it ... establish a drug that had the hormone-like effects, but was unique enough to hold an exclusive patent on. The statistically significant rise in cancer among users was a bonus.

Can you say "class-action lawsuit?"

Posted by: Bill from INDC at April 18, 2006 03:39 PM

Bill:

Good post. It is critical to take Pharma claims with shovelfuls of salt the money involved is too large for it not to play a large influence. That said, there are definitely cases where a drug like tamoxifen or other estrogen can block the actual formation of cancers. The simplest example is a mutation occurs that makes otherwise resting and/or unreactive to estrogen cells now respond to estrogen (this is not caused by estrogen but by one of the other factors you mention). This causes unnatural growth which can be a tumor. Tumors can be benign or cancerous, usually growth over time increases the risk of turning cancerous. So a chemical that blocks the tumor's response to estrogen can be seen as preventing cancers by inhibiting the tumors chances of progressing to cancer. Estrogen is a risk factor in breast cancers (and the absence of estrogen is a risk factor in others).

Posted by: fish at April 18, 2006 04:37 PM

The simplest example is a mutation occurs that makes otherwise resting and/or unreactive to estrogen cells now respond to estrogen (this is not caused by estrogen but by one of the other factors you mention). This causes unnatural growth which can be a tumor.

That's an excellent example. But I haven't come across a documented example of it, or an epidemiological result that indicates this tendency. (that doesn't mean that it doesn't exist, of course)

So a chemical that blocks the tumor's response to estrogen can be seen as preventing cancers by inhibiting the tumors chances of progressing to cancer.

Definitely. But blocking the estrogen is sort of like chemo, only in that it's a very blunt, side-effect laden object to attack the problem (thankfully not poisonous like chemo).

I agree with your comment, but note that the original cause of the cancer is still the mutation, whether estrogen is a major (or even essential) co-factor in a tumor's development or not. Thus, for an estrogen blocker to actually "prevent" cancer in otherwise healthy individuals with no signs of cancer, folks would have to chronically and preemptively take a drug that blocks natural estrogen. To me, that's crazy, as estrogen does a lot of essential things.

And how can you identify the folks with mutations making estrogen the key co-factor before a tumor develops? At this point, we can't.

Good comment.

Posted by: Bill from INDC at April 18, 2006 05:11 PM

That's interesting. Aromatase inhibibitors are well-known in the bodybuilding community, for different reasons (breasts don't look good on a man).

I think Bill makes a good point: estrogen doesn't CAUSE the cancer, it just encourages its growth. You know what else you could do to inhibit cancer growth? Stop drinking water. Cancer needs water, right? Oh, wait, you mean water does something besides keep cancer alive? Etc.

I think they're really missing the boat by not first and foremost recommending supplementary intake of things like green tea and curcumin that scavenge the free radicals which cause the damage to the nucleus that allows cancer to get started in the first place, and generally encourage expression of anti-cancer genes.

The data on these two supplements is so compelling, it's criminal that ontologists are not recommending them.

Posted by: TallDave at April 18, 2006 06:00 PM

100% agree on the preventative angle.

Posted by: Bill from INDC at April 18, 2006 06:11 PM

Nitpick correction: "Hormones are a specific class of the bazillions of different proteins..." is incorrect, as not all hormones are proteins. All proteins are amino acid polymers (peptides), whereas hormones include certain other chemicals, i.e., steroids (such as estrogen or testosterone). You also use this characterization in the "simplistic review."

Your greater point, of course, still remains, and seems valid to another non-expert (but one who has taken some classes.)

Posted by: Patrick O'Leary at April 18, 2006 09:38 PM

You are correct. Apologies. Post modified to the non-specific "messengers."

As to the larger point about links between hormones and cancer, synthetic bioidentical supplementation and cancer risk has been an area of great clinical caution and epidemiological scrutiny in the past few years (especially with the rise of HRT for andropause on men and well-publicized women's HRT issues) ... but no link between supplementation and increased cancer. Tho when something synthetic in structure gets thrown in ... blammo.

Which makes it ironic that most doctors that we would intuitively consider "experts" - as they can prescribe this stuff - aren't up on the research.

Posted by: Bill from INDC at April 18, 2006 10:04 PM

but note that the original cause of the cancer is still the mutation, whether estrogen is a major (or even essential) co-factor in a tumor's development or not. Thus, for an estrogen blocker to actually "prevent" cancer in otherwise healthy individuals with no signs of cancer, folks would have to chronically and preemptively take a drug that blocks natural estrogen. To me, that's crazy, as estrogen does a lot of essential things.

Most malignant cancer (in contrast to benign tumors) are not caused by a single mutation, but an accumulation of mutations (the multiple hit hypothesis). Multiple hits are more likely to occur in actively dividing cells (which is one of the big reasons why we see so many cancers in blood and skin). You are right, that estrogen would really be a cofactor in the example I gave, but inhibitors could help prevent invasive cancer by "preventing" the next hit happening. It is sloppy journalism, but forgivable for a non-scientist. I found this quote from the Daily Mail which is probably the actual claim by the scientists and is significantly more accurate:

"They found Evista has fewer side effects and could reduce the risk of developing invasive breast cancer by 50 per cent."

The key part is "developing invasive breast cancer." This is essentially the scenario I described above.

And how can you identify the folks with mutations making estrogen the key co-factor before a tumor develops? At this point, we can't.

That is correct, but once a lump is detected, it can be screened for being estrogen receptor positive or negative and its responsiveness to Tamoxifen or Evista can be predicted based on that. These women would probably benefit from long term use. Those not "at risk", I agree, would be crazy to go on such a program (and at tremendous cost for relatively small effects).

The more insidious part of the article you link is in this paragraph:

Eli Lilly and Co. said it would ask the Food and Drug Administration to approve Evista for breast cancer prevention in postmenopausal women, but doctors are free to prescribe it for that purpose immediately because the drug is already marketed for osteoporosis.

This is standard practice for Pharma, get the drug approved for one use by the FDA, then get huge boosts in sales through "off-label" perscriptions. Many times they do this by generating weak data showing some benefits, distort the results and market to primary care physicians (who are not qualified to evaluate the science).

Posted by: fish at April 19, 2006 12:06 PM

fish -

I'm actually in favor of off-label flexibility, as I think Western regulatory bodies do a crappy, haphazard, slow job of sheparding treatments to appropriate utilizations. Obviously there are cases where this flexibility backfires.

That is correct, but once a lump is detected, it can be screened for being estrogen receptor positive or negative and its responsiveness to Tamoxifen or Evista can be predicted based on that.

Ah, but I have no objection to this. Either the article really is just practicing "sloppy journalism" (and enthusiasm for the drug is merely centered around stemming invasive breast cancer once a tumor occurs), or some folks really have the idea that it's a large scale preventative of breast cancer; I don't know. But once a tumor is discovered, of course it makes sense to throw an estrogen blocker at it.

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