Reducing the Hormone Related Cancer Risk
(Or cabbages, sex hormones and their metabolites).
   By Jonathan Wright M.D.                            

[Ed.- Our thanks to the publication Nutrition and Healing (USA 800 528 0559) for permitting the reprint of this article].

We all know Grandma was right when she told us to eat our vegetables. With varying degrees of enthusiasm, some of us have been doing so, especially those of us approaching grandma's age. Over the last decade or so, researchers have added their findings to Grandma's advice, concluding in one or another study that more vegetables in our diets help reduce our risk of heart disease, strokes, cancer and other ailments. So what's new about eating our vegetables?

Researchers into sex hormone related cancers (breast, prostate, uterus, ovaries) have found that natural substances found in specific vegetables may help lower our sex hormone related cancer risk by predictably altering estrogen metabolism in at least one specific way strongly associated with lower cancer risk. Other researchers suggest that specific hormone supplementation may decrease the risk of breast cancer in pre-menopausal women with a family history of this disease.

There's enough research in medical and scientific journals to make a review worthwhile, and though absolute conclusions can't be drawn, there's enough data to allow us and our physicians to improve our chances of preventing sex hormone related cancer.

I promise to keep what follows in plain English, but for those who get bored with research findings and the inevitable background discussion, and just want a “bottom line”, here it is: To significantly cut our risk of prostate, breast, uterine, ovarian and other “hormonally related” cancers, eat more flaxseed - the seed itself, not the oil--as well as cabbage, cauliflower, Brussels sprouts, broccoli, and soy. (Lycopene may also be useful for prostate cancer prevention, but the way in which lycopene lowers prostate cancer risk isn't known.)

It's also important to know that more and more tests are becoming available, at reasonable (and even low) prices, to help assess the risk of sex hormone related cancer, and that in addition to eating the right vegetables, there are safe, natural supplements—particularly di-indolylmethane, chrysin, and possibly iodine and Vitex Agnes—which may cut the risk of sex-hormone related cancer which may be reflected in these tests. In some cases, progesterone or DHEA supplementation might be indicated.

Sex Hormones and Cancer
This topic has been of increasing concern since the introduction of so-called “hormone replacement therapy”: methyltestosterone for men in the 1940s, and horse estrogen for women in the 1960s, both of which have been proven to increase cancer risk.  We won't waste any ink or further space on these ridiculous but patentable “treatments”, except to predict that our descendants will put them in the same category of “historically bad ideas” as chemotherapy and radiation to “cure” cancer and bleeding George Washington to death.

Those of us who are “into” natural medicine have turned to the logical alternative: Natural Hormone Replacement (NHR), using hormones identical in every way to the ones our own bodies produce, in quantities to which our bodies are accustomed, on schedules for which our bodies are already "programmed”. In this way, we hope to minimize our risk of cancer from hormone ingestion while maximizing our chances of preventing heart and blood vessel disease, osteoporosis, and cognitive decline. [For extensive discussion of natural hormone replacement, see the books Natural Hormone Replacement for Women Over 45 by myself and John Morgenthaler, and Maximize Your Vitality and Potency for Men Over 40 by myself and Lane Lenard, Ph.D.]

[Ed.- Also see the excellent article by Dr. Wright in the May 1998 IAS Anti-Aging Bulletin titled “Don't let your doctor give you horse urine.”]

Of course, sex hormone related cancer is also in a decades-old up-trend among those of us who never took a molecule of hormone replacement. Young women as well as old are developing more breast cancers than ever before, and the rate of prostate cancer is climbing among men, most of whom haven't taken testosterone. Our entire adult population, whether “into” natural medicine and natural hormone replacement or not, has at least a theoretical interest in not developing and perhaps dying of sex-hormone related cancers.

Estrogens; the “estriol hypothesis.¹
One of the first theories about estrogen and cancer was advanced by Henry Lemon, M.D. of the University of Nebraska. Focusing on estriol (the principal circulating estrogen), Dr. Lemon initially argued that greater proportions of estriol are good, and perhaps even anti-carcinogenic. He found that women most likely to survive breast cancer had the largest amounts of estriol. In unpublished work on a small, uncontrolled study, estriol administration appeared to cause remission in a proportion of breast cancers that had metastasized to bone.

Other researchers discovered that Asian women living in Asia, who as a group have lower rates of breast cancer, also had higher proportions of circulating estriol than American women, who have higher rates of breast cancer. Asian women living in Hawaii, who have a breast cancer rate midway between Asian women living in Asia and American women, also have estriol levels midway between those of the other two groups. Sisters and daughters of women who had had breast cancer were found to have lower proportions of estriol than sisters and daughters of women without breast cancer. Considerable animal research appeared to indicate that estriol was anti-carcinogenic or at least non-carcinogenic.
However, other research²⁰ disputed the “estriol hypothesis”, and present-day researchers tend to disregard it in favor of other theories.

The “2/16a-hydroxyestrone ratio” hypothesis

17b-estradiol (usually just called estradiol) is often called the “principal” estrogen. Even though there's much more estriol than estradiol normally in circulation, estradiol is considerably more potent, and has been known for decades to be more “carcinogenic”.

H. Leon Bradlow, M.D. and a group at Strang-Cornell Cancer Research Laboratory, New York City, as well as other prominent researchers have developed a body of evidence concerning two metabolites of estradiol and their relative tendencies to promote cancer growth.

Among other things, estradiol is metabolized into estrone, which in turn can be metabolized into either 2-hydroxyestrone or 16 alpha-hydroxyestrone. Importantly, there's an “inverse” relationship here: if more 2-hydroxyestrone is made, less 16 alpha-hydroxyestrone is usually made, and vice-versa. In at least one of his publications, Dr. Bradlow³² has termed 2-hydroxyestrone “good estrogen”, and has given us evidence that 16 alpha hydroxyestrone is “bad estrogen”. He writes: “Evidence from a long series of studies has demonstrated a specific role for 16a-hydroxyestrone as a transforming estrogen, which is more potent than estradiol itself.” (“Transforming” refers to the tendency of 16a-hydroxyestrone to increase cellular growth and proliferation, and even cancerous transformation in estrogen-responsive tissues). He goes on to note that the preponderance of evidence shows that, by contrast, 2-hydroxyestrone is non-carcinogenic or even anti-carcinogenic. He also notes that treatment which reduces the 2/16a hydroxyestrone ratio has been shown to reverse the growth of human larygneal papillomas, caused by the same family of viruses (HPV) implicated in cervical cancers.  Other researchers hypothesize that cancer in other tissues, including uterus, prostate, liver and kidney, may be affected by the 2/16a hydroxyestrone ratio as well as other estrogen metabolites.

There's considerable and increasing research going on concerning the “2/16a-hydroxyestrone ratio”, with a current minority of researchers disputing its meaning and validity.  A very recent human study⁴³ states: “2-hydroxyestrone levels and 2/16 alpha hydroxyestrone ratios were significantly lower (p<0.05) while 16 alpha hydroxyestrone levels were higher (p<0.01) in breast cancer patients. 2/16 alpha hydroxyestrone ratio was the most significant factor predictive of breast cancer.”

Zumoff⁵⁰ summarizes the evidence for this hypothesis as follows:

1. Increased 16a-hydroxyestrone in women with breast cancer.
2. Increased 16a-hydroxyestrone in women with familial high risk for breast cancer.
3. Increased 16a-hydroxyestrone in mice with high incidence of breast cancer; the degree of increased risk paralleled the degree of increased 16a-hydroxyestrone in different strains of mice.
4. Elevated 16a-hydroxylation inherited as an “autosomal dominant” gene in mice.
5. Mouse breast cancer virus (MMTV) is associated with increased 16a-hydroxyestrone; when MMTV-free mice were given the MMTV virus, 16a-hydroxyestrone went up; removal of the virus from animals, and 16a-hydroxyestrone goes down. (Dr. Zumoff did not note, but studies have found MMTV in nearly half of human breast cancer tissue.)
6. 16a-hydroxyestrone is “genotoxic” (toxic to DNA) in breast epithelial cells in cell cultures, and induces atypical proliferation.
7. Indole-3-carbinol (see below) decreases 16a-hydroxyestrone and largely prevents breast cancer in mice with a high incidence of this disease.

According to Zumoff: “an impressive and consistent body of studies since 1966 has made it clear that increased 16a-hydroxylation of estradiol is associated with breast cancer and risk for breast cancer in both mice and humans….” He also makes it clear that all the research studies on this hypothesis have been done by a single research group, and that “confirmatory results in other laboratories would be reassuring.”

In summary, the “2/16a-hydroxyestrone ratio” theory maintains that this ratio is an important risk factor marker not only for breast cancer, but for any estrogen-related cancer (breast, ovary, uterus, and possibly prostate): a higher “2/16a” ratio is better, and a lower one is worse.

Remember, the significance and utility of the “2/16a-hydroxyestrone ratio” is not absolutely established.  However, there is enough research available to allow us to modify our risk of cancer with diet and supplements.

The “4-hydroxyestrone” theory
Dr. Ercole Cavalieri of the University of Nebraska is perhaps the most prominent dissenter from the “2/16a-hydroxyestrone” ratio enthusiasm. He argues that while 16a-hydroxyestrone indeed promotes abnormally rapid cell growth and proliferation, it is not the cause of the underlying mutation in cellular DNA that initiates tumor cell formation. He reports that 4-hydroxyestrone (another metabolite of estrone; remember that estrone is made from estradiol) when oxidized can react directly with DNA, leaving a “hole” in the DNA that if un-repaired will initiate cancer.  He points to supportive evidence from animal research, and observations of high levels of 4-hydroxyestrone in breast cancer tissue. He notes that high levels of the enzyme producing 4-hydroxyestrone are found in both benign and malignant breast tumors, and that known environmental carcinogens “turn on” the production of 4-hydroxyestrone. (Actually, Dr. Cavalieri's work⁶⁴ goes well past known sex hormone related cancers. In addition to implicating this mechanism in cancer of the breast, prostate, ovary, and endometrium [the lining of the uterus], he says it has a role in brain cancer and many other cancers. He admits that the data isn't in yet, but he's confident it will be developed).

Dr. Cavalieri definitely does not attach the same importance to the 2/16a hydroxyestrone ratio as other researchers, but he does agree that 2-hydroxyestrone is not very dangerous.

The estriol hypothesis- Part 2
Although placing different emphasis on the importance of 16a-hydroxyestrone, both the “2/16a-hydroxyestrone ratio” theory and the “4-hydroxyestrone” theory agree that 16a-hydroxyestrone is not a “favorable” estrogen. As noted above, 16a-hydroxyestrone is made from estrone; what hasn't been mentioned yet is that estriol, which is less carcinogenic (if carcinogenic at all) than 16a-hydroxyestrone, is itself made directly from 16a-hydroxyestrone. (Put simply: estradiol (estrone (16a-hydroxyestrone(estriol.) So, to reduce cancer risk, one can employ a strategy which increases 2-hydroxyestrone at the expense of 16a-hydroxyestrone (remember, as one goes up, the other usually goes down), or one can perhaps “drain off” some of the more hazardous 16a-hydroxyestrone and transform it into the safer estriol. These strategies are discussed below.

Testing for estrogen related cancer risk
Based on Dr. Lemon's work, I have for years performed tests for the three “principal” estrogens: estriol, estradiol, and estrone. Following Dr. Lemon's lead, I've looked for a result with more estriol than estradiol and estrone combined. The more estriol, the more favorable Dr. Lemon thought it was both for recovery from and prevention of cancer. Also following Dr. Lemon's lead, this test has been done on a 24-hour urine collection specimen. It's also possible to test for the “2/16a-hydroxyestrone ratio”, using a single urine specimen. Unfortunately, it's not yet possible for those of us who aren't researchers to test for 4-hyroxyestrone or its even more dangerous oxidized metabolites; hopefully, that testing will be available in two to three years.

Meanwhile, not only is testing for two of the three estrogen-cancer theories available, but there are also dietary and supplemental measures one may take that may affect these ratios favorably. We'll cover these after a look at;

Testosterone and prostate cancer, the di-hydro-testosterone hypothesis⁷⁵
For a number of years, the dominant theory in North America about prostate enlargement and subsequent cancer maintained that di-hydro-testosterone (DHT) metabolized from testosterone within the prostate is the cause of the problem. The DHT theory of cancer is supported by the manufacturers of patent medications, such as “Proscar”, which inhibit the production of DHT from testosterone.

If this theory were true, we'd expect that men who take patented medications such as “Proscar” would have lower rates of prostate cancer. Unfortunately, research finds that the rate of prostate cancer is not only not lower among men who take Proscar, but the risk of one particular type of cancer is actually higher!

Further weakening the “DHT is bad” theory, is the fact that a French urologist asked men to take DHT; he observed that their prostate glands actually shrank.

The testosterone-to-estrogen hypothesis
A much more promising theory of prostate cancer builds on the observation that testosterone can be directly metabolized into estradiol! In fact, this “pathway” is the major source of estrogens for men (both sexes normally have small amounts of “opposite sex” hormones). If estradiol occurs in excess in the male prostate, then all of the “estrogen and cancer” possibilities discussed above may, and likely do, apply. Indirectly, this is strongly suggested by some of the dietary research noted below.

Breast cancer and testosterone
Zumoff combines two groups of studies into an “ovarian dysfunction” hypothesis: one group of studies associates excess testosterone production with higher breast cancer risk, and the other group of studies identifies inadequate progesterone production with higher breast cancer risk. (These latter studies note that women with inadequate progesterone production can still have apparently normal menstrual cycles.)

Zumoff writes: “the findings [of testosterone excess] are consistent and impressive, and they are supported by independent findings from many other laboratories: 18 studies to date have reported elevated testosterone levels, although 7 studies have not found such abnormalities.” He also notes that chronic lack of ovulation, accompanied by low progesterone (see below) is often associated with increased testosterone production: “thus, there is no reason to be surprised that a substantial subset of patients with breast cancer show elevated blood and urine levels of testosterone.”

Testing for testosterone related cancer risk
Based on the above, testing for testosterone-related cancer risk is remarkably similar to testing for estrogen related cancer risk. I use the same 24-hour urine collection test noted above to assess the relative proportions of testosterone and estrogens in men. Of course for men, more testosterone and less estrogen is definitely best, while for women excess testosterone is not desirable.

Now that the “2/16a-hydroxyestrone ratio” test is soon to be available, I'll use it as a follow up for any man who appears to have excess estrogen. If a man has a family history of prostate cancer, I may recommend the test whether or not estrogen levels are high, since we don't know if it takes a lot of estrogen, or maybe just a little of the “wrong” kind to increase cancer risk. The very recent “cabbage and broccoli prostate risk reduction” study noted below suggests it may be the latter.

For men, a simpler approach may be to start with a “serum testosterone/estradiol ratio”. If this is favorable (higher testosterone, lower estradiol), perhaps no further testing is needed. If this ratio is not favorable, or there is a family history of early onset prostate cancer, one of the other tests noted in the prior paragraph can be used for a more exacting follow-up. (A caveat: an occasional male “24-hour urine for sex steroids” determination has shown low estradiol, but high estrone and/or estriol.)

For women, a serum testosterone determination could be used; the studies mentioned above used urine or serum levels.

Please remember that each individual's circumstances are different, and that testing of potential risk factors for sex-hormone related cancers, if done at all, should be done after consulting with one's personal physician.  Also, as yet, none of these tests should be considered as definite predictors of cancer, but as “risk factors”, to be taken into consideration with other risk factors.

Progesterone and cancer
Low progesterone can result from poor ovarian function or inadequate stimulation of the ovaries by the pituitary hormone LH or by both. “Luteal inadequacy” is the term used to cover both situations.  Zumoff writes: “The evidence for the presence of luteal inadequacy in breast cancer is contradictory but far from negligible.” However, some investigators cited by Zumoff believe that high testosterone accompanying low progesterone is even more important than progesterone alone. Whether low progesterone or high testosterone in women may be considered independent markers of breast cancer risk, or whether they should be considered together, is as yet unclear.  Zumoff appears to favor the “combined” approach, calling it the “ovarian dysfunction” syndrome.

Testing for progesterone
Progesterone tests can be done with either urine or blood. To keep costs down, I usually check progesterone as part of an over-all “sex steroids”, which includes not only progesterone but estrone, estradiol, estriol, testosterone, DHEA, androsterone and etiocholanolone (two metabolites of DHEA very useful in determining DHEA dosage). Of course, timing of specimen collection is important: before the menopause, it should be mid-way in the “luteal phase”, the phase after ovulation (approximately mid-menstrual cycle) and before the next menses. After menopause, it doesn't matter.

Adrenal androgens, DHEA and breast cancer
Adrenal androgens are DHEA and related compounds. Even though these hormones are secreted by the adrenal glands, they're also considered sex hormones because of their androgenic (male hormone like) activity. Zumoff writes: “Dozens of studies during a 37-year period, with little or no refutation, have clearly established the existence of a deficiency of adrenal androgen in women with pre-menopausal breast cancer…..” He continues: “It seems beyond doubt that women with premenopausal breast cancer, as a group, have decreased production and subnormal plasma levels of the adrenal androgens DHEA and DHEA-S. The deficiency antedates [comes before] the onset of clinical disease and is very likely genetic in origin. He cites a study that demonstrated that “DHEA largely prevented the development of breast cancer in a strain of mice that normally has a high incidence of the disease. This study implies that …. DHEA administration might reduce the incidence of breast cancer in women at familial high risk….”

It is also very possible that pre-menopausal women with low levels of DHEA are at somewhat higher risk for breast cancer, since DHEA has been shown in animal studies to aid in the prevention of cancers of various types, including those deliberately induced by carcinogens, and not of genetically linked origin.

Testing for DHEA
DHEA can be tested in serum as DHEA or DHEA-S (the “sulfated” form of DHEA) or both.  To reduce costs, I usually check it as part of the over-all “24-hour urine for sex steroids” panel.

Prolactin and cancer
According to Zumoff¹: “There are four major viable hypotheses concerning hormonal abnormalities in women with breast cancer.” Three of these are discussed elsewhere in this issue; the fourth is the “prolactin hypothesis.”

He writes: “The numerous but inconsistent reports of prolactin abnormalities in breast cancer have always seemed like persistent wisps of smoke, suggesting that fire might exist somewhere. The recent exciting findings regarding the long-term effects of pregnancy on lowering serum prolactin may become highly fruitful. The evidence is that the influence of prolactin may be a permissive one, with protection against breast cancer when the levels are lowered, rather than that prolactin excess increases the risk of breast cancer."

In addition to pregnancies, other ways of lowering prolactin include vitamin B6 (so far, known to be helpful in humans only when prolactin levels are too high),  Vitex Agnus Castus² (in vitro data only), and nickel³ (animal research only).

(Ed.- Bromocryptine (Parlodel) also lowers prolactin levels).

Tests for estrogen-related cancer risk

A “sex steroids” determination includes estrone, estradiol, estriol, progesterone, and testosterone, as well as DHEA and two DHEA metabolites, etiocholanolone and androsterone (these two last steroids are important for properly gauging DHEA dosage).

The “2/16a-hydroxyestrone ratio” can be done using a single urine specimen.

As previously noted, testing for 4-hydroxyestrone and/or its oxidized metabolites is not yet available.

Tests for testosterone related cancer risk

A “serum testosterone/estradiol ratio” (for men) is done using a single serum specimen.  For women, serum testosterone is alone.

A “sex steroids” test checks for testosterone, all three estrogens (not just estradiol), DHEA, and the other steroids is listed above.

Tests for progesterone, prolactin and DHEA related cancer risk

As noted above, we're checking for low levels of these particular sex hormones. Once again, the “sex steroids” test is the most cost-effective way of checking these steroids.

It's also possible to do serum DHEA and/or serum DHEA-S, serum progesterone and serum prolactin tests individually.

Remember that progesterone testing for pre-menopausal women should be timed for halfway between mid-cycle and the next menses.

Where can these tests be done?
Before going further, I'll mention that I've been a consultant for Meridian Valley Laboratory since 1976.  In fact, this laboratory was started specifically to make available “natural medicine” tests which couldn't be found elsewhere.  Over the years, the list of tests has grown.  Meridian is proud of its ability to provide high-quality tests at low prices. Meridian can be reached at USA 253 859 8700 or www.meridianvalleylab.com

Cabbages et al. versus Cancer
Let's go over the most recently reported research first, especially since there's a bit of “local Seattle pride” involved.

Researchers at the Fred Hutchinson Cancer Research Center have just reported⁸⁶ that three “healthy portions” of vegetables daily cut the risk of prostate cancer by 48%. More pertinent here, they also found that three half-cup “servings” per week of cabbage, cauliflower, Brussels sprouts, or broccoli decreases the risk of prostate cancer by 41%!

So what's so powerful about these particular vegetables? They're all members of the Brassica family, also termed “cruciferous vegetables”, and all contain (among many other things) a “phytochemical” called indole-3-carbinol, as well as a much more powerful phytochemical termed “di-indolylmethane”, which is actually just two indole-3-carbinol molecules attached chemically to each other.  Di-indolylmethane and indole-3-carbinol, as well as the vegetables containing them, have all been shown to favorably alter the “2/16a-hydroxyestrone” ratio, inducing the production of more “2 hydroxyestrone” and consequently less “16a-hydroxyestrone”.

But this is estrogen metabolism… how does that affect prostate cancer?  Remember the “testosterone-to-estrogen” cancer hypothesis (in my opinion the much more likely one).

Once testosterone is transformed into estradiol, whether a little or a lot, if too much of that estradiol follows the “estradiol (estrone (16a-hydroxyestrone” path (16a-hydroxyestrone exerts the same negative influence in the prostate as in the breasts and other tissues), and if enough of that 16a-hydroxyestrone isn't “drained away” into the relatively harmless estriol, at the very least there'll be more prostate cell proliferation and growth---benign prostatic hypertrophy (BPH).  Worst case: prostate cancer. If this risk is reducible 41% by three half-cups weekly of cabbage, or broccoli, or Brussels sprouts, or cauliflower…imagine how much more reduction we might obtain with additional amounts of these vegetables, or with supplemental di-indolylmethane?

Other experimenters have shown that broccoli consumption⁹⁷ as well as supplemental indole-3-carbinol¹⁰⁸ improves the “2/16a-hydroxyestrone” ratio.  Di-indolylmethane has been shown to be the most potent natural inducer of 2-hydroxyestrone production¹¹⁹, and is roughly 10 times more potent than indole-3-carbinol.

There's as yet no direct prospective study in humans that Brassica vegetables, indole-3-carbinol, or di-indolylmethane will reduce breast, uterine or ovarian cancer risk. However, Bradlow¹²⁸ lists the many inverse correlations between conditions and items that raise or lower breast cancer risk and higher or lower 2/16a-hydroxyestrone ratios as follows:

	Breast Cancer Risk	“2/16a ratio”
Heredity	UP	DOWN
Obesity	UP	DOWN
Thinness	DOWN	UP
Smoking10	DOWN	UP
High fat diet	UP	DOWN
Fish oil diet	UP	DOWN
Exercise	DOWN	UP
Cruciferous vegetables	DOWN	UP
Indole-3-carbinol11	DOWN	UP
Dioxin12	DOWN	UP

These inverse correlations are quite suggestive, but correlations cannot prove a case; for example, some third factor may be responsible for both sides of the correlation.  However, until the evidence is in, I'm confident that prospective studies of Brassica vegetables, indole-3-carbinol, or di-indolylmethane will show the same tendency to prevent breast, uterine and endometrial cancers as did this Brassica vegetable and prostate cancer study.

Flaxseed versus cancer
In another very recently reported study, 28 postmenopausal women were asked to add 0, 5, or 10 grams (28 grams is one ounce) of ground flaxseed to their usual diets.  According to the report¹³: “Flaxseed supplementation significantly increased urinary 2-hydroxyestrone secretion (p<0.005) and the urinary 2/16a-hydroxyestrone ratio (p<0.05) in a linear, dose response fashion.”  Translated: in this study, the more flaxseed, the more significant the improvement in the “2/16a-hydroxyestrone” ratio. While this was not a direct study of breast or other estrogen-related cancer prevention, it is another very suggestive bit of evidence. While not specifically addressing the “2/16a-hydroxyestrone” hypothesis, previous studies of population groups have shown that both flax and soy can help reduce cancer risk.

Soy (with isoflavones) versus cancer
As noted in Natural Hormone Replacement for Women Over 45, various animal studies have shown that genistein, a soy isoflavone, significantly retards the growth of breast cancers. (This effect has not been proven in women).  However, in another suggestive study, researchers examined the effects of soy with and without isoflavones¹⁴ on the 2/16a-hydroxyestrone ratio.  They reported that soy with 150 milligrams of isoflavones daily significantly increased this ratio (p<0.005), while the same amount of soy without isoflavones did not.

As noted above, previous studies have shown that both soy and flax appear to reduce cancer risk.  Whether the “mechanism” involves their effect on the 2/16a-hydroxyestrone ratio, some as-yet unmeasured effect on 4-hydroxyestrone and its metabolites, another unknown effect, or a combination of factors isn't known.  However, the ability to measure the “2/16a ratio” gives us a start towards assessing estrogen-related cancer risk.

Iodine (and iodide) versus cancer
Years ago, when applying Dr. John Myers very effective iodine therapy for fibrocystic breast disease (see Nutrition and Healing July 1995) some of the women had 24-hour urine tests for estrone, estradiol, and estriol.  To my surprise, in the majority of these women the quantity of estriol greatly increased, and the total quantity of estrone and estradiol (combined) decreased following the iodine treatment.

Since estradiol and estrone can metabolize to estriol only through 16a-hydroxyestrone (estradiol (estrone (16a-hydroxyestrone(estriol) theoretically it appears that iodine somehow greatly stimulated this pathway.  Also theoretically, this may mean that iodine helps to “drain away” 16a-hydroxyestrone (“bad estrogen”) by helping to turn it into estriol.

At the time, it was not possible to check this theory, but it can now easily be done with a combination of the tests noted above.

“Lugol's solution”, a combination of iodine and potassium iodide, was used in the “Myers treatment” noted above.  As large amounts of iodine or iodide can possibly affect the thyroid adversely, it's best to work with a physician if using this material or other relatively high-dose iodine and/or iodide preparations.
A historical note: Max Gerson, M.D., the famous diet and cancer cure physician of the early and mid 1900s, maintained that iodine was a major tool in cancer treatment¹⁸¹⁶.

DHEA, progesterone and Vitex versus cancer
For pre-menopausal women, it appears very possible that bringing low levels of DHEA up to normal will cut breast cancer risk.  At present, supplementation of DHEA itself appears to be the best way to do this.  For women after the menopause, I often recommend improvement of DHEA levels by supplementation to help in prevention of cancer “in general” as well as for improvement in immune system function.

The herb Vitex Agnus Castus (or chaste berry) can improve progesterone levels for some pre-menopausal women.  For others, as well as for women after the menopause, supplementation of progesterone is needed.

For men: Chrysin versus cancer
For men, the flavonoid chrysin (isolated from a species of Passion flower) may also aid in cutting cancer risk.  Men metabolize testosterone directly to estradiol; chrysin inhibits this transformation. (Naringenin, another flavonoid, also inhibits this transformation but not quite as strongly as chrysin).  If we subscribe to the “testosterone-to-estrogen” theory for prostate cancer, then it seems logical that anything which slows this transformation down would also cut cancer risk.

Unfortunately, there are no studies of chrysin and cancer prevention yet available.  If chrysin can be shown to favorably alter “before and after” testosterone/estrogen ratio tests for men, then (again theoretically) the risk of cancer should be lessened.  However, as noted above, it may also be additionally useful to promote a favorable “2/16 hydroxyestrone” ratio (with cabbages, broccoli, or supplemental di-indolylmethane) in whatever estrogen remains to further lower men's prostate cancer risk.

Lycopene versus prostate cancer
Lycopene is not known at present to alter sex hormone related metabolites, but it's included here for sake of completeness.  In a comprehensive review¹⁹¹⁵  Dr. E. Giannuci writes: “Among 72 studies identified, 57 reported inverse associations between tomato intake or blood lycopene level and the risk of cancer…. 35 of these inverse associations were statistically significant….. The evidence of benefit was strongest for cancers of the prostate, lung and stomach.  Data was also suggestive of benefit for cancers of the pancreas, colon and rectum, esophagus, oral cavity, breast, and cervix.”  However, he cautions that a cause-effect relationship cannot be definitively established.

In one well-publicized recent study, men scheduled for prostate cancer surgery were asked to use either lycopene or placebo for approximately 30 days.  At surgery, the cancers of the men in the lycopene group appeared to have regressed, while the cancers of those taking the placebo continued to grow. As yet, no follow-up has been reported.

Where can these various materials be obtained?
A possibly unnecessary reminder: it's always best to start with dietary measures first, supplements second. In that spirit, we can obtain cabbages, broccoli, Brussels sprouts, cauliflower, and soy products at our grocery stores. Flaxseed may be found in a few “enlightened” groceries, but more likely at the natural food store.

Di-indolylmethane (Indolplex() is made available through Tyler Encapsulations, and can be obtained at the Tahoma Clinic Dispensary (USA 253-850-5661 or www.tahomaclinic.com), with which I am of course affiliated. (Di-indolylmethane is two indole-3-carbinol molecules “stuck together” chemically, and much stronger, so it's preferable).

Lycopene and Vitex Agnus are available at Tahoma Clinic Dispensary and most natural food stores.  With the exception of possible allergy or sensitivity, there appear to be no adverse reactions to di-indolylmethane (Indolplex), chrysin, lycopene, or Vitex.

As iodine and iodide preparations can possibly affect thyroid function, Lugol's iodine and other iodine preparations are available only on prescription.

DHEA and progesterone cream appear to be available nearly everywhere, including natural food stores, department stores, discount stores, and on the internet.  As none of these sources of DHEA appear to be “USP grade” (manufactured to the standards of the United States Pharmacopoeia), I prefer to prescribe the USP quality through compounding pharmacies. Since the strength of over-the-counter progesterone “creams” has been documented to vary wildly, I also prefer to prescribe an exact milligramage of the USP variety through compounding pharmacies.  In both cases, it is more expensive, but we know exactly what we're getting.

In summary
Definitive answers in the area of sex hormone related cancers, sex hormone metabolites, testing for sex hormone metabolites, and alteration of sex hormone metabolism with diet and supplements are not yet available.  However, as is often said in clinical preventive medicine, by the time definitive answers are available, many of us will no longer be living, so we must proceed on the best available evidence, knowledge of individual circumstances, and clinical judgment.  It now appears that both enough evidence and enough tools are available for us to rationally undertake further steps in the prevention of sex hormone related cancers.

IAS Comments
We'd like to thank Dr. Wright very much for bringing us all up-to-date with the various methods, tests and substances for reducing the “hormone-related cancer risk.”

Dr. Wright is a recognized leader in the hormonal field and his research and results within the Tahoma Clinic, Washington have managed to “speak for themselves.”

He has also managed to “get-the-word” out through his best-selling series of books about the “unnatural” use of horse-derived hormones that are commonly referred to as HRT (Hormone Replacement Therapy). Today we may consider that precisely following human-nature should be called NRT (or Natural Replacement Therapy) to distinguish it from the “tainted” reputation of the former.

Natural triple-estrogen

As many of you already know, the natural-triple estrogen cream IAS supplies is called Esnatri® and it contains the 3-estrogens in Dr. Wright's recommended ratio of 90% Estriol, 7% Estradiol and 3% Estrone.  We believe that the use of Esnatri®, combined with the other substances that Dr. Wright mentioned here (such as DHEA and progesterone cream),  is the safest and most effective way to natural hormone replacement therapy for women.

Natural hormone replacement therapy for men is also covered in greater detail in a testosterone article by Rick Cohen M.D.

REFERENCES
Your editor is greatly indebted to the review by Barnett Zumoff, M.D. (Zumoff B., Hormonal Profiles in Women With Breast Cancer, Obstet Gyn Clin North America 1994;21(4):751-772) for his concise, comprehensive review of hypotheses concerning hormonal abnormalities in breast cancer. 

1. see Wright JV, Morgenthaler J. Natural Hormone Replacement for Women over 45, Smart Publications, Petaluma, California, 1997, pages 87-98. 

2. Bradlow HL, et al. 2-Hydroxyestrone: the "good" estrogen, J Endocrinol 1996;150:S259-S265. 

3. Ho GH, et al. Using 2/16 alpha hydroxyestrone ratio: correlation with serum insulin-like growth factor binding protein 3 and a potential biomarker of breast cancer risk. Ann Acad Med Singapore 1998;27:294-299. 

4. for the latest example, see Cavalieri EL, et al. Molecular origin of cancer: Catechol estrogen-3,4-quinones as endogenous tumor initiators. Proc Natl. Acad. Sci. USA 1997;94:10937-10942. 

5. A more extensive and detailed discussion can be found in: Wright JV, Lenard L. Maximize Your Vitality and Potency, Smart Publications, Petaluma, California, 1999, pages 153-171. 

6. Veggies may cut by half risk of prostate cancer, Seattle Times, Tuesday January 4, 2000, page 1. Original research to be printed in the Journal of the National Cancer Institute for January 5, 2000. Authors: Kristal A, Cohen J, Stanford J. 

7. Kali MA, Vang O, Klausen J. Effects of dietary broccoli on human drug metabolising activity. Cancer Letters 1997;114:169-170, and Effects of dietary broccoli on human in vivo drug metabolizing enzymes. Carcinogenosis 1996;17:793-799. 

8. Bradlow HL et al. Indole-3-carbinol: A novel approach to breast cancer prevention. Ann NY Acad Sci 1996;768:180-200. 

9. Jellinck PH et al. Ah receptor binding properties of indole carbinols and induction of hepatic estradiol hydroxylation. Biochem Pharmacol 1993;45:1129-1136. 

10. Yes, smoking decreases breast cancer riskÉsee Michnovicz JJ et al., Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking NEJM 1986;315(21):1305-1309É.but remember, smoking increases the risk of many other cancers! 

11. Animal work so farÉ.see Grubbs CJ et al, Chemoprevention of chemically induced mammary carcinogenesis by indole-3-carbinol, Anticancer Research 1995;15:709-716. 

12. although dioxin may decrease breast cancer riskÉ.see Bertazzi PA et al. Ten year mortality study of the population involved in the Seveso incident in 1976, Am J Epidemiol 1989;129(6):1187-1200É.dioxin definitely increases the risk of other cancers. 

13. Haggans CJ et al. Effect of flaxseed consumption on urinary estrogen metabolites in postmenopausal women. Nutr Cancer 1999;33:188-195. 

14. Cree M, et al. Altered urinary excretion of 2-hydroxyestrone to 16-hydroxyestrone in women after soya isoflavone consumption, Proc Am Assoc Canc Res 1999;40:302 Abstract 2007. 

15. Giovannuci E. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature. J Natl Cancer Inst 1999;91(4):317-331. 

16. Gerson, Max. A cancer therapy: results of 50 cases. 3rd edition. Totality Books, Del Mar, California, 1977. Pages 205-206, 409.

ALL INFORMATION IS EDUCATIONAL AND SHOULD NOT REPLACE THE ADVICE OF YOUR PHYSICIAN.

The above  article is copyrighted and may not be copied without the written permission of International Antiaging Systems, Les Autelets  Suite A, Sark  GY9 0SF, Channel Islands, UK.

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