Estradiol v Estriol

[Guest guest]

by Andy Baer, M.D. Hormonal Manipulation

Although the cause of breast cancer has not been found, it has become clear that hormonal manipulation may have a therapeutic impact on the course of the disease. This is why the tumors, when removed during surgery, are studied to find whether or not they are estrogen-receptor positive or negative. If the cancer is estrogen- receptor positive, theoretically there should be a response to manipulation of estrogen. This is exactly the role tamoxifen has played as an adjuvant drug therapy in the treatment of the disease. However, studies have demonstrated that after 2 years, tamoxifen can cause an increase of estrogen in the blood. This is one reason that breast cancer cells may become resistant to tamoxifen treatment. Another reason tamoxifen fails to control cell proliferation is that estrogen-receptor-positive cells often mutate into a cancer cell type that does not need estrogen to proliferate. Tamoxifen can cause serious side effects after 2 years, and for this reason it has been suggested that tamoxifen treatment not go beyond a 2-year time period. Those using tamoxifen should also follow the Thrombosis Prevention protocol because tamoxifen and cancer itself can increase the risk of abnormal blood clots.

Melatonin and vitamin D3 have been shown to synergistically enhance the beneficial effects of tamoxifen, and for this reason, women taking tamoxifen should also take 4000 to 6000 IU of vitamin D3 and 3 to 50 mg of melatonin nightly. While tamoxifen's side effects may limit its use to 2 years, most people can take melatonin and moderate doses of vitamin D3 indefinitely. A few people experience kidney toxicity and abnormal calcium metabolism when taking high doses of vitamin D3, and breast cancer patients are also at a high risk for developing blood calcium disorders. For all these reasons, breast cancer patients who use therapeutic doses of vitamin D3 (4000 to 6000 IU a day) should have a regular blood chemistry panel that will reveal kidney toxicity and calcium imbalances while these problems are still reversible. The importance of melatonin and vitamin D3 will be discussed later in this protocol.

What You Should Know about Tamoxifen

The most well-publicized aspect of tamoxifen's mode of action against breast cancer is that it occupies the estrogen receptor and blocks the "grow" signal. However, what's not usually appreciated is that tamoxifen has other modes of action besides blocking estrogen. The other actions are just as important, or in some cases more important, than the estrogen-blocking effect, and they are not unique to tamoxifen. Tamoxifen also works in estrogen-receptor-negative breast cancers and progesterone-receptor-positive breast cancers. This is because tamoxifen not only blocks the estrogen "grow" signal, but also blocks another type of "grow" signal known as protein kinase C (PKC). PKC is another one of those contact points inside the door jamb, and blocking this signal stops oncogenes (cancer genes) from activating. PKC also controls other signals that could lead to runaway growth and transformation of cells.

Estrogen sends messages to cells through what are known as estrogen receptors. Receptors are essentially "doors" on cells that allow entry of substances like estrogen. In the case of estrogen, the "door" is very big, and it will also allow molecules that resemble estrogen to enter as well. This is why fake estrogens and estrogen blockers can provoke cells to react. If the receptor was very small or very particular, it wouldn't allow the fakes in.

Receptors are not like doors, however, in the sense that they're not square. They're curvy-like a jigsaw puzzle. When a molecule of the right shape comes along, it fits in the receptor and makes contact with points just inside the receptor's "door jamb." Touching these contact points sets off a series of chemical reactions that send a signal inside the cell.

Another aspect of tamoxifen's anti-cancer action is its ability to interfere with the cell cycle. The cell cycle is a predetermined program a cell goes through to divide. In a healthy state, certain processes occur, then the cell moves on to the next step, finally creating a new cell. At points during the cell cycle, everything stops at predetermined points so that checks can be made to ensure that abnormal cells don't replicate. Cancer cells have abnormal cell cycles because they have lost those checkpoints. Cancer cells proceed through cell division at break-neck speed. One of the ways traditional chemotherapy works is to restore a checkpoint and stop the cell cycle. Tamoxifen is used as a chemotherapeutic agent because it stops the cell cycle.

While some studies show that tamoxifen works better at 5 years than at 2 years, other research has confirmed that tamoxifen may "turn" on its user in months to years, and begins feeding new, tamoxifen-dependent cancer. A new drug is being tested to combat this "problem," but the new drug may create problems of its own.

Meanwhile, there are hints that tamoxifen "resistance," as it's known, is the result of permanent damage caused by the drug. One area that might be damaged is tumor-suppressor gene p53. Gene p53 is a player in the process that stops the cell cycle and makes sure cancer cells don't replicate. In a healthy person, p53 sends signals that stop the cell cycle when abnormal cells are involved and cause them to self-destruct. Using human breast cancer cells, researchers in France showed that tamoxifen stops p53 from working. While this may sensitize cancer cells to the effects of chemotherapy, the same phenomenon in a healthy person would cripple p53's ability to stop cancer.

Natural Estrogen Manipulation

In 1991 researchers at the Institute for Hormone Research announced that they had been able to induce the body to convert the stronger form of estrogen (estradiol) into the weaker form (estriol) without using drugs. Estriol is considered to be a more desirable form of estrogen. It is less active than estradiol, so when it occupies the estrogen receptor, it effectively blocks estradiol's strong "grow" signals.

It took only 1 week to prove that the conversion of estradiol to estriol can be accomplished without drugs. Using a natural substance, researchers were able to increase the conversion of estradiol to estriol by 50% in 12 healthy people. Next, they tested the natural substance in female mice prone to developing breast cancer. The incidence of cancer and the number of tumors fell significantly. What was the substance? Indole-3-carbinol (IC3), a phytochemical isolated from cruciferous vegetables (broccoli, cauliflower, Brussels sprouts, turnips, kale, green cabbage, mustard seed, etc.)

I3C was then given to 17 men and women for 2 months. Again, levels of strong estrogen declined, and levels of weak estrogen increased. But more importantly, the level of an estrogen metabolite associated with breast and endometrial cancer (16- alpha-hydroxyestrone) fell.

In 1997, researchers at Strang Cancer Research Laboratory at Rockefeller University discovered that when I3C changes "strong" estrogen to "weak" estrogen, stops human cancer cells from growing (54-61%) and provokes the cells to self- destruct (apoptosis). Subsequent studies done at the University of California at Berkeley, show that I3C inhibits MCF7 human breast cancer cells from growing by as much as 90% in culture. Growth arrest does not depend on estrogen receptors.

I3C does more than just turn strong estrogen to weak estrogen. 16-alpha-hydroxyestrone (16OHE) and 2-hydroxyestrone (2OHE) are metabolites of estrogen in addition to estriol and estradiol. 2OHE is biologically inactive, while 16OHE is biologically active-i.e., like estradiol, it can send those "grow" signals. In breast cancer, the bad 16OHE is elevated, and the good 2OHE is decreased. Interestingly, cancer-causing chemicals change the metabolism of estrogen so that 16OHE is elevated. Studies show that people who take I3C not only have beneficial increases in estriol, they also have beneficial increases in 2OHE.

In an experiment at New York University, researchers gave African-American women I3C, 400 mg for 5 days. Most of them experienced an increase in the "good" 2OHE and a decrease of the "bad" 16OHE. However, some did not. It turns out that those who did not have a mutation in a gene that helps metabolize estrogen to the 2OHE version. These women have an 8 times higher risk of breast cancer.

I3C Stops Cancer Cells from Growing

I3C has other modes of action similar to tamoxifen. I3C also interrupts the cell cycle. In studies from the University of California mentioned above, I3C inhibited the growth of estrogen-receptor-positive breast cancer cells by 90% compared to tamoxifen's 60% by stopping the cell cycle. Adding tamoxifen to I3C gave a 5% boost (95% inhibition). In estrogen-receptor-negative cells, I3C stopped the synthesis of DNA for new cells by about 50% whereas tamoxifen had no significant effect. I3C also restores p21 and other proteins that act as checkpoints during the synthesis of a new cell. Tamoxifen has no effect on p21. Restoration of these growth regulators is extremely important. Tumor suppressor p53, for example, works through the p21 that I3C restores. I3C also inhibits cancers caused by other types of chemicals. If animals are fed I3C before exposure to cancer-causing chemicals, DNA damage and cancer is virtually eliminated. A study on rodents shows that damaged DNA in breast cells is reduced 91% by I3C. Similar results happen in the liver. And in a study from New York University Medical Center, female smokers taking 400 mg of I3C significantly reduced their levels of a major lung carcinogen. Cigarette chemicals are known to adversely affect estrogen metabolism.

There is no proven breast cancer prevention. The best and most comprehensive scientific evidence so far stands behind phytochemicals such as I3C. I3C beat out more than 80 other substances, including tamoxifen, for anticancer potential in one assay. Recently, researchers at the Hoechst Marrion Roussel drug company staked their claim to dozens of indole-3 look-alikes. They claim that the indoles, which down-regulate estrogen receptors, can be used to treat and prevent cancer and autoimmune diseases such as multiple sclerosis, arthritis, and lupus. They hope to replace all the chemically altered estrogen drugs such as tamoxifen with a new generation of chemically altered indole drugs that fit in the Ah receptor and regulate estrogen indirectly.

How to Use I3C

While the evidence is compelling, it is too premature to know exactly how effective I3C will be as an adjuvant breast cancer therapy. (See the Breast Cancer Reference List for citations pertaining specifically to I3C.)

The suggested dose is one 200-mg capsule, twice a day for those under 120 pounds. For those who weigh over 120, three 200 mg capsules a day may be needed. Take Note: A little is good; a lot is not necessarily better. As with certain antioxidants that can actually promote oxidation at high levels, too much I3C can have the opposite effect of what you want. Therefore, don't exceed the dosage.

CAUTION: Pregnant women should not take I3C because of its modulation of estrogen. The reported aversion to cruciferous vegetables by pregnant women may be associated with their ability to change estrogen metabolism. Estrogen is a growth factor for the fetus.